Transsphenoidal surgery remains the treatment of choice for most patients with acromegaly. Optimal management of the 10 to 50% of patients who do not undergo remission after transsphenoidal surgery and the 20% of patients who experience recurrence of acromegaly after initial transsphenoidal surgery remains less clear. Radiation represents an evolving treatment for acromegaly that warrants consideration as an alternative to medical therapy for cases refractory to transsphenoidal surgery.
Two main types of radiation have been investigated: conventional fractionated radiotherapy and stereotactic radiosurgery. Conventional fractionated radiotherapy in doses of 160-180 cGray (cGy) 4 to 5 times per week over 5 to 6 weeks to a total dose of 45-50 Gy has been used since 1980, and most studies report remission rates of 35 to 75%. Remission takes 10 years to achieve and rates of hypopituitarism range from 50 to 80% during that time.
The need to improve upon remission rates and reduce the rates of hypopituitarism led to studies of stereotactic radiosurgery as an acromegaly treatment. Radiosurgery delivers multiple beams of radiation to the pituitary adenoma with stereotactic precision using a frame affixed to the head, usually in a single session and at most in 5 sessions. The radiation can be delivered as photons using devices such as the Gamma Knife® or CyberKnife® or as charged particles using proton beam radiosurgery. The beam trajectories are calculated to spare critical structures near the pituitary adenoma.
While reported remission rates have been comparable to those seen with conventional fractionated radiotherapy, radiosurgery causes more rapid remission than conventional fractionated radiotherapy, typically within 3 years of treatment, along with lower rates of hypopituitarism, ranging from 10 to 38%, and has thus replaced fractionated radiotherapy in acromegaly treatment.
Results with Gamma Knife Radiosurgery
There are 4 factors predictive of achieving remission in patients with acromegaly undergoing Gamma Knife radiosurgery:
- The patient is not on medications to treat acromegaly at the time of radiosurgery
- Lower pretreatment hormone levels
- Higher total integral radiation dose
- Lack of cavernous sinus invasion.
Several clinical research groups have found that the patient not taking medications treating acromegaly at the time of radiosurgery correlated with biochemical remission, with the most comprehensive study reporting a hazard ratio of 4.2 in patients who had not been on medications one month before radiosurgery.
Three possible factors behind the finding that antiacromegaly medications inhibit radiosurgery efficacy are:
- Patients unable to wean off antiacromegaly medications prior to radiosurgery may have more difficult tumors to treat, regardless of treatment modality
- Medicines for acromegaly reduce metabolic activity in pituitary adenoma cells, making these cells less proliferative and therefore less responsive to radiation, which causes DNA damage in cells that are replicating at the time of treatment
- Some of the medicines used to treat acromegaly, such as octreotide, contain disulfide bonds, which in adenoma cells are reduced to expose free thiols. Free thiols are scavengers of the oxygen free radicals that arise from ionizing radiation and cause the DNA damage that precedes radiation-induced cell death.
Several groups have found that lower IGF-1 levels are predictive of remission, while adenoma size does not predict chances of remission. One multivariate analysis showed that an IGF-1 level less than 2.25 times the upper limit of normal (hazard ratio 2.9) predicted remission.
CyberKnife and Proton Beam Radiosurgery
Besides the Gamma Knife, other forms of radiosurgery that have been evaluated for the treatment of acromegaly include proton beam and CyberKnife. Proton beam radiosurgery takes advantage of the superior dose distribution of protons versus photons, resulting from the peak in the energy distribution of protons before they come to rest at the treatment depth. The most recent study of proton beam radiosurgery in treating acromegaly found a 59% remission rate, among the highest reported for acromegaly radiosurgery, but a 33% rate of hypopituitarism, also comparably high, suggesting the benefit of the superior dose distribution in the region of the target must be weighed against a greater dose being delivered to the normal gland or pituitary stalk.
The CyberKnife is an image-guided, frameless radiosurgical device that delivers conformal radiation in one or more sessions. One group reported a 44% remission rate, 1-year mean time to remission, and a 33% hormone deficiency rate in 9 patients with acromegaly treated with the CyberKnife from 1998-2005 in 1 to 3 sessions. These encouraging results using multiple modalities of radiosurgery will require verification in larger series conducted over a longer period of time, particularly to allow documentation of the recurrence rates in acromegaly patients who achieve remission after radiosurgery, a facet of radiosurgical treatment of these tumors that has yet to be well reported. The hope is that these goals will be accomplished through trials such as the upcoming Radiation Therapy Oncology Group (RTOG) clinical trial number 0722 studying radiosurgery for growth-hormone-secreting pituitary adenomas.
Future of Radiosurgery in Acromegaly
These encouraging results using multiple modalities of radiosurgery will require verification in larger series conducted over a longer period of time, particularly to allow documentation of the recurrence rates in acromegaly patients who achieve remission after radiosurgery, a facet of radiosurgical treatment of these tumors that has yet to be well reported. The hope is that these goals will be accomplished through trials such as the upcoming Radiation Therapy Oncology Group (RTOG) clinical trial number 0722 studying radiosurgery for growth-hormone-secreting pituitary adenomas.
Written by Manish Aghi MD, PhD