The likelihood of recurrence after surgery alone is variable. Ciric and coworkers reported recurrence rates of 50% after subtotal resection alone and 21% after total resection alone. A 10-year progression-free survival rate of 59% was reported by Gittoes and coworkers after surgery alone compared with 94% after surgery and postoperative RT. The use of postoperative RT was found to be the only significant prognostic factor influencing the probability of local control in that study, Turner and coworkers reported the results of 65 patients treated with surgery alone and noted a 10-year recurrence-free survival rate of 56%. The mean time to detection of recurrence was 5.4 years, and there was no significant difference in the recurrence rates after gross total resection or subtotal resection. On the basis of their results, the authors recommended postoperative RT for all patients with pituitary adenomas until markers for recurrence could be identified.
In an attempt to identify prognostic factors of recurrence, Greenman and coworkers recently reported results of 108 patients with nonsecreting macroadenomas treated with surgery alone. Recurrence-free survival rates at 5 and 10 years were 84% and 65% after gross total resection and 30% and 25% after subtotal resection. Prognostic factors significant for recurrent disease in a multivariate analysis included subtotal resection, preoperative involvement of the cavernous sinus, and extensive postoperative suprasellar extension. The authors concluded that RT would benefit patients with these high-risk features, but surveillance was reasonable for low-risk patients. We observed an increased CSS associated with treatment with stereotactic radiotherapy on multivariate analysis (p = 0.077). This finding was not statistically significant and may be an artifact given the retrospective nature of this study.
Many reports have shown that RT after surgery or RT alone offers a high likelihood of long-term control of pituitary adenomas. Brada and coworkers reported one of the largest conventional RT series on both secreting and nonsecreting adenomas that included 411 patients. Overall, progression-free survival rates were found to be 94% and 88% at 10 and 20 years, respectively. The presence of hormone-secreting tumors was the only prognostic factor that significantly influenced outcome. The 10-year progression-free survival rates were 97% and 89% for nonsecreting and secreting tumors, respectively (p < 0.005). Tsang and coworkers reported the results of 160 patients with nonsecreting pituitary adenomas treated with RT postoperatively or at the time of recurrence. With a median follow-up of 8.3 years, the 10-year actuarial local control rate was 87%. Prognostic factors found to be significant included age and radiation field size.
Grigsby and coworkers reported progression-free survival rates of 80.5%, 73.5%, and 73.5% at 10, 20, and 30 years, respectively, for patients treated with RT only. Progression-free survival rates for patients who received immediate RT after surgery were 92.8%, 71.2%, and 44% at 10, 20, and 30 years, respectively. Hazard function analysis showed that the risk of recurrence after RT alone was greatest in the first 5 years after treatment and decreased to 0 after 20 years. For unknown reasons, this was not true for patients who received immediate RT after surgery. The risk of recurrence for these patients increased with time over the 30 years of follow-up. These data suggest the need for continued long-term follow-up. Our data show that most patients recurred within the first 5 years.
Hypopituitarism is the most common late complication; the likelihood of this event varies from 22% to 60% and may occur after both conventional and stereotactic RT. Although hypopituitarism is usually well managed with hormone replacement therapy, it can adversely affect a patient's quality of life
Neurological side effects, such as vision loss, are also well documented in the literature. The reported incidence of radiation-induced optic neuropathy resulting in vision loss varies from 1% to 7%. Milker-Zabel and coworkers reported an incidence of visual loss after stereotactic RT of 7% with a mean time to occurrence of 17.5 months.
Cerebral vascular accidents may occur after RT for pituitary adenomas as well as in unirradiated patients. Given the underlying risk in the general population, it is not possible to determine whether a post-RT CVA is related to treatment. Three patients in our study suffered CVAs after RT. None of these patients had histories of cardiovascular or cerebrovascular disease, and all had radiological evidence of a CVA in or near the irradiated areas. After 30 years of follow-up, Brada and coworkers reported an observed relative risk increase of CVA of 4.1% for patients who underwent RT compared with the general population in the United Kingdom. They found that the risk increased with age, female sex, RT dose, use of macroscopic surgery, and acromegaly. Others using more modern surgical and RT techniques have not found a direct relationship between the occurrence of CVA and any RT or surgical parameter. However, a relationship between CVA and long-standing untreated pituitary insufficiency has been suggested.
We observed 1 patient (1%) who developed a secondary brain tumor, which is consistent with the reported literature. Brada and coworkers reported a cumulative risk of secondary brain tumors after RT of 1.3% at 10 years and 1.9% at 20 years. A relative risk of 9.4% for patients who underwent RT compared with the general population was based on the occurrence of secondary brain tumors in 5 of 411 patients treated. Minniti and coworkers more recently observed that 11 of 426 patients treated for pituitary adenomas developed secondary brain tumors. Their cumulative risk after RT was 2% at 10 years and 2.4% at 20 years with a relative risk of 10.5% compared with the general population. There were no treatment variables or patient characteristics associated with the incidence of secondary tumors; however, newer RT techniques that minimize the RT dose to normal tissues were thought to decrease this risk.
Conclusion
Subtotally resected pituitary adenomas are associated with a high risk of progression after surgery alone. Moderate dose RT can provide excellent long-term tumor control for patients with incompletely resectable or recurrent tumors after surgery. The likelihood of severe complications is relatively low. Currently, the challenge of RT should be to minimize toxicity. Newer RT techniques that reduce the amount of irradiated normal tissue are currently being investigated, such as stereotactic RT, intensity-modulated RT, and proton therapy. After adequate follow-up, these techniques may prove to maintain a high rate of tumor control while decreasing serious side effects such as vision loss, CVAs, and secondary brain tumors.
Currently, our department's policy is to treat patients with pituitary adenomas with a five-field fractionated stereotactic technique to a dose of 45 Gy in 25 fractions. Patients with secreting tumors located more than 3 mm from the optic chiasm are treated with stereotactic radiosurgery to a dose of 25 to 30 Gy, limiting to 8 Gy. These patients may benefit from a more rapid decrease in hormone secretion. Those with secreting tumors not amenable to radiosurgery may be considered for fractionated proton RT on an institutional protocol. Because proton RT is associated with a significantly lower dose to adjacent normal tissues, higher doses may be investigated in the future in an effort to improve the likelihood of local control of secreting pituitary adenomas.