• Open Access

Linear-Accelerator-Based Modified Radiosurgical Treatment of Pituitary Tumors in Cats: 11 Cases (1997–2008)

Authors


  • A portion of this work was presented at the 23rd Annual Veterinary Cancer Society Conference, September 26–29, 2003, Madison, WI. Work was performed at Washington State University.

Corresponding author: Dr Janean Fidel, Department of Veterinary Clinical Sciences, Washington State University, PO Box 7060, Pullman, WA 99164; e-mail: jfidel@vetmed.wsu.edu.

Abstract

Objective: Determine the efficacy and safety of a linear-accelerator-based single fraction radiosurgical approach to the treatment of pituitary tumors in cats.

Design: Retrospective study.

Animals: Eleven client-owned cats referred for treatment of pituitary tumors causing neurological signs, or poorly controlled diabetes mellitus (DM) secondary either to acromegaly or pituitary-dependent hyperadrenocortism.

Procedures: Cats underwent magnetic resonance imaging (MRI) of the brain to manually plan radiation therapy. After MRI, modified radiosurgery was performed by delivering a single large dose (15 or 20 Gy) of radiation while arcing a linear-accelerator-generated radiation beam around the cat's head with the pituitary mass at the center of the beam. Eight cats were treated once, 2 cats were treated twice, and 1 cat received 3 treatments. Treated cats were evaluated for improvement in endocrine function or resolution of neurological disease by review of medical records or contact with referring veterinarians and owners.

Results: Improvement in clinical signs occurred in 7/11 (63.6%) of treated cats. Five of 9 cats with poorly regulated DM had improved insulin responses, and 2/2 cats with neurological signs had clinical improvement. There were no confirmed acute or late adverse radiation effects. The overall median survival was 25 months (range, 1–60), and 3 cats were still alive.

Conclusions and Clinical Importance: Single fraction modified radiosurgery is a safe and effective approach to the treatment of pituitary tumors in cats.

Abbreviations:
DM

diabetes mellitus

GH

growth hormone

IGF-1

insulin-like growth factor-1

MRI

magnetic resonance imaging

PDH

pituitary-dependent hyperadrenocorticism

PZI

protamine zinc insulin

RT

radiation therapy

VTH

Veterinary Teaching Hospital

Pituitary tumors are uncommon in cats. Clinical signs in cats with pituitary tumors usually are a consequence of either hypercortisolemia secondary to increased ACTH secretion, insulin-resistant diabetes mellitus (DM), and other changes that constitute the syndrome of acromegaly secondary to increased growth hormone (GH) secretion, or the space-occupying nature of a mass.1–7

Treatment options for cats with pituitary tumors include surgical interventions such as hyphophysectomy or adrenalectomy, medical management of the endocrine consequences, or radiation therapy (RT).1–10 Adrenalectomy is considered the treatment of choice for cats with pituitary-dependent hyperadrenocorticism (PDH)9; hypophysectomy has seen limited application in cats with few reported animals having had the procedure performed.8,10 Insulin often is given to cats with DM and acromegaly or hyperadrenocorticism, but insulin responses can be poor despite very large insulin doses. Specific medical therapy to decrease GH secretion in acromegalic cats has included dopamine agonists or somatostatin analogs,2,11 but such approaches have not proven uniformly successful. Trilostane can improve the clinical signs of hyperadrenocorticism in some cats if adrenalectomy is not an option, but in the few reports of the use of this drug in cats with hyperadrenocorticism, improvement in insulin response has not been consistently appreciated.12,13

Acromegalic cats treated with RT have been reported to have resolution or amelioration of clinical signs, including lower insulin requirements. All published reports of RT of pituitary tumors in cats describe total delivered radiation doses ranging from 36 to 54 Gy with typical fraction sizes varying from 2.0 to 4 Gy,1–4,6,7,14 and the number of fractions ranging from 5 to 20 Gy. Fractionated approaches to RT have been effective at controlling clinical signs with approximately 87% of all treated animals with follow-up information available having at least some degree of clinical improvement after RT.1–4,6,7,14,15 Fractionated approaches to RT require prolonged total treatment periods, often several weeks, multiple anesthetic episodes, and considerable expense.

Radiosurgery describes a technique in which a large dose of radiation is delivered, in a highly conformal fashion, to a defined target. In people, radiosurgery of pituitary tumors using a gamma knife or linear accelerator has successfully controlled both tumor growth and signs of endocrine disease.16–19 Over the last 10 years, a modified radiosurgery approach has been offered by the Washington State University Veterinary Teaching Hospital (VTH) to owners of cats with pituitary masses. With this approach, a single, large dose of radiation is delivered in a nonconformal fashion by arcing a linear-accelerator-generated beam with a small field size around the patient's head with the pituitary mass at the center of the beam's rotation. Using a multileaf collimator, a field size of 2 cm × 2 cm is made that when arced around the pituitary mass creates a cylindrical field shape. This approach allows RT with a single anesthetic episode, shorter hospitalization time, and decreased expense as compared with a fractionated protocol. The primary objective of this retrospective study was to determine if linear-accelerator-based modified radiosurgery effectively controlled clinical signs of pituitary tumors in cats. In addition, we wanted to identify the frequency of adverse effects with this approach.

Methods

Medical records of cats undergoing a modified linear-accelerator-based radiosurgery between January 1997 and July 2008 were identified and reviewed. Pertinent information gathered from the medical record included presenting clinical signs, duration of clinical signs, adverse effects and response to RT, date of death, cause of death, and any available postmortem examination findings. Where needed, contact was made with clients or referring veterinarians to determine adverse effects and responses to RT as well as date and cause of death. For those cats that exhibited improvement in clinical signs, attempts were made to establish the interval after radiosurgery at which improvement was appreciated. Other information sought from the medical record included results of clinical pathology assessments before and after radiation, imaging results (computed tomography or magnetic resonance imaging [MRI]) before and after radiation, and results of endocrine testing. Responses to and adverse effects of RT were determined by owner perception, examinations by referring veterinarians or VTH clinicians, and changes in endocrine function, specifically results of insulin-like growth factor assays and changes in absolute insulin doses needed to control hyperglycemia.

All cats were imaged and subsequently treated in sternal recumbency in a positioning device consisting of a head holder and customized block matching the patient's hard palate and upper arcade teeth and a styrofoam bead vacuum mold, the use of which has been described previously in dogs.20 Dorsoventral and lateral port films were obtained with the cat in the positioning device, which was secured on the linear-accelerator couch with pegs at predetermined locations. Port films included a fiducial plate with radio-opaque markers projecting the position of the central ray and 1 cm measured increments away from center in x and y axes defined at isocenter. After port films, the cat was transported to the MRI magnet still contained in the positioning device. Images were obtained (dual echo, flair, and T1) with and without contrast for tumor documentation, localization, and manual treatment planning. After MRI, the cat was returned to the linear-accelerator couch for treatment, remaining within the positioning device at all times. Measurements were made from the surface of the cat to the center of the tumor using axial images to determine the distance from the entry point of the beam to the target tissue. Calculations were done by hand to deliver the target dose to the depth of the center of the tumor. The output factor used had been previously determined using thermoluminescent dosimeters in phantoms and a cadaver for 2 cm × 2 cm, 2.5 cm × 2.5 cm, and 3 cm × 3 cm square fields by a certified medical physicist. The tumor's location was outlined by hand on the port films using anatomical landmarks visible on both MRI and port films. The distance from the tip of the nose to the tumor, and other visible landmarks such as the caudal-most aspect of the frontal sinus, and the location of the center of the bony calvarium all were used to define the location of the tumor. The sella turcica also was nearly always visible on the port films. Planning tumor volume was roughly equal to gross tumor volume plus a minimum of 2 mm margins, and the treatment field was limited to 2 cm × 2 cm in all cases. Tumor size was restricted to tumors that could be treated in a 2 cm × 2 cm field because a larger field would not allow sparing of normal tissues in a feline head. Proper positioning with the tumor at the center of the beam's rotation was confirmed using additional port films obtained in the dorsoventral and lateral directions. The arcing of a square delivered a cylindrical treatment volume, and this entire treatment volume received 100% of the calculated dose. The original calculations of this field in a cat's head by a certified medical physicist determined the 50% isodose line to be 5 mm beyond the 2 cm field.

All treatments were administered using an Elekta SL15a linear accelerator. A total dose of 15 Gy, using 6 MV (10 cats) or 10 MV (1 cat) photons, was planned for delivery to the target while arcing the field dynamically 360° around the patient; 1 cat received 20 Gy on a later treatment. The 360° rotation was divided into a minimum of 2 arcs of 180° because functional limitations of the linear-accelerator gantry did not allow passage beyond the 180° point of rotation. The arc also was divided based on changes in depth of tumor as the beam rotated around the patient. A maximum of 4 arcs was used and the most common division was 3 arcs of 120 degrees: 181°–300°, 301°–60°, and 61°–180°. If distances still varied more than 0.5 cm within 1 arc, bolus was applied to the cat's head where needed to equalize the distances. The total dose delivered was divided equally over the entire rotation. After treatment, the cats recovered from anesthesia and were discharged from the hospital either on the day of treatment or the next morning. The entire procedure from the start of anesthesia to extubation required approximately 3 hours.

Cats were considered to have shown clinical improvement if either improved glycemic control in response to insulin administration or decreased insulin-like growth factor-1 (IGF-1) concentration was documented, or if there was improvement in neurological abnormalities. Survival time was calculated by the Kaplan-Meier method. Survival time was defined by the interval between the day of treatment until death. Because of limited necropsy information, all deaths but 1 were attributed to tumor-related causes. Cats were censored from survival statistics if still alive (3 cats), if lost to follow-up (1 cat) or necropsy documentation was available at death showing complete resolution of tumor and no cause of death obviously related to RT (1 cat).

Results

During the study period, 11 cats with pituitary tumors were treated with modified linear-accelerator-based radiosurgery. There were 9 Domestic Shorthair cats, 1 Maine Coon, and 1 Siamese cat. Ten cats were neutered males that ranged in age from 4 to 16 years (the age of last treatment), and 1 cat was an 11-year-old spayed female. Therapy before referral included insulin, angiotensin-converting enzyme inhibitors, various antibiotics, trilostane, and glucocorticoids for cats with neurological signs. One cat had received two 3.5 Gy fractions of radiation in a fractionated protocol approximately 6 weeks before radiosurgery; radiosurgery subsequently was recommended out of concern regarding this cat's ability to undergo the repeated anesthetic episodes needed to complete the fractionated protocol.

Presenting complaints included poorly regulated DM attributed to excess GH secretion (n = 7); 5 of these cats had concentrations of IGF-1 above the reference range and in the other 2, IGF-1 was not measured. In these latter 2 cats, the diagnosis of excess GH secretion was based on history, lack of evidence of hyperadrenocorticism, and presence of a pituitary mass. Poorly regulated DM and fragile skin attributed to PDH was noted in 2 cats, 1 of which had abnormal results of a low-dose dexamethasone suppression test consistent with hyperadrenocorticism. In the other cat, the diagnosis of PDH was based on clinical history, physical examination, and presence of bilateral adrenomegaly during an abdominal ultrasound examination and the finding of a pituitary mass on MRI. The remaining 2 cats had neurologic signs that included abnormal behavior and vision deficits. Clinical signs in this population of 11 cats had been present for as few as 4 weeks to as long as 12 months before treatment with modified radiosurgery.

Physical examination abnormalities recorded in the medical records of some cats included features consistent with acromegaly or hyperadrenocorticism. One of the cats with acromegaly was noted to have a large head and wide-set eyes, and another was noted to have mild mandibular prognathism. Abdominal distension was noted in 2 cats with acromegaly and in 1 cat with hyperadrenocorticism. One of the cats with hyperadrenocorticism had a large skin tear as a consequence of abnormal skin fragility. Of the cats that presented for signs of neurological disease, 1 cat had dilated, unresponsive pupils but no other recorded neurological abnormalities. The cat with a history of abnormal behavior was considered neurologically normal, possibly as a result of recent glucocorticoid therapy implemented by the referring veterinarian, when admitted for radiosurgery.

Laboratory abnormalities found at presentation were typical of older cats with DM. Hyperglycemia (range, 258–487 mg/dL; reference range, 70–117 mg/dL) was found in all cats that had either acromegaly or hyperadrenocorticism and in 1 cat with neurologic disease (blood glucose concentration: 176 mg/dL); hyperglycemia in this cat was attributed to stress. The other cat that presented for signs of neurological disease had blood glucose concentrations within the reference range. Other observed laboratory abnormalities included mild increases in serum alanine amino transferase (2 cats) and AP activities (2 cats), hypercholesterolemia (2 cats), azotemia in 7 cats (blood urea nitrogen concentration: 29–71 mg/dL; reference range, 9–27 mg/dL; serum creatinine concentration: 1.2–3.7  mg/dL; reference range, 0.7–1.2 mg/dL), glucosuria, and low urine specific gravity (range, 1.017–1.033; reference range, >1.035) in 4 of the 6 cats for which a urine specific gravity was recorded in the medical record.

Eight cats were treated with a single, 15 Gy dose of radiation. Two cats were treated 2 times with 15 Gy doses. One of these 2 received treatments 3 months apart when there was no evidence of clinical improvement after the 1st modified radiosurgery. The other cat was treated 6 weeks after the 1st treatment because of no clinical improvement. One cat was treated 3 times. In this cat, no clinical improvement was noted 8 weeks after the 1st 15 Gy treatment, and a 2nd radiosurgery treatment was administered; the 2nd dose was 20 Gy. After the 2nd treatment, clinical improvement (decreasing insulin dose) occurred, and this cat did well for 40 months with normalization of IGF-1 concentrations, after which time increased IGF-1 concentrations were noted, and the cat was treated a 3rd time with a 15 Gy dose. This cat remained clinically stable for the next 19 months and then was euthanized for refractory seizures.

Of 9 cats with poorly regulated DM, 5 had improvement in insulin responses as judged by decreased insulin doses after therapy; 2 of the cats became insulin independent for a time after radiosurgery. One of these cats was insulin independent at 8 months after radiosurgery, but by 14 months after radiosurgery required insulin for glycemic control. The other cat became insulin independent 4 months after radiosurgery and remained insulin independent for the next 14 months at which time hyperglycemia and abnormally high IGF concentrations were documented. Despite increased IGF concentrations, this cat reportedly required only 1–2 U protamine zinc insulin (PZI) to maintain glycemic control. Three cats that did not become insulin independent still experienced either decreases in the dose of insulin required for glycemic control or improved responses to insulin. One cat had insulin decreased from a pretreatment dose of 17 U twice daily of ultralente insulin to 4 U twice daily of ultralente insulin at 3 months after a 2nd radiosurgery. Before radiosurgery, another cat had been on 8 U twice daily of lente insulin with no decreases in blood glucose concentrations, and at approximately 16 weeks after radiosurgery began to have decreases in blood glucose concentrations, and by 21 weeks after treatment had blood glucose concentrations between 100 and 300 mg/dL on 7 U lente insulin twice daily. Ultimately, this cat had acceptable blood glucose concentrations with a twice daily regimen of 4 U glargine insulin and 4 U PZI with the owner monitoring blood glucose concentrations at home. One cat with PDH 9 months after radiosurgery had exhibited improvement in its skin with healing of skin lacerations and improved glycemic control. This cat still was being treated with trilostane under the supervision of a veterinary internist.

Four cats did not have improvement in glycemic control. One of these cats with acromegaly was euthanized 1 month after modified radiosurgery because of owner perceptions that the cat was not feeling well. Another cat with acromegaly had been treated twice, but was considered a nonresponder because records from the primary veterinarian could not confirm insulin doses. Another cat with PDH was euthanized 2 months after radiosurgery. This cat was presumed to have intra-abdominal neoplasia or other disease process causing multiple intra-abdominal masses that were palpated shortly before the cat's euthanasia. The 4th cat that did not have improved glycemic control had been treated twice with radiosurgery and died at home 9 months after the 2nd radiosurgery.

Of the 2 cats that were treated for neurologic signs, both cats were considered by either the owners or the regular veterinarians to have experienced clinical improvement. One cat had vision improvements appreciated approximately 1 week after receiving radiosurgery. The other cat, which presented for behavior changes and vision deficits, was considered at 5 weeks after RT to have improved vision; an examination by the regular veterinarian at this time documented bilateral pupil dilatation, but the presence of pupillary light responses. Twelve months after treatment, the behavior changes (aggression) that had prompted evaluation were no longer appreciated, although the regular veterinarian was not sure of the cat's visual status at that time.

Acute or late effects of radiosurgery were recognized uncommonly. The cat with DM that was euthanized 4 weeks after radiosurgery for behavior changes and pain or discomfort may have experienced an early delayed radiation effect. There were no late effects observed in any of the cats, including the cats treated multiple times with radiosurgery, although the development of seizures in 1 cat may have been a late effect of RT.

As of May 2009, 3 cats, 1 with PDH and the 2 cats treated for neurologic signs, were still alive 14, 9, and 8 months after completing RT. One cat was lost to follow-up and its status was not known, but this cat had survived at least 38 months after treatment. For survival analysis, this cat was censored. Of the cats that are dead, 2 were euthanized as noted above 1 and 2 months after radiosurgery, and 1 died at home 9 months after the 2nd radiosurgery. The cat that died acutely 9 months after the 2nd radiosurgery had a necropsy examination performed; multiple pancreatic abscesses, blood in the stomach and duodenum, and a pituitary adenoma were found. Histologic lesions included severe, multifocal chronic ductular abscessation with severe atropy of pancreatic lobules, chronic membranoproliferative glomerulonephritis, biliary hyperplasia, parathyroid hyperplasia, nodular hyperplasia of both adrenal glands, and an acidophil adenoma of the pituitary gland. One cat with acromegaly was found dead at home 17 months after radiosurgery; necropsy was not performed. Another cat presented for acromegaly was euthanized 25 months after radiosurgery for complications attributed to chronic renal failure, but still was receiving insulin. The cat that received 3 radiosurgeries was euthanized 19 months after the 3rd radiosurgery for intractable seizures. Another cat was euthanized 46 months after radiosurgery as a consequence of decreased appetite, fluctuating insulin requirements, progressive weight loss, and recurrent obstipation. Tissues submitted by the cat's regular veterinarian were characterized histologically by diffuse, severe fibrosing interstitial nephritis, pancreatic exocrine nodular hyperplasia, pancreatic islet amyloidosis, adrenocortical hyperplasia, and centrilobular hepatocyte degeneration with mild central vein fibrosis; there was no gross or histological evidence of a pituitary mass in the submitted tissue. By Kaplan-Meier analysis (Fig 1), the overall censored median survival of the cats of this report was 25 months (range, 1–60 months). The mean survival was 29.4 months.

Figure 1.

 Kaplan-Meier curve depicting survival (in months) of cats after radiosurgery for pituitary tumor. Cats censored from analysis are represented by diamonds.

Discussion

To our knowledge, this is the 1st report demonstrating the clinical benefits of a single fraction modified radiosurgical approach to the treatment of pituitary tumors in cats. Our results demonstrate that linear-accelerator-based modified radiosurgery was safe (with few reported adverse effects attributable to RT), and effective with 7/11 (63.6%) treated cats having improvement in clinical signs. As appreciated in people, one of the clear advantages of radiosurgery realized in our cats was a decrease in the number of anesthetic episodes and the number of days needed to complete treatment. Previously reported protocols of fractionated RT for pituitary tumors in cats required between 5 and 20 anesthetic episodes to deliver RT, and 3 weeks or more to complete the entire treatment.1–4,6,7,14,15 In our cases, evaluation and treatment typically was completed over the course of 2 working days and necessitated a single anesthetic episode; most cats were discharged the day of radiosurgery. In our hospital, this radiosurgery approach also is associated with a slight cost advantage compared with a fractionated protocol.

Surgical resection is the preferred treatment for many pituitary tumors in people, the exception being prolactin-secreting tumors for which medical management is the preferred approach.21 The success rate of surgery varies, with persistence or recurrence of clinical signs common. Patients with clinical signs after surgery are candidates for medical therapy or RT. Fractionated RT protocols in people can be successful at controlling clinical signs of pituitary disease in individuals who have failed surgery, but compared with radiosurgical approaches, fractionated protocols have the disadvantage of a long period of time to clinical remission.22

Radiosurgery refers to the delivery of a single focused therapeutic dose of radiation. Generally, very small tumors are the best candidates for radiosurgery. Fractionation of the total dose of radiation usually is used to spare normal tissue; however, the goal of radiosurgery is to place a large dose of radiation into the tumor at one time while sparing surrounding tissues by using multiple noncoplanar beams. Depending on the equipment available, this approach can give a 3 dimensional conformal dose at the isocenter of the treatment, with little dose to the surrounding tissues. Currently in human medicine, radiosurgery is performed using either a gamma knife, a radiation device incorporating multiple static 60Cobalt beams intersecting at the center of the unit, proton therapy, or with linear accelerators,21 where beam movement allows for treatment with multiple beam angles. Our limitations of time and technical support necessitated development of a treatment field that was not conformal to tumor, but defined a cylinder into which the tumor fit.

There also may be radiobiologic advantages for the delivery of single, high-dose therapy for some conditions, particularly those that are low grade or benign in nature. It has been theorized that radiosurgery arrests cell division in the target cell population regardless of the cells' mitotic activity, and therefore may have greater effect than traditionally fractionated protocols for some diseases.23

The time after completion of radiosurgery before improvement in clinical signs in our cats was quite variable, and ranged from 4 weeks to several months. In people treated with radiosurgery, times to remission typically are several (7 or more) months. Clinical improvement after fractionated RT in cats with pituitary tumors commonly has been observed within 2 months of completing therapy. In a report by Peterson et al,2 2 of 14 cats with acromegaly were treated with RT with 1 of the 2 cats exhibiting a >50% decrease in size of the tumor and normalization of plasma growth hormone concentration within 2 months of treatment. This cat had short-term (6 months) improvement in insulin responsiveness before insulin resistance re-emerged. The other cat exhibited no response to RT. Goossens et al1 reported that 2 of 3 cats treated with fractionated RT had improved insulin responsiveness within the first 4 weeks after treatment, with 8–10 months needed before these 2 cats no longer needed insulin. Neither of these 2 cats had recurrence of DM after a follow-up period of 16 and 28 months. Normalization of plasma growth hormone concentration was noted in each of these cats. The 3rd cat of this report also exhibited improvement in insulin responsiveness, but insulin resistance re-emerged 4 months after treatment. Kaser-Hotz et al4 saw improvement in neurological signs during the course of treatment in 1 cat, and by 1 week after treatment in 2 others with neurological signs. One of 2 cats with acromegaly and poorly controlled DM in this report had decreases in insulin dose, and although the time to insulin decrease was not reported, the cat died of non-tumor-related causes 5 1/2 months after treatment. Mayer et al3 described decreased insulin doses within 2 months of treatment in 2 of 6 acromegalic cats, with 5 of the 6 requiring insulin for the remainder of their lives. Also in this report, tumor size had decreased in 2 of the 4 cats in which posttreatment images were acquired. Brearley et al6 reported discontinuation of insulin between 8 and 34 weeks after RT in 5 of 8 acromegalic cats, with 1 cat achieving reduction of insulin dose by 46 weeks after RT. In a study by Dunning et al7, improvement in glycemic control was found in 13 of 14 acromegalic cats within 0–20 weeks of completing RT, with 6 cats achieving complete remission of DM within 6 months. One final case report15 documented improvement in glycemic control within 2 months of a hypofractionated RT protocol and ultimately insulin independence for 12 months after RT. This cat had persistence of acromegalic features despite achieving insulin independence, a phenomenon that has been described by others.6,7 Collectively, the posttreatment course in the patients described in other reports suggest that cats with neurological signs from pituitary tumors may exhibit the most rapid clinical improvement. Indeed, the fastest clinical improvement among our cases was noted in the cats with neurological signs.

Improvement in glycemic control in cats with acromegaly and poorly controlled DM among our patients was noted in several cats within 4 months of treatment, a time frame that compares favorably to responses noted in the other reports. As with other reports, we also saw cats with durable (>12 months) endocrine responses and periods of insulin independence.

One of the limitations to this retrospective study is that few cats had follow-up imaging to determine the impact of radiosurgery on the size of the tumor. Of the 3 cats that had multiple radiosurgery treatments, original images were not available and there was insufficient information recorded to make conclusions about changes in size of the pituitary mass. In 1 cat that survived almost 4 years, there was no necropsy evidence of pituitary neoplasia despite continued hyperglycemia. Hyperglycemia is suspected to lead to glucose toxicity of β cells in cats,24 and long-standing hyperglycemia and glucose toxicity is believed to cause irreversible loss of pancreatic beta cell function and an absolute need for insulin. Thus, it is not surprising that some cats with pituitary disease still may require insulin after RT, and the requirement for exogenous insulin for the rest of a cat's life despite improved glycemic control has been observed by others.3,6,7

In people, there is a known disassociation between tumor growth and hormonal hypersecretion such that the dose of radiation delivered to a tumor can be different depending on whether the goal is halting growth of the mass or reversing the endocrinopathy.16,25,26 In a study of linear-accelerator-based radiosurgery in humans,27 with regard to tumor volume, radiosurgery produced a complete response in 3.5% of patients, and a partial response in 28.9%. Hormonal normalization, however, was found in 46.9% of patients with GH-secreting adenomas, 64.7% of patients with Cushing's syndrome, 22.2% of patients with Nelson tumors, and 38.5% of patients with prolactin-secreting tumors. The time from linear-accelerator-based radiosurgery to hormonal normalization was 36 ± 24 months (ranges, 2.1–99.3 months). Considering all types of tumors, an endocrine cure was achieved in 35.2% of patients. Our results, and the results of other reports of pituitary irradiation in cats, are comparable to reported figures for people with regard to improvement or resolution of endocrine signs.

Early adverse effects of radiosurgery were not recognized in this series of cases. The 1 cat that was euthanized within a month of radiosurgery had neurological changes that could have reflected either progression of tumor or early delayed brain injury secondary to radiation. Early delayed brain injury can be appreciated between 2 and 12 weeks after RT28 and can mimic progression of tumor. Early delayed effects can be transient and spontaneously resolve, but when severe usually they are treated with glucocorticoids. The cat with potential early delayed injury was not treated with glucocorticoids before euthanasia.

Clinical signs of late delayed brain injury, which may be seen as early as 6 months or may not be seen until years after RT, were not appreciated in this study. The 3 cats that survived >24 months had no reported adverse effects, but it could be argued that seizures in 1 of these cats were caused by late radiation injury. Had more cats in our series lived longer, late delayed adverse effects may have become apparent. Other reported adverse effects of fractionated RT to the head of cats such as mild epilation, hair depigmentation, and cataracts1,3,4 were not observed in the cats of this series. Cataracts take months to years to develop, but are considered unlikely adverse effects in the cats of our series because the eyes were not included in the radiation field of any of the cats and the manner in which the dose of radiation delivered limited the total dose of radiation to the lens.

Traditional fractionated RT of pituitary tumors in people has disadvantages such as long delays before desired effects. Passage of a decade or more between treatment and clinical response is possible.22 Adverse effects that may be seen in people undergoing fractionated RT include cerebral necrosis, optic or other cranial nerve neuropathy, and secondary tumor induction.29–35 In contrast, radiosurgery (gamma knife or conformal linear accelerator) may offer more rapid decrease in GH secretion, and is uncommonly associated with cerebral necrosis, optic neuropathy, or neurocognitive dysfunction.17,22 The optic nerve in people is more sensitive to radiation-induced injury than other cranial nerves, making limitation of radiation dose to the optic nerve of key planning importance.16,36 Tolerance of the human optic nerve to single fractions of radiation is believed to be around 8–10 Gy,37 although 1 study noted a risk of radiation-induced optic nerve injury of <1.5% for 12 Gy or smaller fraction sizes.38 The susceptibility of the feline optic nerve to radiation-induced injury relative to other cranial nerves is not known, but blindness or visual deficits attributable to RT were not recognized in cats of this study.

Hypopituitarism can develop in people treated with either fractionated RT or radiosurgery protocols. In 1 study of radiosurgery for pituitary macroadenomas in humans, of 114 patients considered at risk, hypothalamic pituitary dysfunction developed in 14 (12.3%) with dysfunction occurring within the 1st 5 years after RT in 12/14. The other 2 patients developed pituitary dysfunction at 86 and 92 months after linear-accelerator-based radiosurgery.27 Other reports of radiosurgery in people suggest that pituitary dysfunction is an uncommon complication of treatment.18 Pituitary dysfunction would be a potential complication of pituitary irradiation in cats, but was not recognized clinically in the cats of this report. Previous reports also have yet to document pituitary dysfunction after RT in cats. Cats of this and other studies may not live long enough after RT to develop clinically apparent pituitary dysfunction.

Survival times in our cats ranged from 1 to 46 months. The cat that received 3 radiation treatments survived 60 months after its 1st radiosurgery, and 19 months beyond its third. Previous reports of survival in cats undergoing pituitary irradiation have ranged from 4 to 42 months,2 16 to 28 months,1 5.5 to 20.5 months,4 8.4 to 63.1 months,3 1 to 66 months,6 and 2.5 to > 60 months.7 Thus, the survival times observed in the cats of our series are similar to survival times reported for cats treated with multiple fraction RT. However, deaths attributable to pituitary disease may have been overestimated in our report because all deaths but one were attributed to pituitary disease, and because few of the cats had necropsy examination, death in some of these cats could have been because of causes unrelated to pituitary tumor.

In our population, cats eligible for treatment were restricted to those with lesions of 1.5 cm in diameter or less because of limitations in field size and shape that could readily be treated with our preplanned field. This potentially limited the number of cats that could be treated with our approach. Changing the position of the leaves in the multileaf collimator throughout the rotation of the beam would have increased the dose conformation of the treatment, and larger tumors could have been treated with limited adverse radiation effects. This approach, however, requires considerably longer time and physics support. The approach used here also meant that if the tumor were smaller, more normal tissue outside of the tumor margins than would be ideal received the dose of radiation, potentially contributing to more adverse effects. However, we saw a very low frequency of adverse effects. In addition, field size smaller than 2 cm2 is very difficult if not impossible to treat accurately using an 80-leaf multileaf collimator.

In summary, we conclude that linear-accelerator-based, single fraction modified radiosurgery is a valid alternative to fractionated RT protocols for the treatment of pituitary tumors in cats. As seen in the cats of this series, clinical improvement was appreciated with little risk of adverse effects even in cats that had been treated more than once with this modified radiosurgery protocol. Given the increased availability of RT facilities, a study of the success of RT for treating pituitary tumors in cats as compared with other strategies, particularly adrenalectomy or medical therapy for cats with PDH, would be warranted.

Footnotes

aPhilips Medical Systems N.A., Bothell, WA

Acknowledgments

The authors thank Drs Heidi Allen, Karen Comer, Neil Cropper, Camille Fischer, and Polly Peterson for valuable follow-up information regarding some of the cats of this report; and Dr Mark H. Phillips for physics support in establishing the protocol for treatment of these cats.

This work was not supported by a grant.

Ancillary