CHAPTER 22 RADIOTHERAPY OF PITUITARYHYPOTHALAMIC TUMORS
Principles and Practice of Endocrinology and Metabolism
CHAPTER 22 RADIOTHERAPY OF PITUITARYHYPOTHALAMIC TUMORS
MINESH P. MEHTA
Growth Hormone–Secreting Tumors
Adrenocorticotropic Hormone–Secreting Tumors
Giant Pituitary Adenomas
Morbidity and Mortality
Radiotherapy for Recurrent Craniopharyngioma
Parasellar and Skull Base Meningioma
Complications of Brain Irradiation
Vision System Complications
Postirradiation Brain Necrosis
Goals of Radiation Therapy and Conventional External Beam Techniques
Innovative Radiation Techniques
Radiotherapeutic management of pituitary adenomas and tumors of the hypothalamus requires a thorough understanding of the various hypersecretory syndromes and their wide spread clinical manifestations, a working knowledge of the diagnostic principles, and an appreciation for the roles of surgery and medical management. Treatment with external beam radiotherapy typically results in little radiographic change in the tumor itself, and endocrine changes may require years to become detectable or stabilized. Meaningful evaluation of pituitary or hypothalamic tumors requires long-term follow-up to assess response and to observe complications.
This chapter addresses the overall management of pituitary adenomas, craniopharyngiomas, hypothalamic tumors (including germ-cell neoplasms), parasellar meningiomas, and astrocytomas. This discussion emphasizes the role of and indications for radiotherapy. Standard external-beam techniques for radiotherapy are outlined, and less common techniques—such as intracavitary radioisotope instillation, brachytherapy, particle beam radiotherapy, and stereotactic radiosurgery—are discussed. The complications of conventional radiotherapy are also addressed.
The role of radiotherapy in the management of pituitary adenomas remains poorly defined because of several factors, including the occasional need for emergent surgical decompression; the availability of competing therapeutic alternatives, such as transsphenoidal adenomectomy and medical treatment with dopamine agonists; the slow decline in hypersecretion after irradiation; the lack of large, well-controlled prospective randomized trials; concerns regarding possible long-term toxic effects of radiotherapy; and the false belief that benign tumors are not effectively treated by radiation therapy.
Available data typically represent experience with a small number of cases accrued over a period of several years or decades and contain the inherent bias of referral patterns at tertiary care centers. Most patients have not been observed for sufficiently long periods to allow adequate interpretation of response and toxicity. Despite these limitations, it has become clear that the role of radiotherapy in the management of pituitary neoplasms falls into two distinct categories: the control of hypersecretion when other modalities have failed or are contraindicated and the control of mass effects. For most pituitary adenomas, external beam irradiation, delivered in conventional fraction sizes of 1.8 to 2 Gy to a total of 45 Gy or more, appears to suffice. Newer techniques—such as radiosurgery, interstitial implantation, and particle beam therapy—are under investigation.
Prolactinomas, predominantly macroadenomas, were previously classified with the nonsecreting tumors as chromophobe adenomas; before the prolactin assay era, the major goal of radiotherapy was the control of the mass effect. With the availability of the prolactin assay, it became clear that some macroadenomas are functionally active. Prolactin-secreting microadenomas usually are effectively managed by bromocriptine or, rarely, by transsphenoidal adenomectomy. Long-term control of hyperprolactinemia after surgery alone is rare. Large tumors and tumors that persistently secrete prolactin despite resection can be treated medically with bromocriptine, a dopamine agonist that decreases prolactin levels and causes tumor shrinkage. The continued use of bromocriptine may be complicated by toxic effects, and its discontinuation often results in resumption of tumor growth and of prolactin hypersecretion. Despite prior therapy with bromocriptine, tumor growth may resume in women who become pregnant.
Radiotherapy is indicated if hyperprolactinemia persists despite transsphenoidal tumor resection or the use of bromocriptine. The results of several single-institution studies are summarized in Table 22-1.1,2,3,4,5,6,7,8 and 9 Although irradiation causes a dramatic decrease in prolactin levels in some patients, the response is not always predictable. Serum assays obtained after radiotherapy have demonstrated a slow and variable decline in prolactin levels. Transient hyperprolactinemia, lasting as long as 2 years, has been described in patients irradiated for other pituitary-hypothalamic conditions.
TABLE 22-1. Control of Prolactinomas with Radiotherapy
After irradiation, prolactin levels decrease by an average of 60% by the end of the first year; after 3 or more years, the mean prolactin level decreases to one-tenth of the preirradiation value.5 In another study, 16 (44%) of 36 prolactin-secreting adenomas were controlled after radiotherapy.8 Another 36 female patients (12 with macroprolactinomas and 24 with microprolactinomas) were irradiated to a total dose of 45 Gy (1.8-Gy fractions) with a three-field technique.9 All patients underwent baseline and periodic reassessment of anterior and posterior pituitary function at intervals of 1 year or less while off bromocriptine for at least 2 months; they also had dynamic screening with thyrotropin-releasing hormone and luteinizing hormone–releasing hormone and hypoglycemic stimulation every 2 to 3 years. The preirradiation prolactin levels ranged from 1150 to 34,000 mU/L. With a mean follow-up of 8.5 years (range, 3–14 years), the postirradiation serum prolactin levels fell to normal (i.e., <360 mU/L) in 18 patients (50%). Another 10 patients (28%) had prolactin levels just above the normal range (378–780 mU/L). Only 2 patients (6%) demonstrated an increase in prolactin levels; another patient had a radiographically confirmed recurrence. Neither the pretreatment prolactin level nor the size of the tumor influenced the outcome from radiotherapy.
In a smaller study, long-term control of hyperprolactinemia was achieved in 7 (70%) of 10 patients after a total dose of 45 Gy (1.8-Gy fractions) of radiation.7 These studies elegantly demonstrated that radiotherapy and dopamine agonists are useful for long-term control of subtotally resected macroprolactinomas. Despite the paucity of long-term longitudinal studies of prolactin secretion after radiation therapy, studies indicate that over 2 to 13 years, prolactin levels return to normal or near-normal levels in >75% of irradiated patients.7,9 However, physiologic symptoms, such as amenorrhea from markedly elevated prolactin production, persist even when these levels fall to baseline. For example, in a series of 24 patients with prolactin-secreting macroadenomas treated with transsphenoidal surgery, dopamine-agonist therapy, and 45 Gy radiotherapy, tumor control and prolactin reductions were achieved in all, but amenorrhea persisted in the majority.10
GROWTH HORMONE–SECRETING TUMORS
Initial reports of the effectiveness of radiotherapy for the treatment of growth hormone (GH)–secreting tumors relied on clinical assessments of response, because direct measurements of GH levels were unavailable. Several investigators have reported clinical control rates of 80% to 90% after irradiation to doses of 40 Gy or more using conventional fraction sizes of 1.8 to 2 Gy per day.11,12,13 and 14 Clinical experience also suggests a dose-response relationship; control improves with doses as great as 40 Gy, and toxic effects occur at doses higher than 50 to 54 Gy. In 105 patients with GH-secreting pituitary adenoma treated to a total dose of 42 to 55 Gy, no improvement in local control was found at doses higher than 45 Gy. Moreover, the advent of the serum GH assay revealed that the functional response by these tumors to radiotherapy occurred slowly. The current definition of cure requires a GH level of <5 mU/L (2 ng/mL), with the understanding that long-term survival is dependent on such a reduction. Although radiation-induced GH reduction requires a lag period, as opposed to the immediate decline seen after surgery, the hypothalamic effects of radiation abrogate the endogenous somatostatin tone, thereby abolishing several responses that may enhance GH secretion. In a 20-patient study, arginine increased GH hypersecretion in those with a prior history of acromegaly whose GH levels had normalized after surgery. This phenomenon could not be demonstrated in patients postradiation.15
Patients treated after incomplete pituitary adenomectomy with high-voltage or with proton beam irradiation achieved an 80% decrease in GH levels after 4.5 years.14 In another report, control of GH secretion was achieved in 9 (60%) of 15 patients after irradiation.8 For 56 acromegalic patients in whom surgery had been unsuccessful, treatment with 50 Gy of radiation brought a 50% reduction in preirradiation GH levels in 51 patients (91%) at 26 months; for 40 of these patients, there was a further 50% decrease in GH levels at 42 months.16 At 2, 5, and 10 years after radiotherapy, endocrinologic control rates (defined by a drop in GH levels to <10 ng/mL) were 38%, 73%, and 81%, respectively.13 These data suggest that in patients who respond to radiotherapy, the GH depression may follow a first-order reaction, with a half-life of just longer than 2 years.16
Because endocrinologic normalization can occur almost immediately after successful transsphenoidal resection, this approach has become the standard. Irradiation of GH-secreting pituitary microadenomas and most macroadenomas is limited to patients with persistent GH hypersecretion after resection and to those in whom surgery is otherwise contraindicated. Overall, ~75% of such patients achieve eventual control, defined as a GH level <10 ng/mL or a lack of progression of growth of the adenoma4,8,11,12,13 and 14,17,18,19,20,21,22 and 23 (Table 22-2). Additionally, some data suggest that macroadenomas may have a higher failure rate after radiotherapy, as exemplified in a 21-patient series in which 5 of 6 failed patients had macroadenomas.23
TABLE 22-2. Control of Growth Hormone–Secreting Adenomas with Radiotherapy
ADRENOCORTICOTROPIC HORMONE–SECRETING TUMORS
Cushing disease is typically associated with adrenocorticotropic hormone (ACTH)–secreting pituitary microadenomas. The standard management for this syndrome remains transsphenoidal adenomectomy, which yields a 75% success rate in the control of hypercortisolism (see Chap. 23 and Chap. 75). Radiotherapy is restricted to inoperable patients or those in whom hypercortisolism persists after resection. Several reports of pituitary irradiation for Cushing disease are summarized in Table 22-3.8,21,22,23,24,25,26,27,28 and 29 The control rates range from 50% to more than 80%. Although a dose-response relationship has not been established in a prospective, randomized trial, retrospective data suggest that the control of hypercortisolism requires doses of 40 to 50 Gy. Cortisol levels normalized in 53% of patients treated with radiotherapy to the extent that no further treatment was required.26
TABLE 22-3. Control of Adrenocorticotropic Hormone–Secreting Adenomas with Radiotherapy
In another study of 21 patients with Cushing disease for whom irradiation was the primary treatment, a total of 45 Gy in 25 fractions was delivered using a three-field technique, and patients were observed for 5.8 to 15.5 years (median of 9.5 years).29 Initially, all patients were treated with metyrapone to normalize cortisol levels; at the latest follow-up evaluation, 57% had normal mean cortisol levels throughout the day and were off all therapy. Five patients required additional treatment with bilateral adrenalectomy or transsphenoidal hypophysectomy, yielding a failure rate for treatment of ACTH-secreting adenomas with radiotherapy of ~25%. The time to normalization of cortisol levels ranged from 0.7 to 10.5 years (median, 4 years).
In one study of 15 children with Cushing disease treated with radiotherapy, an 80% control rate was achieved.28 The time to remission of hypercortisolism was only 9 to 18 months, in contrast to the substantially longer remission times for GH- and prolactin-secreting adenomas.
Nelson syndrome consists of hypersecretion of ACTH and melanocyte–stimulating hormone, with dermal hyperpigmentation and aggressive growth of a pituitary adenoma, after bilateral adrenalectomy. Limited data suggest that the syndrome can successfully be treated with megavoltage pituitary irradiation. In a series of 15 patients observed for a median of 9.6 years (range, 1.5–17.3 years), clinical, radiographic, and endocrinologic improvement was observed in 14 cases (93%) after 45 Gy of megavoltage irradiation.29
The primary goal of therapy for endocrinologically inactive pituitary adenomas is control of the mass effect, which typically manifests with impaired vision, headaches, and pressure-induced atrophic hypopituitarism. The mass effect primarily is a consequence of tumors that were previously referred to as chromophobe adenomas; occasionally, it is caused by GH-secreting macroadenomas. Modern pathologic assessment has demonstrated that some tumors that had been assumed to be nonfunctional chromophobe adenomas are instead prolactin-secreting tumors; these are discussed separately later. Other so-called nonfunctional tumors secrete gonadotropins or their subunits (see Chap. 16).
The consequences of a mass effect from pituitary adenomas can be quite severe. For example, in a report of 140 patients with macroadenomas, visual field deficits were identified in 92%; in 10%, the tumors invaded the brain or the nasopharynx.30 In a subgroup of patients managed surgically without postoperative radiotherapy, the 5-, 10-, and 20-year recurrence-free survival rates were only 38%, 14%, and 0%, respectively. Postoperative radiotherapy increased the recurrence-free survival rates at 5, 10, and 20 years to 96%, 86%, and 73%, respectively. In that same study, 23 patients with relatively minor visual field deficits or with underlying medical conditions precluding surgery were selected for treatment with radiotherapy only; the 15-year recurrence-free survival rate was 93%.30 Radiotherapy normalized visual field deficits in more than two-thirds of patients in whom one quadrant or less was affected, an outcome that compared favorably with the results obtained with surgery. However, in patients with more extensive visual loss, visual restoration was more rapid and effective after surgery than after radiotherapy. The potential for blindness from such large tumors mandates immediate surgical debulking if feasible; however, the probability of residual disease and late recurrence is significant.
Of 112 patients with nonfunctional pituitary adenomas, the actuarial progression-free survival rates after primary irradiation (25 patients) or postoperative irradiation (87 patients) was 97%, 89%, 87%, and 76% at 5, 10, 15, and 20 years, respectively.31 No demonstrable difference in local control rates was identified between patients who underwent postoperative or primary irradiation. Because those data represent the experience of a single institution over more than 2 decades, radiother-apeutic techniques and doses varied. A further analysis of the dose-response relationship revealed no significant advantage in local control at dose levels that ranged between 35.7 and 62.3 Gy. Some data, however, do suggest the existence of a dose-response relationship; a 78% local control rate was obtained after 40 to 50 Gy, compared with a 56% local control rate after 30 to 40 Gy of radiation.32 A summary of local control rates for nonfunctional adenomas after radiotherapy is presented in Table 22-4.7,8,11,12,21,22,31,33,34
TABLE 22-4. Control of Nonfunctioning Pituitary Adenomas with Radiotherapy
Additional data supporting a role for radiotherapy in the preservation and improvement of vision in selected patients come from a report of 25 patients with pituitary macroadenomas causing vision impairment. These patients were treated with radiation therapy alone. Twenty-three patients underwent neuro-ophthalmologic evaluation before and after radiation therapy. With a median follow-up of 3 years, 78% of patients whose pretreatment visual field deficits had less than dense hemianopia and who also did not have diffuse optic atrophy experienced visual field improvement. Only 1 patient experienced tumor progression.35
GIANT PITUITARY ADENOMAS
The giant pituitary adenoma is a rare lesion, and its definition varies among case reports.36 A study of 31 patients with this tumor reserved the term for lesions with 40 mm or more of suprasellar extension.34 Eleven of the tumors were secretory, and 20 were nonfunctional. Four patients were treated with surgery, 2 with radiotherapy, and 25 with surgery plus radiotherapy. The patients who received combined-modality treatment were those with significant residual disease after surgery. With a mean follow-up of 8 years, the recurrence rate in either single-modality treatment group was 67% (4 of 6 patients). The use of combined-modality therapy yielded a local control rate of 84%. Based on limited experience, this rare subcategory of nonfunctional pituitary adenoma is best treated with surgery plus radiotherapy.
Craniopharyngiomas are relatively rare neoplasms that arise from epithelial remnants of the Rathke pouch and are typically found in the suprasellar region in children or adolescents; they account for ~5% of all intracranial neoplasms in childhood.37 These tumors tend to grow slowly, and the patients often present with compression of adjacent neural structures, such as the optic chiasm. Hypopituitarism also may occur. Surgical decompression is the optimal treatment for symptom relief and immediate palliation. However, the location, proximity, and adhesiveness of the tumor to adjacent neural structures often preclude an effective total resection. Aggressive attempts at total resection carry high rates of morbidity and mortality.38 The management options for craniopharyngioma include total resection, which is applicable only to a very small proportion of patients; subtotal resection alone; or subtotal resection and postoperative radiotherapy. To understand the role of postoperative radiotherapy, it is necessary to compare the results for total or subtotal resection alone with subtotal resection plus postoperative radiotherapy. In the absence of a prospective randomized trial, the only data available for comparison are retrospective single-institution reports that span several decades. including an institutional bias regarding therapeutic preference and the impact of technologic advances on diagnosis, resection, and radiotherapy. Although flawed, this database represents the only opportunity to compare the various treatment options for the management of craniopharyngioma.
A review of the English language literature from the mid-1960s through 1998 yields 34 reports from which management and outcome data can be summarized39 (Table 22-5). The data are broken down into three categories representing total resection, subtotal resection, and surgery plus postoperative radiotherapy. Actuarial 5- and 10-year survival rates after total resection were 81% and 69%. After subtotal resection alone, the survival rates were 53% and 37% at 5 and 10 years, and if radiotherapy was added, the survival rates were 89% and 77% at 5 and 10 years, respectively. There is a trend toward longer survival in later reports, which probably reflects improvements in neuroimaging, neurosurgery, radiotherapy, and overall medical management. Nonetheless, the outcome for patients undergoing subtotal resection is inferior to that of patients who also receive postoperative radiotherapy. Although the inferior outcome of patients who undergo subtotal resection could reflect a patient selection bias, the overall 5- and 10-year survival rates of 53% and 37% do not indicate a benign disease process.
TABLE 22-5. Survival Rates 5 and 10 Years after Three Therapeutic Approaches for Craniopharyngioma: Retrospective Data from 34 Reports
Another important factor in the prognosis and management of craniopharyngioma is the local recurrence rate. A review of 31 published studies suggests that local recurrence rates are 29% (90 of 308 patients) after total resection, 73% (163 of 224) after subtotal resection, and 17% (104 of 596) after surgery plus radiotherapy. Even after aggressive resection, recurrences are reported for as many as one-third of patients.40 The 20-year experience in childhood craniopharyngioma from the Joint Center for Radiation Therapy in Boston is a 10-year actuarial rate for freedom from progression of 31% after resection only, 100% after radiotherapy only, and 86% for patients treated with resection plus radiotherapy at the time of diagnosis. A point to consider is that surgical reports comment only on patients in whom resection was attempted. Patients in whom resection was not feasible were not reported as “failure of intent to resect.” Reporting data for an “intent to resect” category could significantly lower the overall local control rates for this treatment approach.
MORBIDITY AND MORTALITY
The morbidity and mortality rates that occur with total resection of craniopharyngiomas are significant. The operative mortality ranges from 2% to 43% (mean, 12%), and the morbidity ranges from 12% to 61% (mean, 30%). Surgical morbidity includes damage to the hypothalamus, which may result in diabetes insipidus or other endocrine anomalies (range, 30%–57%; mean, 40%), visual impairment (range, 10%–35%; mean, 19%), obesity, and memory impairment. In another report, 48% of patients developed obesity, and 57% developed memory impairment.41 In the largest surgical series reported, the operative mortality for total resection was 17%, and the incidence of significant morbidity was 16%.42 In contrast, subtotal resections carry a mortality of ~1%. The risk of late radiation damage to the hypothalamus, pituitary, and optic nerve is relatively low after conventionally fractionated irradiation (i.e., 1.8-Gy fractions to a total dose of 54 Gy). With these dose recommendations, visual impairment ranges between 1% and 1.5%.43 The addition of radiotherapy to subtotal resection does not increase the mortality and adds little to morbidity.
The impairment of cognitive performance is difficult to assess, because few studies address the issue in detail and because the protocols for neuropsychologic evaluation are not standardized. In an analysis of 35 patients with craniopharyngioma who underwent neurologic and neuropsychologic assessment, a lower morbidity rate was observed after subtotal resection followed by radiotherapy than after attempted radical tumor resection alone.44 From this experience, the researchers concluded that primary irradiation caused less frontal lobe dysfunction than radical subfrontal excision. Visual perceptual tests, visual acuity, and ocular motility improved in one-third of conservatively treated patients but deteriorated in patients who underwent radical tumor resection. A common deficit, independent of the treatment modality, was mild impairment of manual dexterity, which became evident in sequential tapping or in slow, smooth pursuit tasks. This deficit may represent the underlying basis for the awkwardness, the slowness, and the stiffness of gross motor function described in patients with craniopharyngioma.
An impairment of orbital-frontal lobe functions, which mainly manifests as persevering responses, was more pronounced in patients who had radical subfrontal excision than in those who had primary radiotherapy. This deficit persisted as long as 19 years after the resection. The intelligence quotients of the surgical and the radiotherapy groups remained within normal limits. Only 1 of the 18 patients in the primary irradiation group showed signs of frontal lobe disorder and had difficulty in school, but 2 patients required some tutoring for mild or moderate learning disability.44 Most of the surgically treated patients were unable to maintain regular employment, achieve expected educational goals, or enjoy a normal family and social life. A review suggests that although total excisions may be appropriate for relatively small craniopharyngiomas, heroic attempts at total resection typically result only in partial resection with enhanced morbidity and mortality rates.45 In light of the excellent results achieved after subtotal resection plus postoperative radiotherapy, this should be considered the standard management.
No prospective randomized trials analyzing dose-response relationships are available for the treatment of craniopharyngioma with radiotherapy. However, most institutions have routinely irradiated these patients to a total dose of 50 to 55 Gy in 1.8- to 2-Gy fractions. A long-term analysis (20 years) of dose-response data revealed a local failure rate of 50% with <54 Gy but only 15% with 54 Gy or higher doses.46 In a retrospective analysis of patients treated with 51.3 to 70 Gy, a higher incidence of radiation-associated complications was identified in those who received >60 Gy (with an actuarial incidence of optic neuropathy of 30% and brain necrosis of 12.5%), without any concomitant improvement in tumor control.47
RADIOTHERAPY FOR RECURRENT CRANIOPHARYNGIOMA
Limited data suggest that radiotherapy at recurrence, after prior resection, yields a 10-year progression-free survival rate of >70% for patients with craniopharyngiomas.48 These results are similar to those obtained with subtotal resection and preliminary irradiation and suggest that radiotherapy may be delayed in very young children, in whom its toxic effects may be more pronounced. However, routinely delaying irradiation may entail additional morbidity from continued tumor growth, the possible requirement for repeat surgery, and irradiation of larger volumes at relapse. Delaying radiotherapy cannot be recommended for older children. Recurrences appear to occur from 3 to 192 months (median, 12 months) after subtotal resection.43
Germinomas typically arise in the floor of the third ventricle and have a propensity to invade and compress adjacent neural structures, such as the optic chiasm, or to spread in the periventricular space, which permits craniospinal seeding. Although germinomas are the most common embryonal cell tumors, choriocarcinoma, endodermal sinus tumors, and teratomas may also occur at this site. The initial intervention for tumors arising in the floor of the third ventricle is often surgical. Surgery is indicated for diagnosis and to decompress the ventricles or to relieve pressure on the chiasm or the pituitary stalk. The rare teratomas in this location are amenable to surgical cure.
Current staging recommendations include contrast-enhanced magnetic resonance imaging (MRI) of the entire craniospinal axis. The incidence of spinal seeding varies and is often a function of the thoroughness of the investigation. The author recommends the use of triple-strength contrast during spinal imaging to assist in the detection of seeding of the leptomeninges or the cauda equina. Cerebrospinal fluid and serum evaluation for a-fetoprotein and the b-subunit of human chorionic gonadotropin (b-hCG) are recommended. Endodermal sinus tumors and, to a lesser extent, embryonal carcinomas cause elevations of a-fetoprotein; choriocarcinomas cause elevations of b-hCG. If either marker is elevated, repeat levels should be obtained postoperatively, after allowing time for the markers to decline. These markers allow monitoring of the treatment and follow-up phases.
Historically, the standard management of germinomas has consisted of craniospinal irradiation. So dramatic is the response of these tumors to radiation therapy that some researchers recommended a low test dose of limitedfield irradiation (to ~20 Gy) as a diagnostic test in place of a biopsy.49 This practice is supported by a report that surgery is associated with a 41% incidence of spinal dissemination compared with a rate of only 2% in nonbiopsied patients.50 Although the issues of total dose and whether the spinal axis should be prophylactically radiated remain controversial, the overall disease-free survival rate for patients with germinoma is usually in excess of 80%.51 Of all patients with confirmed intracranial germ-cell tumors treated at the Hospital of Sick Children from 1952 to 1989, 25 patients with germinoma treated with radiotherapy had a 5-year survival rate of 85%, and 13 patients with nongerminoma germ-cell tumors treated with radiotherapy had a 5-year survival rate of 45.5%.52
The efficacy of chemotherapy for treatment of germ-cell neoplasms in other body sites has led to similar trials for intracranial germ-cell tumors. Preliminary results for treatment with platinum-based combination chemotherapy for 10 patients with intracranial germ-cell tumors are encouraging. Sevenpatients received primary chemotherapy consisting of vincristine, etoposide, and carboplatin before craniospinal axis irradiation; 3 patients had complete responses, 3 had partial responses, and 1 patient had stable disease. All 7 patients were alive and disease free at a median of 12 months after treatment. The author’s treatment for germinomas, attaining complete response after two courses of chemotherapy, is a lowered radiation dose prescription, but nongerminomatous germ-cell tumors receive standard total dose irradiation.53
Because of its considerable morbidity, the value of craniospinal irradiation in very young children with nonseminomatous tumors (e.g., yolk sac tumors) is controversial.
PARASELLAR AND SKULL BASE MENINGIOMA
Adjuvant postoperative external beam irradiation is effective treatment for parasellar meningiomas, because complete resections are usually impossible. Highly customized treatment fields, usually based on computed tomography (CT)- or MRI-guided treatment planning, are routinely used to minimize irradiation of normal tissues. Typically, the radiotherapy prescription is a dose of 54 Gy in 30 fractions of 1.8 Gy each.54 In a series of 186 patients with meningiomas treated with megavoltage photon irradiation between 1963 and 1983, the 10-year actuarial causespecific survival rate was 67%.55 Radiotherapy alone resulted in improvement of neurologic performance in 12 (38%) of 32 patients with inoperable tumors. Multivariate analysis revealed that histology, extent of resection, and performance status at the time of presentation for radiotherapy were independent prognostic variables.
In a series of 115 patients with benign meningioma treated for primary or recurrent disease, 36 patients were treated by subtotal resection plus external beam irradiation, and 79 patients were treated by subtotal resection alone.56 The progression-free survival rate for 17 patients irradiated after initial subtotal resection was 88% at 8 years, compared with 48% for a similar group of patients treated with surgery alone. Sixteen patients whose tumors were incompletely resected at the time of first recurrence were irradiated; 78% were progression free at 8 years. Only 11% of the patients treated with surgery alone were progression free at 8 years (P = 0.001). Twenty-five patients were irradiated with photons alone at doses of 45 to 60 Gy and at a median follow-up time of 57 months; 6 (24%) had recurrences. Eleven patients were treated with combined 10-MV photons and 160-MV protons using three-dimensional treatment planning. After 53 months, none of these patients had a recurrence.
These studies support a role for radiotherapy in the treatment of incompletely resected or inoperable meningioma of all histologic types.55,56 Patients who undergo complete resection of the typical benign meningioma do not require adjuvant irradiation. The roles for stereotactically implanted high-activity iodine-125 seeds (i.e., brachytherapy), radiosurgery, or endocrinologic manipulation in the management of inoperable skull base meningioma are evolving, and these modalities should be considered when the indications are appropriate.57,58,59 and 60
The full histologic spectrum of gliomas, from the benign juvenile pilocytic variant to glioblastoma multiforme, is encountered in the hypothalamus; chiasmal gliomas may also invade the hypothalamus. Occasionally, oligodendroglioma, mixed tumors, and ganglioglioma may be encountered.
The management of juvenile pilocytic astrocytoma and ganglioglioma is surgical. When surgery fails, external beam radiotherapy provides highly effective adjuvant treatment. Other glial tumors usually are not amenable to total resection, and postoperative irradiation is frequently used as adjuvant treatment. In the management of 33 children with hypothalamic-chiasmatic gliomas, the median time to tumor progression was 70 months in patients who received irradiation and 30 months in those who did not (P <0.05).61 Nonirradiated patients who progressed were treated with irradiation. Clinical or radiographic improvement occurred in 11 (46%) of 24 irradiated patients. The 5- and 10-year survival rates for irradiated patients were 93% and 74%, respectively.61
To delay radiotherapy in very young children and to minimize the incidence of long-term complications, there is increasing interest in the initial treatment of histologically benign glial tumors with chemotherapy. In a study of 6 children with optic pathway gliomas who were treated with carboplatin at the time of progression, the median age at diagnosis was 2 years (range, 4 months to 7 years), and the interval between diagnosis and treatment with carboplatin ranged between 7 months and 6.5 years (median, 1.8 years).62 Disease stabilization was observed in all patients, suggesting that carboplatin can arrest growth of progressive optic pathway gliomas in young children and may permit a delay in the use of radiotherapy.62
Among 19 children between the ages of 15 weeks and 15 years (median, 3.2 years) with chiasmal or hypothalamic gliomas who were treated with nitrosourea-based chemotherapy, 12 patients (7 juvenile pilocytic astrocytomas, 2 astrocytomas, 2 highly anaplastic astrocytomas, and 1 subependymal giant cell astrocytoma) received their chemotherapy immediately after diagnosis because of progressive symptoms.63 Another 7 patients (all astrocytomas) received chemotherapy at the time of tumor progression. In 15 (83%) of 18 patients that could be evaluated, the tumor responded to or stabilized after chemotherapy. With a median follow-up of 79 weeks, median time to tumor progression had not been reached, and no tumor-related deaths had occurred. Improvement or stabilization of visual field function was observed in 16 patients. These results suggest that nitrosourea-based chemotherapy is useful for the initial treatment of children with chiasmal or hypothalamic gliomas and allows deferral of irradiation until such time as the tumor progresses.
COMPLICATIONS OF BRAIN IRRADIATION
Modern megavoltage radiotherapy produces minimal acute toxicity, including temporary alopecia, mild dermatitis, and a serous otitis media if the middle ear is included in the treatment field. These acute toxic effects typically are grade 2 or less. The focus of the treatment planning process is to minimize late toxic effects, which are uncommon but can be devastating. Late toxic effects occur predominantly in tissue with a slow turnover time and reflect a combination of direct cellular and indirect vascular injury.
The factors that predict a higher rate of complications include very young age, large total dose, large fraction size, large irradiated volume of normal tissue, and underlying medical conditions. In an unselected series of 134 patients who had undergone pituitary-hypothalamic irradiation over an 18-year period, 97% of whom had been treated to 45 to 50 Gy, complications attributable to radiotherapy occurred in 7 patients (2 second malignancies, 2 auditory deteriorations, and 3 vision deteriorations), underscoring the 5% or less risk from a carefully prescribed course of radiotherapy.64
Despite a low rate of cell proliferation in pituitary adenomas, the sequential assessment of hormone levels has demonstrated that the secretory functions of the pituitary gland are relatively susceptible to irradiation.65 The incidence of hypopituitarism was analyzed in a group of 165 patients who underwent cranial irradiation to total doses of 37.5 to 42.5 Gy in 2.25- to 2.65-Gy fractions.66 The analysis, which spanned a 10-year period, tested anterior pituitary function using insulin hypoglycemia or glucagon stimulation; thyrotropin-releasing hormone and luteinizing hormone–releasing hormone levels; and basal estimations of GH, prolactin, thyroid hormones, and testosterone or estradiol. Tests were repeated at 6- to 12-month intervals. Hyposecretion developed most rapidly for GH and least rapidly for thyroid-stimulating hormone; gonadotropins and ACTH declined at an intermediate rate. The time required for 50% of patients with normal pituitary function to develop a hypofunctional pituitary was 1.2 years for GH, 3 years for luteinizing hormone and follicle-stimulating hormone (Fig. 22-1), and 3.2 years for ACTH. Almost two-thirds of patients exhibited the GH–luteinizing hormone/follicle-stimulating hormone–ACTH–thyroid-stimulating hormone sequence of hypopituitarism. In another report of 84 patients, radiotherapy resulted in local control of the majority of pituitary adenomas, but by 10 years of follow-up, the prevalence of hypopituitarism rose from 29% to 92%, suggesting that residual pituitary function is highly susceptible to long-term negation after radiotherapy. Patients should, therefore, be appropriately evaluated in follow-up and counseled regarding the almost universal need for hormone replacement after radiation.66
FIGURE 22-1. Actuarial probabilityof maintaining normal pituitary function. Growth hormone (GH) declines most rapidly, followed by luteinizing hormone (LH)/follicle-stimulating hormone (FSH) and adrenocorticotropic hormone (ACTH); thyroid-stimulating hormone (TSH) is most resistant to a decline. (Adapted from Littley MD, Shalet SM, Beardwell CG, et al. Hypopituitarism following external radiotherapy for pituitary tumors in adults. Q J Med 1989; 70:145.)
Before attributing hypopituitarism to irradiation, the clinician must consider that a large number of patients present with a compromised endocrine status before commencing radiotherapy and that the preexisting disease and the extent of tumor resection contribute significantly to this process. Additionally, radiation-induced hyperprolactinemia developed in 44% of patients; the mean prolactin rose from 227 to 369 mU/L by 2 years, but the level returned to normal in the following 2 years.66
VISION SYSTEM COMPLICATIONS
Vision loss as a sequela of irradiation usually occurs within 2 years. When the literature was reviewed for reports of blindness as a complication of pituitary irradiation, only two cases of total vision loss were found when the fraction size was maintained below 2 Gy.67 In a series of almost 500 patients with pituitary adenomas treated to a total dose of as much as 50 Gy in fraction sizes of 2 Gy or less, no optic nerve or chiasmal injury was reported.30 A logistic regression dose-response analysis of injury to cranial nerves after proton beam radiation therapy delivered in 1.8-Gy equivalent fractions revealed that the risk of cranial nerve damage was 1% at a total dose equivalent to 60 Gy, and it increased to 5% at a 70-Gy equivalent dose.68
POSTIRRADIATION BRAIN NECROSIS
Brain necrosis is an uncommon complication of cranial irradiation with modern radiotherapeutic technology, fraction size, and total dose prescriptions. In a series of more than 650 patients, only 2 (0.3%) developed brain necrosis, and these cases were associated with the use of opposed lateral fields.30 In the author’s experience, opposed lateral fields are safe if used with very-high-energy photons (10 MV), small field sizes, fraction size no greater than 1.8 Gy, and total doses no higher than 50.4 Gy. Radiation necrosis most often occurs 9 months to 2 years after radiotherapy. The hallmarks of radiation necrosis include an elevated cerebrospinal fluid protein while glucose remains normal, a focal delta that slows on electroencephalography, and T1-weighted magnetic resonance images that show diffuse gadolinium-enhancing lesions in the optic chiasm and hypothalamus. After parasellar irradiation, patients with necrosis may present clinically with progressive vision impairment and dementia. Neurocognitive effects side effects may occur.68a Current treatment planning and dose prescription algorithms are aimed at maintaining the rate of clinically significant necrosis at <1%.
Anecdotal reports have linked the occurrence of single or multiple intracranial aneurysms to irradiation for pituitary adenoma.69 It has been suggested that postirradiation cerebral pathology—from localized to multifocal radiation necrosis and from localized to diffuse vasculopathy—is not rare in children, whose young nervous systems are particularly sensitive to ionizing radiation.70 Of 156 patients irradiated for pituitary adenomas, 7 experienced cerebral strokes at intervals of 3.2 to 14.6 years after irradiation.71 However, the observed incidence was not significantly greater than the expected value of 3.5 cerebral strokes (P = 0.078) for this population. No definitive data support the notion that irradiated patients are at a higher risk of developing strokes.
To quantify the risk of second brain tumors after childhood cranial irradiation, a retrospective analysis of 305 patients treated for pituitary adenomas was performed. Four tumors, all gliomas, occurred within the radiation field after a latency period of 8 to 15 years. This group of patients had a 16 times greater relative risk of developing a malignant brain tumor than an age- and gender-adjusted population. The cumulative actuarial risk of a secondary glioma after radiation therapy was 1.7% at 10 years and 2.7% at 15 years. Meningiomas and sarcomas also have been reported to occur within the radiation field years after irradiation, including the low doses used for treatment of tinea capitis.72
GOALS OF RADIATION THERAPY AND CONVENTIONAL EXTERNAL BEAM TECHNIQUES
The primary goal of irradiation of tumors in the pituitary-hypo-thalamic region is delivery of the prescribed tumor dose with minimal exposure to critical normal surrounding structures, particularly the visual and auditory systems, brainstem, and temporal lobes, and to excessively large volumes of hypothalamus. The modern radiotherapeutic process is based on precise delineation of the target and critical structures, which is achieved using contrast-enhanced, thinslice CT scanning. Further improvements in tumor localization are possible by correlation of CT and MRI data.73
The newer localization techniques can correct for the geometric distortion of MRI data sets and provide three-dimensional CT and magnetic resonance images and target volume correlation. Most patients with neuroendocrine tumors undergo the treatment planning process and the actual radiation treatments with a head immobilization device. The author’s practice is to use a thermoplastic material that is molded to the patient’s face and immobilized to a baseplate. The reproducibility of this device is within 2 to 3 mm on a daily basis during a conventional 5- to 6-week course of radiotherapy.
The treatment planning process itself is typically carried out at a workstation with three-dimensional capability. The objective of the treatment planning process is to evaluate the relative dose distribution to the tumor and surrounding normal tissues of a variety of field arrangements. The optimal plan is selected and is further refined by beam modulation with devices such as beamattenuating wedges, compensators, or customized blocks. The use of two opposed lateral fields with low-energy photons is not recommended because of a slightly higher risk of temporal lobe radionecrosis. Satisfactory dose distribution generally is achieved with a three-field technique that uses two opposed lateral beams and a vertex or coronal field directed downward from the scalp to the pituitary fossa. This technique is less suitable for small tumors with minimal suprasellar extension, because the vertex field traverses a considerable amount of normal brain.
Other acceptable techniques include a four-field arrangement, which typically requires wedges in at least two fields, and the use of an arc technique. The bicoronal 110-degree arc technique with a reversing wedge filter moving in each beam is commonly used. With this setup, the linear accelerator rotates from the level of the ears superiorly to the midline, creating a 110-degree coronal arc. A similar arc is then created on the contralateral side. Although these arc fields can exhibit substantial nonuniformity of dose distribution because of the curvature of the skull, this can be corrected by using wedge filters in the field.
Similarly, an axialoblique bilateral arc arrangement with wedges can be used if the patient’s head can be flexed sufficiently to exclude the eyes from the treatment field. The author’s standard practice is to generate multiple plans for each patient, evaluate the isodose distributions, and select the most appropriate treatment technique. With such refined treatment planning, the dose gradient within the tumor is typically <5%, and the dose falloff to surrounding critical structures is very sharp. An example of such an isodose distribution is presented in Figure 22-2, which illustrates an axialoblique arc pair with 15-degree wedges.
FIGURE 22-2. Isodose distribution using the arc technique (first setting) reveals a sharp dose falloff from the center of the target.
The advent of three-dimensional treatment planning has introduced a new level of sophistication into the simulation process. Using 3-D techniques, three standard 2-D techniques (opposed-lateral two-field setup, 110-degree bilateral arcs, and a three-field technique) were compared with a single 330-degree rotational arc method (avoiding the eyes) and a four-field noncoplanar arc technique in an attempt to identify the optimal technique for minimizing exposure of normal tissues surrounding the pituitary.74 These observations have significant practice implications. The two-field opposed-lateral technique using 6 MV photons resulted in the highest dose to the temporal lobes and, therefore, should not be used routinely. The dose to the temporal lobes could easily be reduced with this technique, simply by using a higher energy beam, such as 18 MV. The three-field technique was superior to the opposed-lateral technique in reducing temporal lobe dose. Both the bilateral arc and single 330-degree rotation technique further decreased temporal lobe dose, in comparison with the fixed two- and three-field techniques. The four-field noncoplanar arc technique yielded the lowest temporal lobe dose but also resulted in the highest lens dose.
After the treatment planning process, the exact field setup is determined during a simulation session. The patient is repositioned in the same configuration as used for the treatment-planning CT or MRI studies, and the central intersection point of the radiation fields, or isocenter, is determined using a coordinate transform system from the planning CT. The isocenter is verified with orthogonal radiographs. External reference land marks—specific points that had been selected at the time of the treatment-planning CT and that were visualized with barium strips or palates—are revisualized on the orthogonal films using radiopaque markers. These serve as external fiducial coordinate reference points that allow the transformation of CT location to orthogonal films. Because the thermoplastic mask provides rigid and reproducible immobilization, there is no need for skin marks; all necessary marks are placed directly on the mask. Daily alignment of the patient at the treatment machine is carried out using reference marks on the mask and a three-point laser system. At the first treatment session, verification portal images are obtained; in routine cases, weekly portal images are obtained. More complex setups using noncoplanar fields incorporate a portal verification imaging system.
The author uses a total dose of 45 Gy in 1.8-Gy fractions for patients with pituitary adenoma. This dose is delivered in five fractions per week over a 5-week period. Although a clear dose-response relationship has not been established, most reports suggest that 40 to 45 Gy in 1.8- to 2.25-Gy fraction sizes produces high local control rates for most pituitary microadenomas.75 For craniopharyngioma and meningioma, the total dose is increased to 54 Gy. For low-grade glioma, the total dose is a function of the exact histologic type, the extent of residual disease, and the proximity of critical neural structures to the treatment field.
INNOVATIVE RADIATION TECHNIQUES
PARTICLE BEAM IRRADIATION OF THE PITUITARY GLAND
In the early 1950s, studies were performed with stereotactic-charged particles in patients with metastatic breast carcinoma to produce pituitary hormone suppression. Since then, more than 3500 patients have been treated worldwide to reduce primary pituitary tumors and to suppress pituitary function for the management of diabetic retinopathy, breast cancer, prostate cancer, and other conditions. Most of this experience was accrued at four institutions: the University of California at Berkeley, Massachusetts General Hospital, the Institute for Theoretical and Experimental Physics in Moscow, and the Institute of Nuclear Physics in St. Petersburg. The results in the management of more than 2000 patients with pituitary tumors have been excellent and are summarized in the following sections.
Treatment of Acromegaly. More than 200 patients with acromegaly have been treated with helium ion radiosurgery to a total dose of 30 to 50 Gy in four fractions delivered over 5 days. GH levels dropped more than two-thirds within the first year; by 4 years, the mean GH level had fallen below the normal value of 5 ng/mL. Although patients with microadenoma appeared to have an earlier and more dramatic decline, there was no difference by 4 years in GH levels between patients with microadenomas or macroadenomas.76 Reported remission rates in acromegalic patients by 4 years have been 80% and 90%.77,78
Treatment of Cushing Disease. In a cohort of 44 patients with ACTH-secreting adenomas treated with stereotactic radiotherapy, the mean basal cortisol levels and dexamethasone suppression test results returned to normal within 1 year of treatment and remained normal during long-term follow-up. Although early failures were reported with a regimen of alternateday irradiation, a total dose of 60 to 150 Gy in three to four fractions was successful in 40 of 42 patients. The mean ACTH level decreased from 90 pg/mL before treatment to 58 pg/mL 1 year after treatment. Plasma cortisol suppression by dexamethasone and plasma 11-deoxycortisol response to metyrapone normalized 1 year after treatment. Approximately two-thirds of 175 patients with Cushing disease treated with particle beam irradiation exhibited complete remission with restoration of clinical and laboratory parameters to normal.77 Another 224 patients had similar responses.78
Treatment of Prolactinomas. In a cohort of 29 patients with prolactinoma treated with particle beam irradiation, 19 of 20 patients had marked decreases in their prolactin levels within 1 year. Partial or total remission of prolactin secretion was observed in 85% of patients after treatment with particle beam proton radiosurgery to doses ranging between 100 and 120 Gy.79
RADIOSURGERY: PITUITARY ADENOMA AND CRANIOPHARYNGIOMA
Radiosurgery, a technique in which a single large fraction of radiation is deposited within a small intracranial target, has been used in several varieties of pituitary-hypothalamic tumors.79a,79b The appeal of this technique as compared with fractionated techniques includes a single fraction of radiation (as opposed to several weeks of fractionated radiotherapy), the ability to minimize exposure of surrounding normal brain tissue, and the possibility of a more rapid endocrine decline.
A major limitation to the use of stereotactic radiotherapy for the treatment of pituitary adenomas has been the low tolerance of the optic chiasm (probably <8 Gy) to radiation. Nevertheless, preliminary results using stereotactic radiosurgery have been reported. In an analysis of 77 patients, 42 (82%) of 51 patients with Cushing disease were described as cured.80 Dose and tumor subtype may be critical factors in achieving an early response in secreting tumors. No endocrinologic response was observed with greater than 6 months follow-up in 14 patients having prolactinoma, Cushing syndrome, or Nelson syndrome after 8 to 20 Gy maximum dose, whereas significant hormonal declines occurred within 6 months in 14 acromegalic patients treated similarly.81 In contrast, when higher doses—in the range of 25 to 60 Gy maximum—were used, endocrinologic normalization occurred within 2 years in 36 of 37 patients, and major radiographic shrinkage occurred in all 13 patients observed for more than two years.82 Similarly, in 27 patients treated with maximum doses of 25 to 75 Gy, 13 of 16 patients with secreting tumors experienced endocrinologic normalization or a >50% decrease within 10 months.83 At lower maximum doses of 10 to 27 Gy, there was a significant endocrinologic response within 12 months in both prolactinomas and GH-secreting tumors, with 11 of 13 prolactinomas becoming normal within a year. Unlike the experience with fractionated radiation, a major radiographic response was observed in 15 of 21 patients with serial imaging studies.84
In perhaps the best comparison between single-fraction radiosurgery and fractionated radiotherapy,85 the Mantel log-rank test was used to obtain the Kaplan-Meier estimate of time to GH normalization in 16 patients treated with radiosurgery (25 Gy minimum, 50 Gy maximum) and 40 patients treated with standard radiotherapy (40 Gy). The mean time to normalization was 1.4 years in the radiosurgery group as compared with 7.1 years in the fractionated radiotherapy group (P <0.0001).
Radiosurgical treatment has been reported for 61 patients with meningiomas (42 patients), craniopharyngiomas (4), pituitary adenomas (5), gliomas (3), and miscellaneous lesions in and around the cavernous sinus (7).86 Long-term tumor control rates have not been analyzed, but an evaluation of toxicity revealed a 19% incidence of cranial neuropathies. Others have reported smaller series; the data are difficult to interpret because of short follow-up and patient heterogeneity. Clearly, these small experiences remain intriguing but need to be tested more rigorously through clinical trials.
Several reports indicate >90% local control rates for meningioma treated with subtotal resection and radiosurgery. These reports include parasellar meningioma as a subset of other intracranial meningiomas. One of the few reports specifically evaluating petroclival meningioma described the experience with 62 patients, of whom 39 (63%) had previously undergone surgical resection and 7 (11%) had received fractionated external beam radiation therapy.87 The radiosurgery marginal dose ranged from 11 to 20 Gy. With a median follow-up of 37 months, the tumor volume decreased in 14 (23%), remained stable in 42 (68%), and increased in 5 patients (8%), for an overall control rate of 92%. Complications from radiosurgery were rare. Five patients (8%) developed new cranial nerve deficits within 24 months, which resolved completely in two patients within another 6 months.
In an Austrian report, 97 patients with skull base meningiomas were treated with radiosurgery; 53 had partial removal or recurrent growth and 44 underwent radiosurgery as primary treatment. The mean peripheral tumor dose was 13.8 Gy (range: 7–25 Gy). In 78 patients, follow-up scans were available. Follow-up imaging revealed decreased volume in 31 cases (40%), stabilization in 44 cases (56%), and progression in 3 cases (4%). In 8 cases, marked central tumor necrosis was seen.88 When radiosurgery was performed on 50 patients with skull base meningiomas—5 sellar, 26 cavernous sinus, and 12 petroclival, with a mean peripheral dose of 18.0 Gy—the 1- and 2-year tumor control rates were 97% and 100%, respectively.89
In the largest linear-accelerator–based meningioma radiosurgery report to date, 127 patients with 155 meningiomas were observed for 31 months. The median marginal dose was 15 Gy, and 82 of the tumors were skull based. Freedom from progression was observed in 107 patients (84.3%) at a median time of 22.9 months. Actuarial tumor control for the patients with benign meningiomas was 100%, 92.9%, 89.3%, 89.3%, and 89.3% at 1, 2, 3, 4, and 5 years, respectively. Six patients (4.7%) had permanent complications attributable to the radiosurgery.90
Whereas the preliminary retrospective reports provide encouraging early data, many questions remain unanswered about the precise role of radiosurgery in these patients, especially in terms of patient selection, appropriate dose definition, and toxicity. As stated earlier, cranial neuropathies remain a concern. In a retrospective review, the endurance of the visual pathways and cranial nerves was evaluated after radiosurgery in 50 patients who had undergone radiosurgery for skull base tumors. With a mean follow-up of 40 months, the actuarial incidence of optic neuropathy was zero for patients who received <10 Gy, 26.7% for patients receiving <15 Gy, and 77.8% for those who received >15 Gy (P <0.0001). No neuropathy was seen in patients whose cavernous sinus cranial nerves received 5 to 30 Gy, suggesting that the visual pathways exhibit a much higher sensitivity to single-fraction radiation than do other cranial nerves.91
Yet another infrequent complication to consider is the development of radiation-induced edema. To evaluate the causative factors after radiosurgery, a retrospective study was performed in 34 patients. The minimum dose was 12 Gy, and the follow-up was 1 to 3 years. Edema developed preferentially in nonbasal tumors, especially those around the midline and sagittal sinus. In all but one case in which radiation-induced edema was observed, the marginal tumor dose was 18 Gy or more.92
INTRACAVITARY INSTILLATION OF RADIOISOTOPES
Intracavitary instillation of isotopes such as yttrium-90, gold-198, and phosphorus-32 has been attempted for the treatment of cystic craniopharyngioma.93 This therapeutic approach is attractive, because ~60% of craniopharyngiomas present as a single large cyst, and early refilling is frequent after drainage. Intermittent aspiration of the cyst by stereotactic puncture or drainage through an Ommaya reservoir is frequently necessary. Some reports have suggested that prognosis is worse for tumors with a large cystic component, reflecting the extensive attachment of the cyst wall to adjacent vital structures. The major advantage of intracystic radioisotope instillation is the reduced radiation dose to adjacent normal structures such as the optic chiasm, hypothalamus, and surrounding brain. Intra-cavitary radiotherapy can be used in patients who have previously been irradiated. The maximum range of particles from phosphorus-32 in soft tissue is ~8 mm, with more than one-half the dose absorbed within the first 1.5 mm, allowing ablation of secretory cells within the cyst wall without significant exposure of the surrounding brain to radiation. An acute inflammatory reaction has been reported after the procedure, leading some investigators to recommend the routine prophylactic use of corticosteroids. This treatment approach may be useful in the management of recurrent cystic craniopharyngioma.
Stereotactic instillation of radioisotopes into the cystic cavity of craniopharyngioma has been combined with radiosurgical treatment of the solid component.94 With follow-up ranging from 10 to 23 years, 31 (74%) of 42 patients are alive. Moreover, the patients remained socially well adapted and maintained a high rate of full-time work and a low rate of intercurrent disease. The authors advocate a less aggressive surgical approach to craniopharyngioma.
Intracavitary yttrium-90 was used as primary treatment for 31 patients with craniopharyngioma, with an 84% overall survival rate for follow-up ranging from 2 to 80 months (median, 44 months). Visual acuity improved or stabilized in 42%, and visual fields improved in 48%.95 Local control, defined as cyst stabilization (6 patients), reduction (12), or complete resolution (10), was observed in 28 (90%) of 31 patients. These results further support the use of intracavitary radioisotope instillation in the initial management of craniopharyngioma.
The interstitial implantation of radioisotopes for the management of intracranial neoplasms has a long history, but technical difficulties have limited its widespread application in tumors of the pituitary-hypothalamic region. Permanent interstitial implantation of pituitary tumors was used in England in the 1960s. In the 1980s, the technique of transnasal transsphenoidal implantation of iodine-125 was introduced.96 Iodine-125 implantation has the advantage of rapid dose attenuation outside the target volume, with the ability to minimize normal tissue complications. It also has several hypothetical radiobiologic advantages. Because implanting tumors in this location is complex, its role in the management of recurrent pituitary-hypotha-lamic tumors is based only on anecdotal reports.
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