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1Division of Radiation Oncology, Department of Oncology; 2Department of Neurosurgery
The Johns Hopkins University School of Medicine, Baltimore, MD 21287.
Corresponding author: Dr. Jeffery A. Williams
The Johns Hopkins University School of Medicine
Baltimore, MD 21287-8811
Tel: (410) 614-2886
Purpose: Stereotactic radiotherapy (SRT) for secretory pituitary adenoma offers precise localization of dose with potential sparing of optic and hypothalamic functions. We collated the indications, treatment parameters and both the clinical and biochemical results of stereotactic radiotherapy for ACTH- and prolactin-secreting pituitary adenoma.
Materials: Between 5/90 and 2/96, nine patients (4 males and 5 females) with a mean age of 31.9 years, had fractionated stereotactic radiotherapy (SRT) for ACTH- or prolactin-secreting pituitary adenomas (Cushing’s disease: n=5; prolactinoma: n=3; Nelson’s syndrome: n=1). These nine patients had subtotal transphenoidal resections before SRT. An additional patient with Cushing’s disease had aborted transphenoidal surgery and single-fraction stereotactic radiosurgery (SRS). Prior to SRT, four patients received planned conventional fractionated external beam radiotherapy (XRT) (median dose = 33.3 Gy). The median SRT dose was 34.5 Gy (range 14.4 - 50.4 Gy). The median total radiation dose (XRT plus SRT) for patients receiving fractionated treatment was 47.7 Gy.
Results: The median follow up was 62 months (range 22-91 months). One patient with Nelson’s syndrome was lost to follow-up. Of the nine evaluable patients, none required re-operation for growth of pituitary tumor and all had radiographic control as shown by serial MRI scans. In four of the six patients with Cushing’s disease, treatment resulted in normalization of hormone levels and resolution of symptoms. All four patients were able to discontinue medications. In two patients, normalization occurred within four months of treatment. Two patients with Cushing’s disease failed, requiring adrenalectomy. For patients with prolactinoma, treatments resulted in a significant decrease of plasma prolactin levels. All patients treated for prolactinoma became asymptomatic; two were able to discontinue bromocriptine and one patient had a successful pregnancy. After radiation therapy one patient developed new hypopituitarism. No patient developed worsened visual acuity, visual fields or new neurological deficits.
Conclusions: SRT with or without XRT may yield meaningful reductions in hormone levels with concomitant clinical improvement in selected patients with prolactinomas or Cushing’s disease. In certain situations, combining conventional XRT with SRT is appropriate. Modifications of the stereotactic radiation delivery may maximally reduce the hypothalamic dose, thereby possibly reducing the risk of clinical hypopituitarism. This treatment is safe and is without visual or other neurological toxicity.
Key Words: stereotactic radiotherapy, radiosurgery, Cushing’s disease, prolactinoma, pituitary adenoma
Presently, the standard initial management of symptomatic prolactin-secreting pituitary adenoma (prolactinoma) is medical.1,2 For lesions <5 mm diameter, observation is an option if the patient can tolerate the symptoms of amenorrhea and galatorrhea (or impotence and diminished libido in males). Bromocriptine or other dopamine agonists can reduce both serum prolactin levels as well as the tumor mass effect in the majority of patients. However, withdrawal of bromocriptine leads to a return of symptoms in most cases, thus necessitating indefinite medical treatment.1,2 In patients who are non-compliant or unresponsive to medical management, definitive therapy may be required. Transphenoidal surgery is a standard procedure when medical therapy is unsuccessful. Good results however, can be achieved with primary radiotherapy.3,4 For other secretory pituitary tumors, transphenoidal resection is considered the primary therapeutic modality. If definitive surgery fails to adequately decompress the optic apparatus or if symptoms secondary to hormonal excess are not relieved, adjuvant radiation therapy is indicated. We report the results of stereotactic radiotherapy either as a "boost" after conventional external beam radiation or as the sole radiotherapeutic treatment, after unsuccessful transphenoidal resection.
Ten patients (5 males and 5 females) with secretory pituitary adenomas were treated at The Johns Hopkins Hospital between 5/90 and 2/96. Clinically, six patients had Cushing’s disease, one had Nelson’s syndrome and three had prolactinoma. The hormonal levels prior to radiation therapy are given in Table I. Hormonal evaluation for Cushing’s disease patients included 24 hour urinary cortisol, serum cortisol, and/or serum ACTH levels. Patients with prolactinoma were assessed through serum prolactin levels. All patients had serial cranial MRI studies as part of both the initial assessment and routine follow-up. The mean age was 31.9 years.
One patient with Cushing’s disease (patient 9) received single-fraction stereotactic radiosurgery with a dose of 22 Gy after two attempted transphenoidal resections were aborted due to excessive bleeding. The other nine patients had prior subtotal transphenoidal resections followed by post-operative radiation therapy. Four patients received conventional fractionated external beam radiation (XRT) prior to stereotactic radiotherapy. Both XRT and SRT were administered five days per week. There was no planned break between XRT and SRT. The XRT was given in 1.8 Gy fractions to a median dose of 33.3 Gy (range 18 - 36 Gy). Similarly, the modal stereotactic radiotherapy (SRT) fractional dose was 1.8 Gy. The SRT in all cases was done with nominal 10 MV photons on a linear accelerator (Varian Clinac 18) using concentric arcs. A single isocenter was used in each case. A relocatable thermoplastic mask was used for localization in fractionated SRS. The doses delivered by stereotactic radiotherapy ranged from 14.4 Gy to 50.4 Gy with a median of 34.5 Gy. Total doses (XRT plus SRT) for the nine patients who received fractionated treatment ranged from 41.4 to 60 Gy (median 47.7 Gy). The collimator sizes and isodose prescription lines are described in Table II. In two cases, transverse arcs alone were chosen specifically to minimize hypothalamic irradiation in an effort to reduce the likelihood of future hypopituitarism. These arcs are slightly angled off the horizontal such that the entry and exit do not overlap, thus the temporal lobes do not receive a high dose which would sacrifice one of the beneficial advantages of SRT. (Figure 1.)
The median follow-up is 62 months (range: 22 - 91). The single patient with Nelson’s syndrome (patient 6) was lost to follow-up. All nine evaluable patients had radiographic control of their tumors. No patient required reoperation for recurrent local tumor growth after SRT.
Of the six patients with Cushing’s disease, four attained normalization of hormone levels and were able to discontinue medication. Two achieved normalization within four months of treatment. One patient (patient 2) received ketoconazole for 20 months post-treatment but has subsequently remained recurrence-free for 10 months without medication. Two patients failed to achieve satisfactory declines in hormonal levels and subsequently required adrenalectomy. Of note, one of these was the patient treated in a single fraction after two failed attempts at transphenoidal resection.
All three prolactinoma patients became asymptomatic while achieving a significant decrease in serum prolactin levels (>90%). Prolactin (ng/ml) values before SRT vs. the most recent observation were 788 vs. 54, 633 vs. 56, and 5000 vs. 226. Two were able to discontinue bromocriptine, and one patient was able to significantly decrease the dose. One patient who presented with amenorrhea (patient 5) eventually completed a successful pregnancy. Once hormonal normalization or symptomatic relief was attained, no patient experienced a clinical relapse or showed radiographic recurrence.
Among the four patients in whom we administered conventional radiation therapy prior to SRT as part of a planned treatment course, two patients (both with Cushing’s disease) received a total dose of 60 Gy (36 Gy XRT/ 24 Gy SRT). In both cases, symptoms subsided and the urinary cortisol levels normalized. Another patient with a macroprolactinoma and preoperative prolactin level >5000 ng/ml received 50.4 Gy (36 Gy XRT/ 14.4 Gy SRS). Although this patient’s serum prolactin has not normalized, it has fallen significantly, and importantly, appears to be stable without bromocriptine. As this patient presented with headaches (which have resolved) and visual field deficits (which have stabilized) along with poor tolerance of bromocriptine, treatment can be considered successful. The fourth patient who received combined XRT/SRT was poorly compliant with treatment, and was subsequently lost to follow-up.
The course of SRT was well-tolerated in all cases. No patient developed any neurological deficit after treatment. Visual acuity was not worsened nor was the field of vision diminished in any patient. Four patients had evidence of hypopituitarism prior to radiotherapy. Three patients were found to not have hypopituitarism through adequate initial endocrine evaluation before radiotherapy. One of these patients developed hypothyroidism and hypogonadism six years after treatment.
Unselected autopsy series have reported an incidence of pituitary adenoma in excess of 20%, making this the most common intracranial neoplasm.5 However, clinically significant pituitary adenomas requiring treatment represent only about 15% of all intracranial tumors.1 Of the adenomas which come to medical attention, approximately 60% are secretory. For most patients with prolactinoma, the initial therapy is medical. Bromocriptine or other dopamine agonists effectively lower serum prolactin levels in the majority of patients. However, tumor regrowth is typical after drug withdrawal thus necessitating an indefinite duration of treatment. In certain patients (for example, women with amenorrhea who wish to conceive or patients who cannot tolerate medical treatment or who are poorly responsive), definitive treatment with surgery or radiotherapy may be indicated. For patients likely to require future definitive treatment, prolonged preoperative bromocriptine use is not advised, as subsequent surgery may be more difficult due to fibrotic changes which can develop in the residual tumor.6 Although somatostatin analogues such as octreotide are useful in managing acromegaly,7 medical treatment is generally less successful for patients with growth hormone, cortisol, gonadotropin, or thyrotropin-secreting tumors than for prolactinoma patients. For patients with such secretory pituitary adenomas who are medically able to undergo surgery, transphenoidal resection is the definitive treatment of choice.
Conventional external beam radiation therapy can effectively control residual or recurrent disease after surgery. For recurrent Cushing’s disease, Estrada et al.8 showed that radiotherapy can salvage over 80% of patients. This compares favorably with historical data from repeat transphenoidal resection.9,10 Re-resection carries a very small but finite risk of surgical mortality and is associated with risks of hypopituitarism (including diabetes insipidus) and visual loss. Conventional radiation therapy likewise carries risks such as hypopituitarism and radiation injury to the brain and optic apparatus. These risks appear to be related to daily fraction size as well as total dose.24,25,26 Standard radiotherapy delivers essentially full dose to the adjacent normal structures, including the optic chiasm and hypothalamus. While complications are rare, radiation dose to these structures should ideally be kept to a minimum.
Stereotactic radiosurgery minimizes dose to surrounding normal structures while simultaneously allowing higher tumor doses to be administered. Single-fraction radiosurgery, while decreasing the actual total dose to normal tissues, poses an inherent risk due to the large dose of radiation administered at a single setting. Visual complication rates as high as 28% have been reported in pituitary adenoma patients treated with radiosurgery.11 Rocher et al, thus do not recommend single fraction stereotactic radiosurgery unless the lesion is <2 cm in diameter and not in proximity to the optic chiasm.
The radiobiological disadvantage of radiosurgery can be avoided by fractionating the treatment, i.e. using stereotactic radiotherapy (SRT).12 For example, the maximal tolerable dose to the optic chiasm in a single fraction appears to be approximately 8-10 Gy,32 in contrast to an estimated tolerance of over 50 Gy when conventionally fractionated. This approach preserves the favorable features of radiosurgery including precise localization of radiation dose and diminished dose to normal structures, while exploiting the sparing effects of fractionation. The latter may permit dose escalation with greater confidence. Grigsby et al. have observed a dose-response relationship for pituitary adenoma.2,14 Among 121 patients receiving conventional radiation therapy for pituitary adenomas from 1954-1982, failure rates were approximately 72% for patients treated to <30 Gy, 25% at 30-39.9 Gy, 15% at 40-49.9 Gy, 7% at 50-54 Gy, and 0% at >54 Gy. Stereotactic radiotherapy permits higher doses to be delivered to the tumor while theoretically minimizing complications. In some of our patients, fractionated total doses of 60 Gy were delivered with no untoward effects.
A drawback of stereotactic radiation treatments and other highly conformal radiotherapeutic techniques is the possibility of "geographic miss" in the effort to minimize the dose to normal surrounding tissues. Stereotactic radiotherapy is limited in that the lesion must be visualizable on the treatment planning CT for adequate definition of the target. Possibly, part of the lesion that is not seen on the treatment planning imaging study could be underdosed during the radiation delivery. All patients should therefore have formal diagnostic CT or MRI evaluation which can be directly compared to the radiosurgery treatment-planning imaging study. When possible, image fusion techniques15 are helpful if there is any discrepancy between the two studies. Given the excellent tumor control achievable with conventional radiation therapy, the group at the Harvard Joint Center for Radiation Therapy16 has included both cavernous sinuses in the treatment volume for fractionated SRT of pituitary adenomas to ensure adequate coverage.
For lesions that are large and irregular, or if there is any doubt about the adequacy of the treatment-planning imaging study, conventional external beam radiotherapy is appropriate. In some situations, combined conventional external beam radiation along with stereotactic radiotherapy is a reasonable option. This reduces the concerns of possibly missing part of the lesion if stereotactic irradiation is used alone. Additionally, this approach may potentially reduce the risk of hypopituitarism and visual complications compared to a full course of conventional radiation therapy. The combination of conventional radiation with stereotactic radiotherapy thus presents a means of escalating dose to the lesion without concomitantly administering excessive dose to the surrounding sensitive structures. As there is no literature describing this combination of XRT/SRT, our study represents the first series exploring this approach.
There is evidence that the hypopituitarism following radiation therapy for pituitary adenoma results more from the hypothalamic radiation dose than to actual pituitary parenchyma dose.17,18,19 The observed hypopituitarism in patients treated with conventional radiation for pituitary adenoma may be due more to failure of the hypothalamus in the production of releasing-hormones than to primary failure of the pituitary. By keeping the XRT dose <36 Gy while still delivering up to 60 Gy to the adenoma via SRT, the risk of clinical hypopituitarism may be diminished. More patients with longer follow-up are required to verify this hypothesis, particularly given the significant delay in the appearance of hypopituitarism after radiotherapy.
Growth hormone deficiency is not uncommon after radiation therapy to the sellar region. GH is usually the first pituitary hormone to become diminished after cranial irradiation. In one study, growth hormone deficiency was universally seen over the dose range from 35-45 Gy20 and the critical dose for inducing GH deficiency may be as low as 20 Gy.21 In humans, GH release is controlled by the arcuate nucleus of the hypothalamus, the major source of growth hormone releasing hormone (GHRH). Therefore, reduction of the radiation dose to the arcuate nucleus (which is approximately in the same transverse plane as the optic chiasm) could be beneficial, especially in the pediatric population. For women with an inability to conceive secondary to amenorrhea from prolactinoma, treatment technique should aim to avoid sequelae which might defeat one purpose of the treatment. In other words, secondary hypogonadism and infertility may result from radiation therapy. Thus, avoidance of excessive radiation dose to the pre-optic nucleus of the hypothalamus, the major source of gonadotropin-releasing hormone, is a major objective. In two patients for whom we specifically wished to minimize radiation to the hypothalamus while still delivering tumoricidal doses to the adenoma, we used only transverse arcs (slightly angled off the horizontal). Follow-up evaluation in these two patients revealed no evidence of hypopituitarism. One patient treated at age 11 subsequently went through puberty and attained normal height, while the other patient regained normal menses and conceived.
A disadvantage of definitive radiation therapy in the management of secretory pituitary adenoma is the relatively lengthy interval until response to treatment.4,22 This delay can be up to several years before significant hormone decline is observed. In potentially life-threatening Cushing’s disease, this is unacceptable and thus definitive resection is the primary treatment of choice when hormone levels need to be lowered quickly. If hormone levels remain high despite surgery, radiation therapy (conventional or stereotactic) can effectively normalize hormone values, especially if adjuvant medical therapy is added.8 Loeffler et al.23 observed better results in secretory pituitary adenomas when single-fraction radiosurgery was employed rather than SRT. They recommended radiosurgery if the tumor could be well-localized by imaging and was at least 5 mm away from the optic chiasm or optic nerves. In our patients, the time until normalization was not excessively prolonged. Thus, 2 of the 4 responding Cushing’s disease patients achieved normalization within four months and the longest duration that any patient remained on cortisol-reducing medication was 20 months. The 67% cure rate among the Cushing’s disease patients in this study is comparable to the results of other radiosurgery27,28 and conventional29,30,31 radiation therapy results, although the sample size is admittedly small.
In this series of patients with ACTH- or prolactin-secreting pituitary adenomas, fractionated stereotactic radiotherapy was safe and effective. A combination of fractionated stereotactic radiotherapy with conventional external radiation therapy is an option in certain clinical settings such as when the tumor is relatively large, irregular and extensive. As the hypothalamic radiation dose may be critical with respect to treatment-induced clinical hypopituitarism, the use of transverse arcs alone to further reduce hypothalamic dose may be justified. Our results with this method are encouraging. Patients who responded to treatment did so over a reasonable amount of time in this series. In most cases of secretory pituitary adenoma, we advocate fractionated stereotactic radiotherapy with adjuvant medical therapy until the medication can be discontinued, rather than single-fraction high-dose radiosurgery. This sequence avoids the potential late complications associated with single high fractional doses of radiation yet still results in high rates of response.
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XRT: fractionated external beam radiation therapy
SRT: stereotactic radiation therapy
*adrenalectomy required to control hypercortisolism
+ patient lost to follow-up
Dose vs. volume histograms. For a representative case, the pituitary adenoma, hypothalamus, and temporal lobes were contoured. Using the radiosurgical treatment planning system, the dose vs. volume histogram for each structure was calculated and plotted. The results show uniform dose (Gy) to the pituitary adenoma, insignificant dose to the hypothalamus and low dose to the temporal lobes.