by Allan F. Thornton, M.D. and Jay S. Loeffler, M.D.
NECC Newsletter MGH Neuroendocrine Center Bulletin Volume 4, Issue 1, Winter 1997
With the opening of the Northeast Proton Therapy Center (NPTC) in the fall of 1998, a quantum increase in the available resources of proton therapy will occur, allowing many pituitary patients to realize the benefits of this important modality. The Massachusetts General Hospital has long been a pioneer in the development of stereotactic precision irradiation of pituitary neoplasia. Since 1963, the Departments of Neurosurgery, Endocrinology, and Radiation Oncology have used proton beam therapy (Bragg Peak Particle therapy) available through the Harvard Cyclotron Laboratory to irradiate precisely a variety of skull base tumors. Although this effort in its early years was a limited program, many of the seminal discoveries and elemental techniques of the field of radiosurgery (treatment of small volumes of tissue with high-dose, precision irradiation) were developed within the MGH-HCL proton program and later inspired the development of gamma-knife and focused stereotactic linear accelerator therapy. The treatment of benign pituitary neoplasia remains one of the most important applications of this therapy. This method allows physicians to deliver curative doses of irradiation in a sufficiently focused manner to preclude damage to adjacent tissues, while delivering sufficiently high doses to obtain lasting tumor mass and hormonal control.
The management of pituitary tumors has undergone major changes over the past 20 years, necessitating re-evaluation of the roles of both conventional radiotherapy and radiosurgical applications. Both the availability of MRI imaging offering resolution of greater than 2mm in an area previously difficult for CT to image, as well as transsphenoidal ressection as a safer method of surgery, have radically changed the management of these tumors. Development of the agents bromocriptine and cabergoline, and, the somatostatin analogue, Octreotide, has led medical management of functioning adenomas. Finally, the development of improved radioimmunoassay techniques now allows both early diagnosis and sensitive detection of recurrence of pituitary adenomas. As a consequence, these tumors are detected at an earlier stage, and alternatives to surgical resection and wide-field irradiation are now possible.
In general, radiation therapy, whether by conventional fractionation over a six week period, or by radiosurgery, has the advantage of non-invasively treating and potentially curing unresectable pituitary disease, either in the post-operative setting or for patients who are not surgical candidates. However, there are several disadvantages of current conventional irradiation techniques which may be improved by stereotactic proton radiotherapy. The first lies in the relatively slow (6 months to 3 years) decrease in hormone excess symptoms after irradiation. Second, although complications after fractionated irradiation are rare, given present conformal irradiation techniques and energies available, many patients develop some degree of hypopituitarism several years following the irradiation requiring replacement hormonal therapy. Third, current techniques often irradiate the visual apparatus unnecessarily, increasing the potential risk to the optic pathways either from the initial treatment (rare, occurring in less than 1% of cases when doses of less than 4600 cGy at 200 cGy per fraction are observed), or from reirradiation, should the tumor recur years later. And finally, the risk of second malignancies induced from large-field irradiation in not negligible, estimated at just under 3% in recent studies from Canada.
The use of conventional irradiation for the treatment of neoplasia of the pituitary region has routinely involved the use of relatively simple orientations of treatment portals intending to treat the MRI-defined pituitary volume in addition to a relatively generous margin of normal brain. These treatment plans customarily involve 2 or 3 axial-plane static fields, but may incorporate the use of dynamic, arcing treatment designs intending to focus on a confined volume of brain, thereby allowing a lower "safe" dose of radiation to be delivered to the normal brain. More complicated planning has been performed, usually incorporating multiple beam angles (5-6), all within an axial plane. However, inherent risks of irradiation employing these plans include temporal lobe damage and failure to include the marginal target zones, particularly important for larger lesions, including those with cavernous sinus extension. The recent advances in imaging of tumors of the pituitary region incorporating MRI now offer the potential of more precise dose confinement, thus decreasing the recognized risk of temporal lobe damage, while increasing confidence of adequate irradiation of tumor margins. Proton radiotherapy realizes this precise dose confinement through the marriage of MR-based 3-dimensional treatment planning with an irradiation modality capable of homogeneous (within ± 5%) treatment of small, irregularly shaped treatment volumes.
The advantages of proton radiotherapy are entirely provided by the physical properties of the beam. The finite range of penetration of protons is affected by both the initial beam energy and the electron density of the absorbing material. The rapid increase in the rate of energy loss near the end of the range of a particle (proton) results in a well-defined volume of increased dose, known as the Bragg peak. By appropriate distribution of proton energies, the Bragg peaks may be grouped so as to provide a uniform dose across the target. This absence of exit dose offers important advantages to patients with sellar pathology. Proton irradiation delivers substantially higher doses to the target tissues, while respecting accepted dose constraints on critical normal tissues (chiasm, optic nerve, brain stem).
Accurate treatment with particle irradiation requires accurate dosimetry, reflecting the correct prediction of proton absorption within the scattering material. Such dosimetry relies on complex algorithms to provide information on the likely patterns of scattering and absorption of incident protons and involves computer modeling incorporating beam’s eye view perspectives (BEV) of the relative positions of the tumor, target, and critical structure volumes. However, this accurate prediction of dose deposition mandates excellent, and consistent, patient immobilization and correlation of imaging studies. Patients are immobilized in the supine treatment position using thermoplastic cranial immobilization. Patients are imaged with CT and MRI, using minimum slice spacing and contrast, in the treatment position using the above masks. Implanted metallic fiducials are used within the cranium to further enhance the stereotaxic precision of the beam planning and delivery. Following image acquisition, treatment image correlation is performed using both CT and MRI information within an integrated 3-D RTTP system running on a microcomputer.
Stereotactic irradiation at the MGH may be delivered either with fractionated therapy over 6-7 weeks, or in a single, radiosurgical method (e.g., 24 Gy). Currently, we reserve radiosurgery for lesions that are intrasellar and greater than 7mm to the optic apparatus. This distance is necessary to avoid excessive dose to the optic chiasm and represents the proton beam edge. Delivered with full incorporation of 3-dimensional treatment planning, stereotactic frame cranial immobilization, and cranial fiducial localization, patients treated with single-fraction treatment (radiosurgery) are rotated about the proton beam using a STAR patient immobilization system developed for the the Harvard Cyclotron in conjunction with the Department of Neurosurgery.
Patients with larger pituitary tumors are eligible for fractionated irradiation protocols. Currently, the Departments of Endocrinology, Neurosurgery, and Radiation Oncology are embarking on a randomized, dose-escalation protocol comparing standard (50.4 Gy) irradiation to escalated (59.4 Gy) doses delivered to secretory pituitary adenomas. This proton therapy effort has been piloted and demonstrates a significant increase in dose to the pituitary adenoma, while maintaining no increased risk to the optic apparatus. Because long-term, retrospective series of secretory pituitary adenomas treated with convention irradiation to 40-50 Gy have demonstrated hormonal control not exceeding 45% after fifteen years, this protocol will represent the first effort to improve on cure rates with fractionated irradiation. As proton therapy resources increase with the opening of the NPTC, non-functioning pituitary adenomas will be treated in a similar manner to slightly lower doses. For these patients, the advantage of proton therapy lies in avoidance of the visual system, affording the potential for retreatment with irradiation in the future with less visual risk.
Finally, patients with recurrent tumors, previously irradiated may be eligible for re-irradiation with proton therapy, provided the geometry of the recurrent tumor allows adequate sparing of the visual system. Two previous series suggest a significant salvage rate with reirradiation to conventional doses. However, temporal lobe and visual system damage remain concerns in this group of patients - risks that may be minimized with proton stereotaxy.
Inquiries regarding pituitary irradiation with proton therapy may be made to Dr.Swearingen (617) 726-3910, Dr. Klibanski (617) 726- 3874, or to Drs. Loeffler and Thornton (617) 726-8150