Aggressive Pituitary Tumors

I have a problem with the currently fashionable term "aggressive pituitary adenoma" because it is a self-fulfilling diagnosis; it is a term used for pituitary adenomas that "do badly" after therapy. The commendable aspects of the article by Blevins et al relate to their attempt to define clinical, radiologic, surgical, standard histologic, immunohistochemical, and cytogenetic markers that will predict this aspect of aggressive behavior at the time of presentation. To my mind, only after those definitions have been made will the term "aggressive pituitary adenoma" be clinically useful. The deficiencies in their paper relate to the paucity of discussion of optimal multimodality therapy.

Surgery and postoperative radiotherapy lead to high rates of progression-free survival. Brada et al[1] reported that the actuarial progression-free survival rates following such therapy were 94% at 10 years and 88% at 20 years for all patients treated at their institution. For nonfunctioning tumors, the control rates were even higher: 97% at 5 years and 92% at 20 years.

These rates agree with data from other sources indicating that functioning tumors may be slightly less easily controlled than nonfunctioning tumors (although secreting tumors are more easily diagnosed as "persistent"). This last interesting observation should not, however, detract from the overall very high progression-free survival rates achieved when specialized centers treat these tumors with standard surgery and conventionally fractionated radiotherapy. It is with regard to optimal current management that I can add some useful comments to the article by Blevins et al.

When Can Postoperative Radiotherapy Be Omitted?

Radiotherapy is a key therapeutic modality for pituitary adenoma and is recommended following surgery for patients with most macroadenomas.[2] Although there are exceptions to this general statement (eg, the somatotroph adenoma, following the resection of which there is undetectable, or nearly undetectable, serum growth hormone on a day curve and normal IGF-1 levels), the general principle still holds true.

If the techniques described by Blevins et al to define the "aggressive" pituitary adenomas are validated, hopefully it will be possible to omit post-operative radiotherapy in a larger proportion of "less aggressive" tumors without encountering higher relapse rates. For sure, no one wants to irradiate all benign pituitary adenomas, but the historical data,[2] as well as some studies cited by Blevins et al, demonstrate the potentially high relapse rates when radiotherapy is withheld. Without some more accurate predictors of recurrence, it is difficult to select patients who should not be irradiated. The fact that modern magnetic resonance imaging (MRI) techniques enable clinicians to detect recurrences earlier than was possible in the past is also a factor in the physician’s wish to eschew the routine use of radiotherapy--but only if one can predict low-risk patients.

Conventional Radiotherapy vs Stereotactic Radiosurgery

One of the greatest current controversies relates to the choice between conventionally fractionated radiotherapy and stereotactic radiosurgery. The former technique has been validated with regard to high long-term control rates and is safe with respect to optic nerve/chiasm tolerance. It is, however, wider-field radiotherapy than one might wish to deliver to benign intracranial lesions.

The perceived advantages of radiosurgery relate to the faster decline in secretory hormone production and the lower radiation dose delivered to surrounding structures. The proximity of the optic chiasm, however, poses a potential hazard, as the high single doses employed in radiosurgery disproportionately risk this special sensory nerve, if the target volume approaches the interclinoid line.[2] Also, for truly aggressive pituitary adenomas, the extremely tight delivery of dose to part of the fossa may be too limited and risk a higher relapse rate which probably accounts for inferior control rates in radiosurgery series.

The problem is that radiosurgeons usually work and report their data apart from radiation oncologists. As a result, the issue will take a long time to resolve. Once again, the ability to distinguish aggressive from standard-risk pituitary adenomas might well help clinicians choose the best radiation therapy modality for an individual patient.

Optimal Therapy for Prolactinomas

With particular regard to prolactinomas, the distinction of pseudoprolactinomas from prolactinomas and the optimal sequencing of dopamine agonist therapy (which should almost always be given first, before either surgery or radiotherapy,[3] and should be continued for some time after radiotherapy) will yield better results than are predicted by Blevins et al. I doubt that somatotrophin analog (eg, octreotide [Sandostatin]) therapy will result in 50% shrinkage of somatotroph adenomas, although the reduction in hormone product secretion is useful and is predicted by the finding of somatostatin tumor receptors by the octreotide radioisotope scan. It can be stated with confidence that somatostatin analog therapy will not produce the sort of dramatic tumor shrinkages that have been seen almost routinely following dopamine agonist therapy of prolactinomas.

Researchers have, therefore, recently tried to make the somatostatin analogs more potent weapons: By labeling octreotide with yttrium-90, one can achieve a radioisotope analog that has therapeutic potential. The area of yttrium-90-labeled octreotide therapy has yet to be explored but is definitely worthy of mention in the context of aggressive and recurrent pituitary adenomas and carcinomas.

The same can be said for the field of chemotherapy. Here, there is another controversy as to whether the classic Mayo Clinic chemotherapy for malignant apudoma, eg streptozotocin (Zanosar) or some other nitrosourea analog (or doxorubicin) plus fluorouracil (nowadays with folinic acid and some infusional component), has been eclipsed by cisplatin (Platinol)-type malignant neuroendocrine chemotherapy protocols. Both of these types of chemotherapy can cause useful partial responses after some duration of therapy. Again, the subject is relevant to the issue of treating aggressive adenomas/carcinomas of the pituitary.

References:

1. Brada M, Rajan B, Traish et al: The long term efficacy of conservative surgery and radiotherapy in the control of pituitary adenomas. Clin Endocrinol 38:571-578, 1993.

2. Plowman PN: Radiotherapy for pituitary tumors, in Fagin A (ed): Bailliere’s Clinical Endocrinology and Metabolism, pp 407-420. London, Bailliere Tindall, 1995.

3. Plowman PN, Grossman AB: Radiotherapy in the treatment of pituitary tumors. Int J Radiat Oncol Biol Phys 19:229-230, 1990.