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Radiotherapy for nonfunctioning pituitary adenomas: from conventional to modern stereotactic radiation techniques

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Abstract

The initial management of nonfunctioning pituitary macroadenomas (NFAs) is usually surgery; however, a significant proportion of NFAs may require further treatment. Radiotherapy is currently used in patients with residual tumour and achieves excellent long-term control, but there are concerns about potential late toxicity. Stereotactic radiotherapy, both in the form of radiosurgery or fractionated stereotactic radiotherapy, has been developed as a more accurate technique of irradiation with more precise tumour localization and consequently a reduction in the volume of normal tissue, particularly the brain, irradiated to high radiation doses. A review of the literature suggests that new radiation techniques offer safe and effective treatment for recurrent or residual pituitary adenomas; however longer follow-up is necessary to confirm the excellent tumour control and the potential reduction of long-term radiation toxicity. Currently, radiotherapy has an important role in patients with residual or progressive disease after surgery. Patients with small or no residual tumours after surgery may generally continue on a policy of surveillance without immediate irradiation, in order to avoid the potential toxicity of treatment.

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Acknowledgements

This study was supported by the Neuro-oncology Research Funds of University of Rome “la Sapienza”.

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Authors and Affiliations

  1. Department of Clinical Oncology, Neurooncology Unit, S Andrea Hospital, University “La Sapienza”, Rome, Italy

    Giuseppe Minniti, Mattia Osti & Riccardo Maurizi Enrici

  2. Department of Neurological Sciences, Neuromed Institute, Pozzilli (IS), Italy

    Giuseppe Minniti, Marie-Lise Jaffrain-Rea & Giampaolo Cantore

  3. Department of Experimental Medicine, University of L’Aquila, L’Aquila, Italy

    Marie-Lise Jaffrain-Rea

  4. Department of Clinical Oncology, S Andrea Hospital, Via di Grottarossa, 1035, 00189, Rome, Italy

    Giuseppe Minniti

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  1. Giuseppe Minniti
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  2. Marie-Lise Jaffrain-Rea
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  3. Mattia Osti
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  4. Giampaolo Cantore
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  5. Riccardo Maurizi Enrici
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Correspondence to Giuseppe Minniti.

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Comments

William Couldwell, Salt Lake City, USA

The authors have provided an excellent review of the literature on the treatment of nonfunctional pituitary adenomas (NFA) with radiation therapy. The paper discusses standard fractionated field treatments and provides an overview of radiosurgery and newer methods of delivering stereotactic radiotherapy. This is a useful update of the current “state of the art” for all clinicians involved with the treatment of these patients.

The results from multiple series document the excellent control rates with residual or recurrent NFA with radiation therapy, either delivered in single or multiple fractions. The controversy exists as to when to recommend treatment of residual lesion. Our philosophy has been to defer treatment to known residual nonfunctional tumours (or in cases of radiographic complete resection) until there is documentation of growth of the tumour. This is for purposes of delaying radiation-induced hypopituitarism, which manifests in a significant number of patients with long-term follow-up with both fractionated and single treatments (Tables 1 and 2). Deferring radiation until growth is documented also may avoid or delay the small by definite risk of neuropathy to cavernous cranial nerves and optic apparatus. We fully inform patients that offering adjuvant radiation immediately after surgery will reduce recurrence, but we prefer to delay radiation for these reasons. One exception is the patient with a documented aggressive pituitary tumour on previous serial imaging studies, or those with tumours that are aggressive histologically [high MIB-1 fraction (greater than 3% Ki-67 labelling index), extensive p53 immunopositivity (1,2)], in which we may consider early aggressive multimodal treatment.

One other point deserves consideration. As noted by the authors, there is a higher incidence of cerebrovascular accidents in patients who have received radiation therapy for pituitary tumour. I have personally witnessed several recent cases of progressive occlusion of the cavernous carotid artery following SRS for cavernous sinus meningioma. Some of these patients have had severe CVA. Whether this occurs with a higher propensity in patients with cavernous meningioma as compared to other tumours is unknown; but with increasing numbers of patients being treated with SRS or SRT to the cavernous sinus, we must be vigilant and document all long-term related complications of such treatment.

References

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2. Thapar K, Scheithauer BW, Kovacs K, Pernicone PJ, Laws ER Jr (1996) p53 expression in pituitary adenomas and carcinomas: correlation with invasiveness and tumor growth fractions. Neurosurgery 38:765–770

Peter Herbert Kann, Marburg, Germany

I am commenting on the irradiation of pituitary adenomas from the endocrinologist’s point of view.

Pituitary adenomas occur more frequently than often suspected. Referring to autopsy and clinical imaging studies, their prevalence was reported to be up to one in every six people. However, their clinical relevance has to be considered differently. Even if positive by immunochemical analysis for pituitary hormones, they usually are defined as inactive by criteria of clinical endocrinology. A very large proportion of them will never cause symptoms that could be disturbances of the endocrine system–hormonal excess and/or hypopituitarism–or mechanical complications, especially compression of the optical nerve. This huge majority of pituitary adenomas thus will never come to clinical diagnosis, and thus never require treatment. In a recent study, the prevalence of clinically relevant pituitary adenomas was found to be almost 1 in 1,000–more than reported previously. In this cohort, 2/3 were prolactinomas [1].

Specific treatment is required when tumour control is mandatory. The correct assessment of non-functioning pituitary microadenomas may even be analysis of endocrine function, substitution of deficiencies if necessary, and wait and see. Besides surgery, tumour control can be achieved by dopamine agonists in prolactinomas–the treatment of first choice–and in acromegaly, or somatostatine analogues in acromegaly. Radiotherapy may be considered in a minority of patients who fail on treatment options mentioned above.

Minniti et al. report in this issue of Neurosurgical Review on stereotactic radiotherapy, i.e., radiosurgery or fractionated stereotactic radiotherapy. Reviewing literature and considering conventional and stereotactic radiotherapy, they suggest that these new techniques may be safe (safer?) and effective (more effective?). However, they also come to a very important point: Longer follow-up is necessary to confirm tumour control and radiation toxicity.

How long is an appropriate follow-up period? How can toxicity be assessed in an appropriate way?

Agha et al. [2] reported about hypothalamic pituitary dysfunction after irradiation of nonpituitary brain tumours in adults. Two messages of this paper seem to be relevant for considering radiotoxicity: Over an observation period of 15 years, peak stimulated growth hormone as a parameter of function of the somatotrophic axis following insulin-induced hypoglycaemia or glucagon obviously decreased continuously. And, of course, radiotoxicity depended on a biological effective dose. It can be assumed that other pituitary functions may react comparably on irradiation.

Brada et al. [3] investigated cerebrovascular mortality in patients with pituitary adenomas. In their pituitary adenoma cohort, the relative risk of death was 1.58 compared to the general population; relative risk for cerebrovascular death was 4.11. Beyond others, radiotherapy was identified as a possible risk factor. Analysing an observation period of 20 years after radiotherapy, the relative risk for death tended to increase with time from radiotherapy–stimulating me again to require very long follow-up periods to study radiotoxicity.

Ayuk et al. [4] studied increased mortality in acromegalic patients. In 50% of their 419 patients, radiotherapy was performed. The standardised mortality ratio was calculated as 1.26 for the whole cohort. Previous treatment with radiotherapy was associated with increased mortality (relative risk 1.67), with cerebrovascular disease the predominant cause of death (standardized mortality ratio 4.42). The authors conclude that their study highlights the potential deleterious effect of radiotherapy.

From my point of view, indication for radiotherapy still has to be considered carefully including endocrinologists and neurosurgeons into the decision process. If radiotherapy is judged to be the best suitable strategy in an individual situation, it has to be performed consequently. New techniques with the methodical advantages discussed by Minniti et al. should be used. However, follow-up of these patients over a period of 2 decades–maybe longer–is mandatory. It would be helpful to analyse pituitary functions with more sophistication as Minniti et al. did in their review by taking methods of pituitary testing into account, i.e., basal parameters versus stimulation tests, which stimulation test, which protocol, which assay to measure hormones and, which cut off to define pituitary function. To perform a prospective study on this issue would be perfect. This should also include analysis of morbidity and mortality.

References

1. Daly et al (2006) J Clin Endocrinol Metab 91:4769–4775

2. Agha et al (2005) J Clin Endocrinol Metab 90:6355–6360

3. Brada et al (2002) Clin Endocrinol 57:713–717

4. Ayuk et al (2004) J Clin Endocrinol Metab 89:1613–1617

R. Engenhart-Cabillic, M.W. Gross, Marburg, Germany

The authors provided a clear and well-written review of the recent literature concerning methods and effectiveness in radiotherapy of non-secreting pituitary adenomas. They recommend retentiveness in postoperative irradiation after subtotal tumour removal due to its potential late effects.

From a radiobiological view, one can argue that the radiation dose needed to inactivate a tumour exponentially increases with tumour volume. An early beginning of the radiotherapy may be preferable to optimise the local control rate for the given dose. Sasaki and colleagues [2] found in non-secreting adenomas a 10-year control rate of 98%, which was significantly better than the control rates for the secreting adenomas. Whether the adenoma was secreting or non-secreting was the most significant prognostic factor for local control. Repeated computed tomography and magnetic resonance imaging examinations showed that many non-secreting adenomas exhibited a “delayed effect” as tumours continued to shrink years after the completion of radiotherapy. On the other hand, a review of 65 non-irradiated patients with non-secreting adenomas showed a regrowth rate of nearly 50% at 10 years [3].

When comparing the effectiveness of stereotactic radiosurgery (SRS) with stereotactic radiotherapy (SRT), it is important to consider the biologic effect of a large single fraction of radiation. A single fraction of 15 Gy is probably equivalent to somewhere between 56 and 67 Gy of conventional fractionated radiation with a 1.8-Gy fraction, assuming that the ratio of normal brain tissue is in the range of 2 to 3. Stereotactic irradiation has an advantage over conventional external beam radiation therapy in that it can minimise the dose to the adjacent normal tissue by sharply focusing the dose distribution. In addition, SRT has a further radiobiological advantage in that the damage of the normal tissue will be smaller in fractionated irradiation. Despite these considerations, hypopituitarism represents the most commonly reported late complication of radiotherapy, occurring in approximately 30% of irradiated patients after 5–10 years. Other late complications are very rarely seen. A comparison of radiosurgery and stereotactic radiotherapy by Mitsumori et al. [1] revealed 27% adverse effects of nerval function and 23% pituitary insufficiency after radiosurgery versus 0 and 20% after stereotactic radiotherapy, respectively. Therefore, the lower morbidity after fractionated stereotactically guided radiotherapy seems to be preferable and we recommend SRT with conventional fractionation for the treatment of pituitary adenoma whenever possible. SRS can be used in limited situations where normal tissue such as temporal lobe, optic nerve, and optic chiasm can be spared. Special attention should be paid to the dose distribution in the adjacent brain parenchyma should a lesion in the cavernous sinus be treated with SRS.

Until we are able to predict which tumours are likely to regrow, the fact that despite experienced surgical input the only predictive factor associated with a significantly lowered risk of recurrence is radiotherapy administered within 12 months of surgery suggests that this management strategy has to be at least carefully considered in every patient.

References

1. Mitsumori M, Shrieve DC, Alexander E 3rd et al (1998) Initial clinical results of LINAC-based stereotactic radiosurgery and stereotactic radiotherapy for pituitary adenomas. Int J Radiat Oncol Biol Phys 42:573–580

2. Sasaki R, Murakami M, Okamoto Y et al (2000) The efficacy of conventional radiation therapy in the management of pituitary adenoma. Int J Radiat Oncol Biol Phys 47:1337–1345

3. Turner HE, Stratton IM, Byrne JV et al (1999) Audit of selected patients with nonfunctioning pituitary adenomas treated without irradiation—a follow-up study. Clin Endocrinol 51:281–284

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Minniti, G., Jaffrain-Rea, ML., Osti, M. et al. Radiotherapy for nonfunctioning pituitary adenomas: from conventional to modern stereotactic radiation techniques. Neurosurg Rev 30, 167–176 (2007). https://doi.org/10.1007/s10143-007-0072-x

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