Radiotherapy for Pituitary and Hypothalamic Tumours by MikeJenny


									Chapter 14. Radiotherapy for Pituitary and Hypothalamic

      Conventionally fractionated radiotherapy has a long established place in the therapy
      of pituitary adenoma.
      In 1909 Beclere published his famous case report entitled: "the radiotherapeutic treat-
      ment of tumours of the hypophysis. gigantism and acromegaly". In this paper he de-
      scribed the first case:A young girl of sixteen suffering from hypophysomegaly. The
      xrays showed a notable enlargement of the sella turcica. She suffers from violent at-
      tacks of cephalalgia, severe visual troubles, gigantism, genital infantilism and excess
      adiposity . . . "
      Concerning radiotherapy, he wrote:"The seances have now been carried out once a
      week for ten weeks. At each seance, the hypophysis was treated by cross fire through
      four or five different areas on the fronto-temporal region, the skin dose on each being
      3H. The attacks of cephalalgia have completely disappeared. Still important is the
      improvement in the visual troubles."
      Some fifty years ago, in an era before modern MR scanning, Sheline described re-
      currence free intervals at 5 and 10 years of only 25% and 9% following transcranial
      surgery for adenomas of the pituitary. However, with the routine delivery of post op-
      erative radiotherapy, the recurrence free statistic became 79% disease free at 10 years,
      and subsequent data confirmed this protection from relapse. Brada et al (2) found an
      actuarial progression-free survival rate of 94% at five and 88% at ten years (slightly
      worse control rates for secretory than non-functioning adenomas) with the routine
      use of post-operative radiotherapy. Other data have unequivocally demonstrated the
      slow but progressive decline in the circulating hormone product of secreting tumours
      over many years, following conventionally fractionated external beam radiotherapy
      for acromegaly (3), Cushings Disease, Nelson’s syndrome(4,.5) and prolactinoma (6)
      - reviewed below. By observance of careful modern planning and dose prescription
      delivery, the risks to the normal surrounding nervous system should be extremely

      The term radiotherapy refers to the delivery of ionising radiation onto tumours to
      arrest their growth (by DNA damage and preventing mitosis), whilst not destroying
      the structure or function of the surrounding normal tissues. As cellular damage me-
      diated by ionising radiation is not tumour selective, radiotherapy must exploit other
      differences to enhance the therapeutic ratio and clinical effectiveness.
      The first and most obvious objective is to deposit more radiation on the tumour than
      on the surrounding normal tissues - this is achieved by careful planning techniques.
      In conventional radiotherapy, it is usual practice to make an individually constructed
      mask to immobilise the patient’s head and then to bring in at least three beams from
      different directions to ’cross-fire’ the pituitary/tumour and thus concentrate the dose
      on the target, whilst sparing the normal surrounding structures that do not lie in this
      tight cross-fire zone.
      Nowadays, linear accelerators generating megavoltage photon beams are employed.
      These are deeply penetrating beams with higher doses at depth, per unit dose de-
      posited on the surface/skin than the old-fashioned deep X-ray therapy machines
      (DXT orthovoltage). The megavoltage, linear accelerator generated beams are also
      much better collimated than DXT beams (i.e.less side scatter to adjacent organs). The
      three usual beam directions are from an antero-superior approach and two lateral
Chapter 14. Radiotherapy for Pituitary and Hypothalamic Tumours

           approaches, but in some of the newer stereotactically mapped or IMRT techniques
           there are up to five or six beams approaching from more directions, and each util-
           ising microcollimation to shape or conform the beam to the patient’s tumour/target
           volume. In Tomotherapy the beam is a continuous spiral and the thin ‘fan’ beam is
           modified in its dimensions continuously throughout therapy to more sophisticatedly
           conform the high dose of treatment to the individual tumour’s dimensions – this is a
           form of Intensity Modulated Radiation Therapy (IMRT).
           The second feature to improve the clinical efficacy of radiotherapy is the delivery
           of the total radiation dose in a small number of ’fractions’. It has been known for
           some ninety years that fractionation (the splitting up of a large total dose into small
           daily doses - fractions) allows more sparing to the normal tissues than to tumours.
           Normal tissues are under homeostatic influences to sense and repair cellular dam-
           age/depletion whereas tumour cells have lost this sense – Thus, fractionation allows
           a differentially damaging effect to be unleashed on the tumour versus that on normal
           tissues (with repair capacity).
           For all the above reasons, patient are currently treated, immobilised in an individu-
           ally constructed plastic mask. A dose prescription of 45 Gy is delivered in 25 fractions
           of 1.8 Gy each on week-days over five weeks.
           Note that all this :- fractionation and multiple cross-firing portals is, in principle, what
           Beclere was practising 100 years ago, albeit with the old-fashioned orthovoltage x-ray
           "Stereotactic radiosurgery" is a more recently introduced radiotherapeutic treatment
           method for pituitary adenoma and is a generally less understood mode of radia-
           tion therapy outside interested radiotherapy or neurosurgical circles. Its potential has
           only been realised in the last few years, since the advent of high Tesla MRI facilities
           and the increased sophistication of the planning and treatment hardware. Stereotac-
           tic technology allows precise target definition, and thereby allows concentration of
           the treatment beam of radiation more specifically on the mapped target (e.g. a dis-
           creet target within the pituitary fossa). There are several methods of delivering this
           therapy. The first is a charged particle beam (protons) that allows the precise deposi-
           tion of dose due to manipulation of the Bragg peak; as this method is not generally
           available, it will not be further discussed here.
           The other methods employ megavoltage photons and are rather more generally
           available. This is the exact same modality of ionising radiation therapy that
           conventional linear accelerators generate - the point being that there is no difference
           in the radiobiological interaction/relative biological efficacy of the beams employed
           in radiosurgical methods vis a vis conventional radiation therapy. The difference lies
           in the exactitude of the targeting (no margin of "safety" taken around the lesion) and
           the sharp "fall-off’ of dose at the edge of the radiosurgical treatment volume - i.e.
           better sparing of adjacent normal structures. Consequently, a single large dose of
           this photon radiation can safely be deposited because surrounding normal tissues
           are not subjected to such a large percentage of the prescsribed dose. Such a large
           single dsoe is more cytocidal than a similar total dose of fractionated radiation.
           The first method is the Swedish gamma unit (Gamma Knife, Electa instruments, AB
           Linkoping, Sweden), a second method is the linear accelerator method (the planning
           software acquiring the name: "x-knife" Radionics, Mass, USA) and latterly the Cy-
           berknife (Accuray, USA) has entered the field.
           In the current gamma unit (Gamma Knife), there are 201 fixed cobalt sources, each
           as a thin rod of l mm diameter, the long axis of which is oriented along a radius of
           a hemisphere (the helmet into which the patients head fits for therapy). The centre
           point (or isocentre) of this hemisphere is the point at which the stereotactic coor-
           dinates of the mapped intracranial target are positioned, and the 201 emissions are
           thereby simultaneously concentrated on this target. The patient’s head is rigidly con-
           fined within four bars of a pinned stereotactic frame – pinnend to the head under
           local anaesthetic. By using a combination of different ‘shots’ a highly conformal dose
           plan is achieved, bespoke for even the most irregular shaped target volume.

                             Chapter 14. Radiotherapy for Pituitary and Hypothalamic Tumours

     Many centres (particularly neurosurgical units possessing Gamma Knife technol-
     ogy) are moving from conventional, fractionated radiotherapy to stereotactic radi-
     ation/radiosurgery by single dose Gamma Knife methodology for the post operative
     therapy of pituitary adenoma. For example, the MR delineated residuum that lies in
     the cavernous sinus – a difficult place for the surgeon to clear in trans-sphenoidal
     surgery – represents an excellent example of the ‘good target’ that Gamma Knife can
     ‘focus on’ and upon which it can deliver an obliterative dose of radiation safely. The
     method seems less attractive when the whole pituitary fossa and adjacent tissues are
     at risk of tumour regrgowth and here conventional radiotherapy still scores better
     – Neurosurgeons working with Gamma Knife, in isolation from good radiotherapy
     facilities, may be reticent to concede this point.
     The $65 million question is: which method is best? Early Swedish Gamma Knife data
     on the outcome of treating pituitary adenoma were not persuasive for the use of
     Gamma Knife technology (reviewed in a separate section later in this manuscript),
     but latterly the coupling of modern MR imaging into the planning process and the
     improved technology of the equipment has allowed a much more sophisticated pro-
     cess to more accurately deliver high focused radiation onto more certainly imaged
     targets; we therefore may be able to discount the relatively poor early results. Al-
     though the Gamma Knife data are not as mature as the conventionally fractionated
     radiotherapy results, nevertheless, it has become a popular and effective alternative
     . The Cyberknife is probably a rival to the Gamma Knife but the data on therapy for
     pituitary adenoma is still to be forthcoming.
     The l linear accelerator method again involves the stereotactic mapping. Verhey et al
     (1998) noted that the conformity index (the "moulding" of the high dose isodoses to
     the target volume) was considerably better on the gamma unit than the x-unit, but at
     the cost of a higher internal dose gradient. Plowman and Doughty (1999) took these
     observations further with specific reference to pituitary adenomas. The usual clini-
     cal situation in pituitary adenoma radiotherapy is for the target volume to abut the
     hypothalamus and optic chiasm. These workers compared the optimal dose plans
     for both technologies. They found that the gamma unit gave the faster fall-off on the
     rostral border (fig 1). This is important; Plowman and Doughty found that, for exam-
     ple, whereas the optic chiasm might receive 20% of the marginal adenoma radiation
     dose on the linac radiosurgery plan, it only received 10% on the gamma unit (Gamma
     Knife) plan. Taking this further, to illustrate the importance of this difference, one can
     imagine a typical patient referred to a radiosurgical facility with a recurrence of ade-
     noma following previous surgery and radiotherapy (during which the optic chiasm
     has received full dose). The recurrent tumor comes to within 5mm of the chiasm and
     the treating clinician is faced with delivering a therapeutic radiosurgical dose to the
     recurrent tumour without overdosing the previously irradiated and highly radiosen-
     sitive chiasm. We normally try to keep the dose to the chiasm down to 250 cGy or
     less in this circumstance. That the gamma unit allows us to deliver twice the dose to
     the tumour margin for the same dose to the chiasm is obviously advantageous in this
     circumstance; the fact that there is a higher internal dose gradient to the centre of the
     tumour is also advantageous and so, on both counts, the gamma unit is preferred (fig

     A study of the usefulness of conventionally fractionated radiotherapy for pituitary
     adenoma associated with acromegaly was reported by Cicarelli et al (1998). These
     workers followed a cohort of patients, treated by the modern three field, linear accel-
     erator method, using a prescription of 45Gy in 25 fractions over 35 days (exactly as
     we now still prescribe). Seventy three patients were followed long term, 61 unoper-
     ated and 12 post-operative patients. All data points of growth hormone measurement
     were performed off medical therapy. The importance of this single institution series
     is that it included some relatively advanced cases that would not nowadays be diag-
     nosed so late in the course of their disease - due to advances in imaging and manage-

Chapter 14. Radiotherapy for Pituitary and Hypothalamic Tumours

           ment. Thus the mean pre-radiotherapy serum GH level was 103 +/- 14 mU/l, (51.5
           +/- mU/l) - *to convert mU/l to <61549>g/l divide by a factor of three. Following
           radiotherapy, a slow but progressive decline in the GH level occurred over the next
           decade such that the GH level at the ten year follow up point was 12.2 +/- 2.4 mU/l
           (6.1 +/- 1.2 mU/l). Furthermore, in 31 patients who had been followed for more than
           10 years there was a significant further fall in the next five year period. These data
           are important and are complemented by other data, all of which confirms the pro-
           gressive fall in GH; the level of GH is approximately 50% of the baseline figure by
           two years post-radiotherapy and 25% by five years.
           More recently, Jenkins et al (1999) pooled data on 372 conventionally irradiated
           acromegalic patients to present a modern series of results. The mean baseline GH
           level was 24.2 mU/l which fell to 12.5 mU/l by two years and 7.8 mU/l by five
           A level of serum GH of less than 5 mU/l (the target ’safe’ level, associated with a
           normal age-related serum IGF-1) was achieved in 44% by five years and 59% by ten
           years and 100% by twenty years. Given that over 50% of the fall in the GH occurs in
           the first two years, it is obvious that the patients with the lowest initial GH levels will
           achieve this clinically useful definition of ’cure’. In the series reported by Jenkins et
           al (1999), 70% of those who had an initial, pre-radiotherapy GH level of less than 10
           mU/l had achieved a GH of less five by 1.7 years, whereas 45% of those whose initial
           GH level was between 10 and 30 achieved this but after 4.7 years. In those patients
           who presented with a GH of more than 60 mU/l, only 31% had achieved a GH level
           of under 5 mU/l by 7.6 years. Larger tumours tend to be correlated with higher GH
           levels in the serum and are anyway less easy to permanently control by radiotherapy,
           thus arguing for primary surgery for larger tumours and higher serum GH levels.
           Thus only a small, intrasellar, growth hormone secreting adenoma, where the GH is
           less than 20 would one routinely consider primary radiotherapy. In unfit patients,
           the indications for primary radiotherapy obviously broaden, but interim medical
           therapy with somatostatin analogues will be required. Radiotherapy is used in the
           post-operative situation where there is macroscopic residuum, a very large tumour
           at the outset and where the post-operative GH level remains raised.
           Following the introduction of the IGF- 1 assay, some authorities advocated the mea-
           surement of this rather than GH in the response assessment. Powell et al (2000) re-
           ported that more than 60% of patients achieved a normal IGF-1 level at ten years
           after radiotherapy which increased to 80% on longer follow-up. Biermasz et al (2000)
           reported that 70% of patients at ten years and 84% at fifteen years had achieved nor-
           mal IGF-I levels. Jenkins et al (1999) reported normalisation of IGF-I levels in 27% of
           patients by 3 years, 53% by 7 years and 56% by 10 years after radiotherapy. However,
           IGF- 1 for GH is not a simple substitution. Whilst there is a statistical correlation
           between a single IGF-l level and a mean GH day curve value, it must be remem-
           bered that other factors may affect the IGF- 1 result, for example hepatic function
           and diet and also that some recent data suggest that it is local paracrine/autocrine
           IGF-1 production/concentration rather than serum concentrations that mediate the
           growth promoting effects of GH. Thus, GH assessment of the response of acromegaly
           to therapy will continue to be employed, as well as serum IGF-1 .
           There appear to be no differences in the response of tumours that co-secrete prolactin
           as well as GH as compared to the pure GH secreting tumours. However, there is
           another phenomenon going on in the post-irradiation period which influences the
           results of serial monitoring of prolactin levels. Whilst tumour derived prolactin levels
           fall progressively, post-radiation effects on the hypothalamus lead to damage to the
           dopaminergic, inhibitory control over the pituitary lactotroph cells with a consequent
           tendency for the prolactin levels to rise (Cicarelli et al l 989), although this usually
           gradually then returns to normal over time.

                            Chapter 14. Radiotherapy for Pituitary and Hypothalamic Tumours

     Most authorities would now agree that dopamine agonist medical therapy is first
     line therapy for patients with prolactinomas. However, whether the long term use of
     such medical therapy is optimal management is more questionable, given the risks
     of tumour rebound on discontinuation of therapy, and, for women contemplating
     pregnancy. the risk of tumour swelling during pregnancy.
     Surgery is excellent therapy for pro lactinomas, used after medically induced shrink-
     age of the tumour back into the fossa but the long term cure rates of surgery, particu-
     larly for macroadenomas has been suboptimal and recurrence is common. There are
     now good data supporting the use of radiotherapy in the achievement of long term
     A study from St Bartholomew’s Hospital , reported by Tsagarakis et al (1991), de-
     scribed the long term outcomes of 36 women who had been irradiated for prolacti-
     noma and followed. Twelve patients had macroprolactinomas and 24 had micropro-
     lactinomas; all prolactin data were assessed off dopamine agonist medical therapy.
     Before radiotherapy, serum prolactin levels ranged from 1150 to 34,000 mU/I (57
     to 1700ng/ml). After radiotherapy, with a mean follow-up of 8.5 years (range 3-14
     years) the serum prolactin fell to normal (Less than 360 mU/l) in 18 of 36 patients
     (50%) and to just above normal (in the 378-780 mU/I range) in a further 10 patients
     (28%). In two patients the prolactin levels rose and in one there was evidence of tu-
     mour progression on scan. Twenty three per cent of patients developed post radio-
     therapy gonadal deficiency, 94% GH deficiency and 14% TSH and ACTH deficiencies.
     The authors concluded that there was a progressive fall over time in the serum pro-
     lactin levels, and no growth on scans, in the vast majority of patients demonstrating
     the efficacy of this form of therapy in prolactinoma patients.
     Although many clinicians have, in the past, treated microprolactinoma patients with
     radiotherapy, to restore menses and allow conception off dopamine agonist therapy
     and free from the risks of pregnancy induced tumour growth, this treatment method
     is now usually reserved for macroprolactinomas.
     In a minority of patients receiving conventional radiotherapy for pituitary adenoma,
     the serum prolactin may rise in the late follow-up period due to radiation effects on
     the hypothalamo-pituitary inhibitory pathway on the pituitary lactotroph, as men-
     tioned above. Such rises are relatively small but can serve to confuse the interpre-
     tation of hormonal data in the follow-up period of all pituitary adenoma patients,
     including prolactinoma patients.

     It has been established for some thirty years that radiotherapy is useful in the man-
     agement of pituitary dependent Cushing’s disease. Orth and Liddle (1971) reported a
     relatively low remission rate but Ross et al (1979) and Lamberts et al (1980) reported
     that 50% and 52% of patients followed for a mean of 4 and 6.5 years respectively
     achieved a remission after radiotherapy, albeit in combination with medical therapy;
     the use of medical therapy and the use of adrenalectomy being potential ’obscur-
     ers’ of long term efficacy of radiotherapy. A study of the usefulness of conventionally
     fractionated radiotherapy in Cushing’s disease and Nelson’s syndrome was reported
     from St. Bartholomew’s Hospital (Howlett et al 1989). These workers studied 52 pa-
     tients with Cushing’s disease or Nelson’s syndrome followed long term after radio-
     therapy. All patients had been treated by modern linear accelerator technology and
     to 45Gy in 25 fractions over 35 days. Twenty one patients had received radiotherapy
     as primary therapy for their Cushing’s disease, all having achieved initial normali-
     sation of circulating cortisol levels and complete medical remission on metyrapone
     medical therapy, and were under follow up with a mean interval of 9.5 years after
     Twelve of the twenty one patients (57%) were off all medical therapy and in clini-
     cal remission with a normal mean cortisol levels throughout the day. However, only
Chapter 14. Radiotherapy for Pituitary and Hypothalamic Tumours

           two demonstrated completely normal plasma cortisol responses to dynamic testing.
           Medical therapy requirements progressively fell and only four patients were still
           on medical therapy, although five patients had undergone some alternative therapy
           adrenalectomy or transsphenoidal hypophysectomy because of inadequate control.
           Fifteen patients received radiotherapy for Nelson’s syndrome developing after bi-
           lateral adrenalectomy and had been followed for a mean of 9.6 years. Fourteen of
           these fifteen patients had responded with progressive depigmentation, shrinkage of
           the adenoma on scanning and a median ACTH level reduced to 16% of the original
           pre-radiotherapy value. Of nine patients who received radiotherapy after unsuccess-
           ful transphenoidal surgery, five were of all therapy at an early mean follow up point
           of three years, and of four who received prophylactic radiotherapy after transsphe-
           noidal surgery only one had subsequently developed Nelson’s syndrome.
           This publication by Howlett et al was important in that it was a relatively large series
           of patients followed long term after modern radiotherapeutic therapy. It established
           that radiotherapy has a definite role as primary or second-line therapy for Cushing’s
           disease and successfully achieves long-term control of the hyperpigmentation and
           tumour enlargement in Nelson’s syndrome.

           In the last decade, several surgical series have demonstrated that, with earlier di-
           agnosis of pituitary tumours in the modern scanning era, and following modern
           transsphenoidal surgery, there are some patients who have a low risk of later relapse
           and do not require post-operative radiotherapy. In a predominantly surgery only se-
           ries, Laws and Thapar (32) found ten year recurrences of 8% for acromegaly, 12% for
           Cushing’s disease, 17% for functionless pituitary adenoma and 24% for prolactinoma.
           Comtois et al (33) reviewed a large series of functionless tumour patients treated by
           operation alone and found a 21% recurrence rate at 6 years. In a more recent se-
           ries Lillehei et (34) looked at 32 functionless patients who had radical resections and
           no post-operative tumour identifiable on post-operative scanning (MR). There were
           only 6% recurrences at 5.5 years - both relapsing patients being salvaged by radio-
           therapy at the time of relapse. However, in 1999, a counterweight opinion came from
           Oxford (Turner et al 1999) - a centre with acknowledged expertise in pituitary ade-
           noma management. A cohort of 65 patients were reported with functionless pituitary
           adenomas who had undergone radical surgery, without post-operative radiotherapy
           and by one specialist surgeon. The lifetable analysis of the group demonstrated an
           18% recurrence rate at 5 years but 44% at ten years. Thus, from the modern literature,
           one can assess that following surgery alone for pituitary adenoma there is an up to
           20% risk of recurrence at five years and up to 44% risk by ten years
           Clearly, the surgeon’s report and post-operative MRI scans are of importance in se-
           lecting patients for a careful ’watch" policy but we know from secretory tumour hor-
           mone data that the surgeon’s assessment is imperfect. Serial MRI scanning in follow-
           up is mandatory in such patients. For patients with secretory adenomas, there are
           hormone markers and the definitions of endocrine cure are largely agreed. These
           have been the post-operative parameters by which we have assessed the need for
           post-operative radiotherapy until recently.
           Nowadays. the concept of prospectively defining "aggressive " adenomas is a poten-
           tially important one. The first criterion is that of invasiveness, several studies demon-
           strating that this correlates with higher relapse rates (35-37). MRI/CT scans help to
           define invasiveness: cavernous sinus invasion can be concluded with certainty if the
           tumour encircles the intracavernous carotid artery and complete erosion of the dor-
           sum sellae/clivus indicates invasiveness (over a pressure only effect) and presence
           of tumour within the sphenoid sinus indicates more than a pressure effect on the
           fossa floor. Adenomas infiltrating parasellar tissues including dura, bone, cavernous
           sinuses, paranasal sinuses, subarachoid space and leptomeninges are obviously in-
           vasive/aggressive. However, in one study by Selman et al (38), it was found that
           there was microscopic evidence of dural invasion in 88% of intrasellar macroadeno-
                            Chapter 14. Radiotherapy for Pituitary and Hypothalamic Tumours

     mas and 94% ofthose with suprasellar extension: this suggests that dependence upon
     this criterion alone would overestimate the need for radiotherapy - and ann also that
     the "cottage-loaf" effect through the diaphragma sellae is usually associated with mi-
     croscopic infiltration of this structure. Otherwise, routine histology (including the
     morphology of constituent cells) is not of great help in the definition of aggressive
     adenomas (39).
     A number of immunohistochemical staining techniques have been studied in this
     regard. Specifically, determination of proliferation rates of pituitary adenomas by
     immunohistochemical detection of PCNA, Ki-67 and MIB-l have been reported to
     be positive in those tumors that will prove to be "aggressive" (40-45). For example
     Thapar et al (44) demonstrated that there were higher mean proliferative indices in
     invasive adenoma ( and pituitary carcinoma), when they employed MIB -l immuno-
     histochemistry to study the proliferation rates among 70 patients. The implication
     of their results, as would be as anticipated, is that the growth fraction of pituitary
     adenomas predicts clinical behaviour.
     Other work suggested that decreased immunohistochemical staining for nm-23 (a
     purine binding product of a metastasising suppressor gene) may be another predictor
     of aggressive behaviour (46). p-53 expression, overexpression of epidermal growth
     factor and increased protein kinase activity may all also correlate (47-49).
     However, the absence of immunoreactivity for the tumour suppressor gene product,
     p-27, whilst correlating with tumour malignancy, did not prove useful in defining
     aggressive or recurrent adenoma in one recent study (50).
     The next logical step is to select the immunohistochemical predictors of aggressive
     behaviour that most closely correlate with recurrence rates and integrate them with
     the previously mentioned criteria for selecting the need of post-operative radiother-
     When post-operative radiotherapy is recommended, and in our current practice this
     includes all patients presenting with large tumours or features of invasiveness, as
     outlined above, it is our current policy to normally select conventionally fractionated
     radiotherapy. Such radiotherapy concentrates the beam on the target volume (the
     whole fossa and any tumour extension beyond) by a "cross-fire" technique of several
     portals, each pointing at the target and with the patient immobilised in a tight fitting
     mask. These portals are conformed to irregular shaped volumes. Stereotactic radio-
     therapy techniques such as the Gamma Knife are used for specific well delineated
     targets (areas of known residual disease that are well demarcated on MR).
     In summary, radiotherapy is less de rigeur in the post operative setting than ten to
     twenty years ago and the widespread availability of surveillance MR imaging has
     rendered this a safer policy – as relapses can be picked up earlier. Nevertheless, ra-
     diotherapy is an effective means of reducing the recurrence rates (and controller of
     uncured endocrine syndromes) in pituitary disease and should be a well studied and
     practised subject.

     There are several potential complications to pituitary radiation, due to the nature
     and radiosensitivity of the pituitary itself and to that ofthe adjacent delicate nervous
     system: optic pathway and hypothalamus in particular.
     The reason that radiotherapists now confidently assert that the risks to the optic chi-
     asm are low is that the pathological basis for radiation morbidity to the chiasm via its
     vasa nervorum is better understood. Not surprisingly, the major factors in the radia-
     tion prescription that contribute to the morbidity risks are the total dose and the dose
     per fraction. Whilst employing radiotherapy for pituitary adenoma in a dose range
     of 4200-5900 cGy in Boston in 1963-1973, Harris and Levine (7) found radiation in-
     duced optic neuropathy in 4 out of 55 patients, but in none who received a daily dose
     per fraction of less than 250 cGy. Aristazabal et al (8) reviewed 122 patients treated
Chapter 14. Radiotherapy for Pituitary and Hypothalamic Tumours

           for pituitary adenoma with radiotherapy and found optic neuropathy in 4 cases - all
           four patients occuring in a subgroup of 26 patients who had received more than 4600
           cGy total dose and all four patients had received a daily dose of more than 200 cGy
           per fraction. Several other publications support the conclusion that large daily dose
           fractions put the optic chiasm at greater risk (9-12). A long-term, tumour compressed
           chiasm with optic atrophy on fundoscopy prior to radiation therapy must be a more
           vulnerable one. In the modern era these late visual sequelae should be of historic in-
           terest only, but they nevertheless serve to warn us of the dangers of badly conducted
           radiotherapeutic practice
           In the last decade there are few recorded instances of such damage in the conven-
           tional radiotherapeutic literature and this testifies to the now general acceptance of
           these dose limitations for safety. In single arm series, using conventionally fraction-
           ated (200 cGy/ day or less) radiotherapy, Brada et al (2) recorded two cases of late
           and otherwise unexplained visual deterioration in a series of 411 patients treated
           with doses up to 5000 cGy (neither led to blindness). Jones (13) found no cases of late
           optic neuropathy in 332 patients treated to 4500 cGy in 180 cGy daily fractions. The
           perception of the risk of current standard conventionally fractionated dose prescrip-
           tion radiotherapy causing optic pathway damage should now be revised.
           The total dose prescribed and probably the dose per daily treatment fraction are also
           the major factors determining the risk and speed of onset of any radiation induced
           hypopituitarism (15,16). This risk increases with time after therapy. The GH axis is
           the most sensitive to the late effects of radiotherapy (17), the radiation induced de-
           fect occurring largely at hypothalamic level (1 8). Rises in prolactin post-radiotherapy
           also have their origins at hypothalamic level (19) as may the observation of occasional
           early or accelerated puberty post-pituitary radiation (20,21). The gonadotrophin and
           corticotrophin axes are the next most sensitive to radiation damage, the TSH axis is
           least sensitive, and diabetes insipidus very rarely occurs. The reasons for this rank or-
           der of sensitivity to radiation is not known. As O’Halleran and Shalet (14) point out,
           the observation that radiation induced changes occur at hypothalamic level is rele-
           vant to therapy: it may be physiologically advantageous to treat gonadotrophin defi-
           ciency by pulsatile gonadotrophin secreting hormone and GH deficiency by GHRH
           The overall incidence of hypopituitarism is greater the more disturbed the pitu-
           itary function is prior to radiotherapy (i.e. tumour or surgery related). These fac-
           tors temper the acceptance of exact ’percentage" statistics on the incidence of post-
           radiotherapy hypopituiarism. Nevertheless, in our patients with acromegaly , 25%
           required new endocrine replacement therapy by five years after radiotherapy and the
           need continued to rise in the next five years (22). Feek et al (23) reported that by 10
           years post radiotherapy, 47% of patients were hypogonadal, 30% were hypoadrenal,
           and 16% were hypothyroid. These incidences were 70%, 54% and 38% respectively
           when surgery preceded radiotherapy.
           Whether the late risk of carcinogenesis is as high as 1-2% remains contentious (13,
           24-26). In a long-term follow-up study of 334 patients treated for pituitary adenoma
           by radiotherapy, Brada et al (24) described the development of two gliomas, two
           meningiomas and one meningeal sarcoma, concluding that there is an increased risk
           of developing second tumours following this procedure of 1.9% at 20 years. Tsang et
           al (25) observed the occurrence of four gliomas (two in the brainstem) in the long-
           term follow-up of 367 irradiated pituitary adenoma patients. Jones (18) reported the
           occurence of one glioma, one petrosal spine tumour and two cases of myelogenous
           leukaemia ( one acute and one chronic) in the late follow-up of 332 irradiated pi-
           tuitary adenoma patients. However he observed the occurrence of one glioma in
           an equal group of unirradiated pituitary adenoma patients and warned of use of
           background population statistic comparisons, rather than disease specific groups,
           advice which has been reinterated (27) and which may seem more pertinent in this
           age of GH tumour-growth-factor research. Bliss et a] (28) observed one malignant
           brain lymphoma in a patient who had also previously undergone chemotherapy for
           Hodgkin’s disease, and one meningioma in the long-term follow-up of 193 irradi-
           ated pituitary adenoma patients. If we total these four series, we find that, in the
                       Chapter 14. Radiotherapy for Pituitary and Hypothalamic Tumours

late follow-up of 1226 irradiated pituitary adenoma patients, there have been seven
gliomas, two benign meningiomas (although the Tsang et al reference might not
have recorded benign tumours) and one malignant meningeal sarcoma/parasellar
fibrosarcoma. When compared to background population incidences ( e.g three per
thousand for glioma), albeit with whatever shortcomings these may have due to non
-disease specificity, it is clear that any excess risks are small.
There was a concern, first voiced in the pediatric brain treatment literature, that lo-
calised radiotherapy to this area of brain led to more neuropsychological late changes
than partial brain radiotherapy received by other brain sites or to the whole brain
(28). However, although some workers have explored the possibility of neurocogni-
tive late morbidity following radiotherapy for pituitary adenoma, any changes were
found to be unrelated to radiotherapy (29-31). Grattan-Smith et al (29) from Australia
found more neuropsychological disturbances than expected in pituitary adenoma
patients, but this was unrelated to whether the patients had received radiotherapy.
An English study (30) found poor social adjustment, including mood disorders (31)
related to therapy ( but as part of a multifactorial problem, to which surgery and
hormonal imbalance also contributed). Further research is required before and after
therapy in hypothalamo-pituitary tumour patients.

Figure 1. Top panel: Coronal MRI of pituitary adenoma that is extensive across the
whole fossa and lies only just below the chiasm. The case for radiosurgery here is
weak as conventional radiotherapy will more easily encompass the whole extent
of disease and carry less risk (dose) to the chiasm which is so close to the target

Chapter 14. Radiotherapy for Pituitary and Hypothalamic Tumours

           volume. Bottom panel: Coronal MRJ scan of small discrete pituitary adenoma. If
           surgery is not curative, the optimal radiation therapy method for such a tumour is
           controversial. Whilst stereotactic radiosurgery at first seems ideal for such a well
           demarcated and small lesion, well away from the chiasm, is it too focal for a case
           that surgery has failed to cure and would it jeopardise subsequent conventional
           radiotherapy, for which the ’pedigree’ is better?

           Figure 2. Sagittal MR scans of pituitary adenoma with superimposed Gamma
           Knife isodosimetry. Left panel demonstrates standard isodosimetry with the
           fifty per cent isodose well-encompassing the target/tumour; the optic chiasm is
           outlined in purple and the twenty per cent isodose is seen to just ’touch’ this
           structure. On the right, the added facility of blocking portals facing the chiasm
           has been employed (blocking pattern shown in bottom panel) with the added
           advantage (particularly in a retreatment situation - where the patient has already
           received radiotherapy) viz. the reduction in dose to the chiasm to the ten per cent
           isodose is seen - see isodoses in the top right photo.


           Results and potential for re-treatment.
           It is in the retreatment of previously irradiated cases that this difference is most im-
           portant and it is also this situation where we have used radiosurgery most in the ther-
           apy of pituitary adenomas. In our experience, it is recurrent disease in the cavernous
           sinus (out of radical resection reach of the surgeon) that constitutes the majority of
           referrals for radiosurgery to our unit.
           Kjellberg and Kliman (1979) published a large pituitary adenoma therapy’ data set
           on proton beam radiosurgery with generally good results. In a series of 234 unoper-
           ated pateients with acromegaly, there was a 70% decline in growth hormone levels
                       Chapter 14. Radiotherapy for Pituitary and Hypothalamic Tumours

at one year and this decline continued up to the point of publication at ten years -
a robust piece of supportive data for the technique. In a series of 175 Cushing’s dis-
ease patients, they observed complete cure in 21% and a further 20% were able to
come off all medical therapy. In this current day and age, these early data on very
large numbers of patients treated by radiosurgery are often forgotten and yet repre-
sent probably some of the best results supporting the technique. It is a pity that they
never appeared in a proper peer reviewed definitive journal format and that the pre-
sented endocrine data were insufficient for assessment of the claims, and this detracts
from the weight that can be ascribed to them.
In the first Swedish results on photon therapy for Cushing’s disease, there was a
remission rate of 14/29 (48%) (57) whereas it was only between l0-20% in 21 patients
with acromegaly (58) ( seven of whom had received previous radiotherapy). Some
additional patients were "rescued" by further radiosurgery applications - the risks
of which (or indeed the risks for subsequently required conventional radiotherapy)
were not properly quantified. These poor early photon results have persuaded us to
rely on the conventionally fractionated therapy for routine usage, notwithstanding
the fact that conventional radiotherapy carries the disadvantage of a relatively slow
normal isation of any hormone produced.
However, it is highly likely that these early studies were performed by isolated neu-
rosurgeons practising without great experience of the appropriateness of a highly fo-
cal (often partial fossa) radiation therapy method, versus conventionally fractionated
radiation methods (unavailable to themselves) and with relatively crude radiosurgi-
cal technology.
Pollock et al (59) reported on the results of 35 patients treated with gamma knife tech-
nology. Of 15 treated Cushing’s disease patients 11 were evaluable. Eight patients
developed normal hormone levels and the cortisol was decreased in 2 and increased
in one, but we are told that five patients were still on adrenosuppressive therapy
at the analysis point. Of 8 evaluable patients with acromegaly , serum growth hor-
mone was ’normalised’ in 3 (without definition), decreased in 3 and increased in
two. Two patients out of 35 developed complications in this series : one visual and
one hypothalamic.The incidence of visual complications is perceived to be lower in
current series where a cap of 800 cGy to the chiasm is practised during single fraction
radiosurgery. Park et al (60) reported another series of 27 pituitary patients treated
by gamma knife. In 3/7 patients with acromegaly the serum levels GH returned to
normal and a good response was seen in a fourth patient. In 2/5 Cushings disease
patients, the post-therapy urinary free cortisol returned to normal. In 5/7 prolacti-
noma patients the prolactin reduced to less than 50% the pre-treatment level. The
authors concluded that 6/19 patients with functional pituitary adenomas were hor-
monally cured , by their criteria. At least two other groups have published similarly
unimpressive data (61,62).
Some more recent work appears to demonstrate better results of first-time cure with
radiosurgery. In a recent publication from Zurich, Landolt et al (63) compared a non-
randomised series of 50 patients with acromegaly , presenting with a mean pre-
treatment GH level of 28 mIUIL (14?g/l) and follow-up of 7.5 years having been
treated with conventional radiotherapy, with 16 patients with acromegaly treated
radiosurgically and a mean presenting mean GH level of 18 mlU/L (14?g/l) and
1.4 years follow-up. They concluded that normalisation of GH occurs faster with
gamma knife (and interestingly 70% of the 16 patients achieved this by 18 months)
whereas the same percentage achieved this following conventional radiotherapy but
this took up to 7 years to occur. However, the radiosurgical follow-up is very short
when compared to long-term conventional radiotherapy data, a problem with most
radiosurgery results to date.
In a Virginia (USA) series reported at a recent 1998 London symposium, Laws et
al. found that 58% of 39 Cushing’s Disease patients treated by radiosurgery had
achieved normal urinary free cortisols by 13 months after therapy and that 25% of
56 patients with acromegaly had normal IGF-l levels by 20 months , with others con-
tinuing to improve. The results in their prolactinoma and Nelson’s syndrome patients

Chapter 14. Radiotherapy for Pituitary and Hypothalamic Tumours

           were poor (1 of 9 Nelson’s patients remitting).
           What seems to be emerging is that fast and impressive falls in secretory hormone
           product follow radiosurgery, but that it is not appropriate for every case, (and bad
           initial selection may prejudice later alternative therapy as partial radiation tolerance
           will have been delivered). Once again, no long-term recurrence data were available
           from the large Virginia series.
           In summary, the Zurich data (63), supported by the Virginia results provide good
           evidence of rapid improvement in growth hormone levels following photon radio-
           surgery for acromegaly, and the latter group have provided similar data for Cush-
           ing’s disease. However, no one since the non-definitive, non-peer reviewed work of
           Kjellman and Kliman (1 979), using protons, has published durable control data - this
           is badly required if radiosurgery, as first line radiation therapy, is to gain rountine use.
           Whether late endocrine deficiency sequelae are more or less common than after con-
           ventional radiotherapy is not yet evaluated . On the one hand, large single fractions
           of radiotherapy are perceived to be more damaging to normal tissues such as the
           normal cells of the anterior pituitary. On the other hand, partial fossa radiation tech-
           niques and sparing of the hypothalamus may prove less morbid. For sure, late ante-
           rior pituitary dysfunction may also occur after radiosurgery.
           Late carcinogenesis risks may be imperceptibly different from conventional radio-
           therapy in the surrounding tissues, despite the faster fall-off in dose, due to the fact
           that second tumours tend to occur outside the high dose volume.
           In conclusion, stereotactic radiosurgery gives the clinician another radiation therapy
           tool to use in pituitary adenoma treatment. As primary radiation therapy, we are
           currently wary’ as the technique may, in our opinion, often be too focal (partial fossa
           radiation, when the disease is potentially further afield); long term follow-up data
           on patients treated by radiosurgery as primay radiation therapy is needed, and crite-
           ria for use of this technology for definitive radiation therapy are needed. We believe
           that within the next decade such criteria will be drawn up, and that there will be a
           selected use of stereotactic radiosurgery as primary radiation therapy. Our greater ex-
           perience is in the relapse situation (after conventional radiotherapy) and particularly
           with inoperable relapse of these adenomas in the cavernous sinus. We believe that
           this highly focal modality of radiation therapy has great advantages over all other
           modalities of therapy and we have accumulating evidence of its efficacy.

           Cytotoxic Chemotherapy for recurrent/aggressive or malignant
           pituitary adenoma/carcinoma
           When conventional therapies (surgery/conventional radiation therapy /stereotactic
           radiosurgery) have failed to control the disease, cytotoxic chemotherapy has been
           used with limited success.In the 1980’s, when we first became interested in this
           problem, the standard best palliative chemotherapy for malignant ’apudoma’
           Iineage/neuroendocrine tumours (usually carcinoids) was a combination of a
           nitrosourea and 5-fluorouracil and our reported experience largely relates to this
           chemotherapy regime. We reported seven patients, three with highly aggressive and
           four with frankly malignant pituitary tumours (three with extracranial metastatic
           spread), who received between two and six courses of a chemotherapy regime
           of CCNU/lomustine and 5-fluorourracil/folinate. Two patients, one with an
           aggressive local tumor and one with metastatic spread, obtained symptomatic
           improvement and two of the seven patients obtained a 50% reduction in their
           hormone marker. Over the last five years or so we have substiututed the orally
           active 5-fluorouracil pro-drug: capecitabine for 5-fluourouracil such the regime is
           now all orally active (CCNU and capecitabine).
           Since the 1980’s, the usefulness of chemotherapy based on the drug cis-platinum has
           become more established and the current chemotherapeutic for more aggressiove tu-
           mours (those with a high Ki67 index indicating more cells in active mitotic cycle) is
           with drug combinations which include this drug – cis-platinum and etoposide being
                            Chapter 14. Radiotherapy for Pituitary and Hypothalamic Tumours

     ouir first line therapy in such patients. Although the responses that we have encoun-
     tered in all chemotherapy patients have been relatively short and palliative only, the
     data that we and others have accumulated demonstrate clearly that this disease may
     respond to cytotoxic chemotherapy and that this will continue to have a role in the
     late palliation of better performance patients with advanced disease.

     Craniopharyngioma constitutes 8% of all childhood tumours and 2% of adult tu-
     mours of the central nervous system (CNS) - with a median age of presentation
     of8 years and two thirds of patients presenting before the age of 20 years. Grossly,
     craniopharyngiomas are cystic, solid or partly both, not obviously encapsulated and
     not separated by leptomeminges from the brain parenchyma. Indeed, spread in the
     brain tissues , particularly tuber cinereum and hypothalamus, make radical resec-
     tion potentially hazardous as it is difficult to define surgical planes between tumour
     and critical central nervous system.Thus, while all authorities agree that surgical ex-
     cision is optimal primary initial management, there is persisting controversy as to
     whether radical resection should be attempted due to its significant risk of morbidity.
     However, without radical resection, the regrowth rate of subtotally resected tumours
     is high. In a pooled series of 111 subtotally resected craniopharyngioma patients,
     Amacher found that 75% regrew, requiring further treatment. In a San Francisco se-
     ries, the surgeons considered that they had achieved complete excision in only 10%
     of 74 consecutive craniopharyngioma patients. Thus, it is clear that safe complete
     excision is both difficult to achieve and difficult to forecast even at the end of the
     operation. In patients with incomplete tumour excision, fewer than half survive for
     ten years and 50-75% have recurrent disease within 2-5 years, in the absence of ra-
     Accumulating data heavily support the practice of post-operative radiotherapy. Hei-
     deman and his colleagues pooled the actuarial 5 and 10 year survival rates from
     various series to obtain the following results: 1) "total resection" : 58-100% and 24-
     100%, 2) subtotal excision :37-71% and 31-52%, and 3) subtotal excision and post-
     operative radiotherapy : 69-95% and 62-84% respectively. Additionally, neuropsy-
     chological function was better preserved in the combined modality group. The case
     for post-operative radiotherapy therefore appears to be overwhelming. As for pitu-
     itary adenoma, there has been interest in the use of stereotactic radiosurgery for this
     disease which is clearly a well demarcated volume of benign tumour in the brain
     of usually young patients. The use of such focal radiation technology at first seems
     compelling (Fig 3). However. the optic chiasm usually lies within the treatment vol-
     ume and is likely to receive the full dose of this single high dose technique of radi-
     ation therapy and complications are likely. The problem of recurrent cystic cranio-
     pharyngioma is an occasional but very difficult one for clinicians interested in this
     disease. Beta ion ising radiation has been shown in vivo and in tissue culture in vitro
     to destroy epithelial lining of craniopharyngioma cysts.The early Scandinavian work
     established that instillation of a beta emitting isotope into a craniophayngioma cyst
     resulted in the therapeutically useful reduction in cyst wall secretion. We recently col-
     lated the published experience since that time. From a total of 149 cysts treated, 121
     either reduced in size (and more importantly stopped re-filling) or were obliterated.
     Our own experience to date is with nine cases and we have used 90-yttrium colloidal
     solution to effect the dose to the secreting epithelium of the cyst of 200 Gy (Fig 4).
     The future will undoubtedly hold more for stereotactic delivered radiation therapy
     for solid craniopharyngiomas components and intracystic instillation of isotopes for
     cystic disease.

Chapter 14. Radiotherapy for Pituitary and Hypothalamic Tumours

           Figure 3. Axial CT scans of recurrent craniopharyngioma before (top panels)
           and after (bottom panels) sterotactic radiosurgery demonstrating the complete
           response of this solid recurrence.

           Figure 4. Recurent cystic craniopharyngioma before (left panels) and after (right
           panels) intracystic instillation of 90-yttrium colloidal solution, demonstrating a
           good response on plain lateral skull films with intracystic instillation of contrast
           (lesion arrowed), and CT (left panels) and MR (right panels) scans.

                             Chapter 14. Radiotherapy for Pituitary and Hypothalamic Tumours

      Formerly called Histiocytosis X, LCH is a disease characterised by the aggressive in-
      filtration of tissues by Langerhans cells (a unique subset of macrophages) and in up to
      15% of childhood cases (the commonest age group) diabetes insipidus occurs due to
      LCH affecting the posterior pituitary and hypothalamus. Medical therapy (steroids
      and chemotherapy with agents such as vinca alkaloids or etoposide or immunother-
      apy with cyclosporin) is used as therapy particularly where there is multi-system
      disease. Low dose radiotherapy (1200-1500 cGy in 8-10 fractions) to this brain region
      may be useful in limiting the diabetes insipidus where this defect is the dominant
      problem. Whenever cytotoxic chemotherapy or radiotherapy is to be used for ’be-
      nign’ disease, the pretreatment counselling has to be thorough.

      When sarcoidosis affects the nervous system, the sites of predisposition for
      lesions are the hypothalamus, pituitary and the third ventricle, as well as cranial
      nerves (most frequently the facial and optic nerves) as part of a basal meningitis.
      Diabetes insipidus occurs in 33% of patients with neurosarcoidosis and other
      features of hypothalamo-pituitary dysfunction frequently accompany this, e.g.
      somnolence/sleep disorder, weight gain, impotence/hypogonadism, amenorrhoea
      and panhypopitutiarism. The hypothalamus is the usual site of first involvement in
      this region but the anterior pituitary itself may be affected, although its involvement
      by itself(without diabetes insipidus) is rare. Imaging may demonstrate ’space
      occupying’ granulomata or thickened basal meninges and the CSF may show a
      raised lymphocyte count and protein as well as ACE levels, but importantly may
      also be normal.
      Corticosteroid treatment in high dosage (e.g. prednisolone at 80 mg per day) may
      be useful therapy in the acute labile phase but the disease is not particularly steroid
      sensitive and those patients demonstrating a partial response may need longer term
      maintenance. Isolated reports of responses to low dose equivalent radiotherapy jus-
      tify the inclusion of the problem here although the current author has yet to see a
      convincing response having irradiated two or three patients in a fifteen year period.

      Primary intracranial germ cell cell tumours (IGCT) are rare and most commonly ocur
      in the first two decades of life. The incidence varies geographically; thus, although
      they account for 4-10% of all childhood brain tumours in Japan, the comparable fig-
      ure in the West is 0.2-2%. The annual incidence in the USA is 40 per year.IGCT are
      histologically a heterogenous group of tumours and their clinical presentation also
      differs according to their site of origin. Germinomatous germ cell tumours or ger-
      minomas (GGCT) - the homologue of seminoma - are the most exquisitely chemo
      and radio-sensitive. Non-germinomatous germ cell tumours (NGGCT), comprising
      choriocarcinoma, teratoma and embryonal sinus (yolk sac) tumur and embryonal
      carcinoma have a poorer overall response to therapy and prognosis. Human chori-
      onic gonadotropin-beta (hCG) may be produced by germinomas in small amounts
      but is secreted by choriocarcinoma elements of NGGCT in large amounts. We de-
      scribed that when paired measurements are taken in secreting IGCT, the CSF:blood
      ratio of hCG shows a 10:1 ratio. Alpha-foetoprotein is secreted by yolk sac elements of
      NGGCT. Detection of these markers in the serum or CSF is diagnostically and prog-
      nostically useful. IGCT most commonly occur in the pineal and then the suprasellar
      region at the hypothalamus; less commonly they occur in other midline brain sites.
      Synchronous IGCT occuring at pineal and suprasellar locations is a well recognised
      phenomenon (Fig 5). Whereas there is a definite male preponderance in the incidence
      of pineal IGCT this sex inequality is not found in suprasellar IGCT where there is

Chapter 14. Radiotherapy for Pituitary and Hypothalamic Tumours

           either an equal sex incidence or even a slight female preponderance. In our small
           experience, dual site primaries did show a male preponderance.

           Figure 5. Sagittal MR scans of a dual site intracranial germ cell tumour before
           (left panel) and after (right panel) chemo-radiotherapy, demonstrating a complete
           imaging response (also reflected in normalistaion of markers).

           Suprasellar IGCT represent 30% of all IGCT, are most commonly GGCT and present
           with diabetes insipidus, visual failure and hypopituitarism. Indeed, in our own series
           of 10 cases , diabetes insipidus was invariably present at presentation. Hyperprolacti-
           noma due to stalk disruption was also very common. There was a high incidence of
           abnormalities of thirst, which, in combination with diabetes insipidus, led to some
           serious abnormalities in fluid balance in our series - compounded when we used
           platinum based chemotherapy (for which pre- and post- hydration is mandatory).
           Weight loss due to anorexia was also a feature in our series.
           Diagnosis is nowadays based on MRI demonstrating a midline mass (positive on
           PET scanning unlike benign tumours of these regions) and either diagnostic levels of
           CSF/serum markers and/or biopsy.
           Curative therapy is with chemo-radiotherapy (Fig 5). Traditionally the results of ra-
           diotherapy for this disease have been good but more recently it has been appreci-
           ated that there are differing cure rates within the IGCT spectrum. Sano demonstrated
           from the Japanese data that the prognosis for GGCT was excellent, whereas it was
           poor for AFP/hCG secreting NGGCT. Furthermore, with the increasing success of
           chemotherapy for extracranial germ cell tumours, systemic chemotherapy was found
           to be useful. Our current view is that initial chemotherapy – perhaps four cycles of
           a cis-platinum bsed regime suitable for germ cell tumours followed by radiotherapy,
           perhaps dose reduced where there has been a good clinical response (and particularly
           in GGCT) - is current best medicine. The necessity for whole neuraxis prophylactic
           radiotherapy to all patients is controversial – the present author is still in the phase
           of neuraxis radiation dose reduction in patients with GGCT who have achieved a
           complete response on MRI to the primary chemotherapy regime.

           Secondary cancer (metastatic deposits) occur with a preferential disposition in the
           posterior pituitary and bronchus and breast primary carcinomas are common sites of
           origin. Radiotherapy is the treatment of choice.
           Meningiomas of the sphenoid ridge and cavernous sinus commonly spread across
           the fossa and clivus chordomas and chondrosarcomas similarly. Both may present
                             Chapter 14. Radiotherapy for Pituitary and Hypothalamic Tumours

      with pituitary endocrinopathy. Other conditions include the advanced nasopharyn-
      geal carcinoma that has infiltrated through the skull base and other skull base tu-
      mours of which a plasmacytoma has recently been treated in our unit. Radiotherapy
      has an important role in the management of all these conditions.

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