Peptide receptor radionuclide therapy for aggressive atypicalpituitary adenoma/carcinoma: variable clinical responsein preliminary evaluation

Jillian Maclean • Matthew Aldridge •

Jamshed Bomanji • Susan Short • Naomi Fersht

� Springer Science+Business Media New York 2013

Abstract

Purpose There are limited treatment options for pro-

gressive atypical pituitary adenomas and carcinomas.

Peptide receptor radionuclide therapy that targets somato-

statin receptors has recently been proposed as a potential

treatment option. The theoretical rationale for efficacy is

elegant but evaluation of outcomes in the first patients

treated for this indication is required to assess whether

further study is warranted.

Methods We performed a case review of the three pitui-

tary patients we have treated with 177Lutetium DOTA-

TATE in our institution (two atypical adenomas, one

carcinoma) and dosimetric analysis of the radiation uptake

in one patient.

Results Treatment was well tolerated. One patient with

slowly progressive pituitary carcinoma has stable disease

40 months after completing the planned 4 cycles of treat-

ment. Two patients with rapidly progressive atypical ade-

nomas terminated treatment early due to continued disease

progression. Dosimetric evaluation revealed inhomogenous

uptake across the tumour (1.3–11.9 Gy with one cycle).

Conclusion We have found mixed results in our first 3

patients with stable disease achieved only in the patient

with the more slowly progressive tumour. As only a limited

number of centres offer Peptide receptor radionuclide

therapy, a formal study with prospective data collection

may be feasible and if carried out should include dosi-

metric evaluation of absorbed dose.

Keywords Pituitary carcinoma � Atypical pituitary

adenoma � Peptide receptor radionuclide therapy �Lutetium

Introduction

The vast majority of pituitary adenomas are benign.

However, 2.7–15 % are classified as atypical adenomas,

characterized by increased mitotic activity, a Ki-67 label-

ling index [3 %, and excessive p53 immunoreactivity [1,

2]. Such tumours exhibit a propensity for recurrence and

aggressive behaviour. A further 0.1–0.2 % are true pitui-

tary carcinomas. These are defined by craniospinal or

systemic metastases [1] and need not have aggressive

histological features, but prognosis overall appears poor

with a mean survival of \4 years following the develop-

ment of metastases [3, 4].

Management of relentlessly progressive pituitary tumours

is challenging. Patients generally undergo multiple opera-

tions (transphenoidal and via craniotomy) and radiotherapy/

radiosurgery to residual disease after the first or second

recurrence. Resistance to endocrine therapies, e.g. cabergo-

line or bromocriptine, can develop in tumours that were

initially responsive (generally prolactinomas). Evidence for

further treatments is based on case reports/series with small

patient numbers. Temozolomide is considered the chemo-

therapy of choice as 60 % of pituitary adenomas (n = 18/

30) and 69 % of pituitary carcinomas (n = 9/16) reported in

the literature responded to treatment [5]. An inverse corre-

lation appears to exist between tumour O6-methylguanine-

DNA methyltransferase (MGMT) status and response to

J. Maclean (&) � M. Aldridge � J. Bomanji � S. Short �N. Fersht

University College London Hospitals NHS Foundation Trust,

235 Euston Road, London NW1 2BU, UK

e-mail: jillianmaclean@nhs.net

S. Short

Leeds Institute of Cancer and Pathology, St James University

Hospital, Beckett St, Leeds LS9 7TF, UK

123

Pituitary

DOI 10.1007/s11102-013-0540-y

temozolomide and determination of MGMT expression may

prove a useful clinical decision-making tool [5]. Whilst a few

case reports document disease stabilisation/response to vari-

ous other chemotherapy regimens, these generally appear

ineffective and, although interferon has some effect in pre-

clinical studies, this does not seem to be effective in the

clinic [6, 7]. Surgical implantation of Gliadel (carmustine)

wafers has been reported in nine patients with relentlessly

progressive pituitary adenoma (plus one craniopharyngioma).

At 19 months mean follow-up, three patients had died, four

were disease-free, two had stable residual disease, and one

patient had progressive disease [8]. The potential for post-

operative CSF leak and delayed wound healing, along with

the lack of evidence for therapeutic activity of systemic

carmustine against pituitary adenomas may have limited

development of larger studies. Further investigation may be

warranted into the angiogenesis inhibitor bevacizumab

following a case report of 26 month disease control [9].

Overall, data on systemic agents for this indication are

disappointing.

Somatostatin is a key regulator of anterior pituitary

hormone production and the expression of somatostatin

receptors (sst) in all subtypes of pituitary adenoma, both

functioning and non-functioning, has been consistently

demonstrated [10–15]. The therapeutic value of sst

manipulation with somatostatin analogue therapy early in

the disease process is well established in many types of

functioning pituitary tumours, but resistance can develop

[16]. Such therapy has also been evaluated in non-func-

tioning tumours and although most patients in these studies

achieve stable disease after treatment, patients were gen-

erally treated at an early stage and tumours were typical

adenomas without aggressive features [17].

Sst can be identified in tissue samples with immuno-

histochemistry or the tumour can be imaged with octreotide

scintigraphy or 68Ga-DOTATATE PET/CT, which has

increased sensitivity and a higher spatial resolution [18].

Studies evaluating normal tissue uptake of 68Ga-DOTA-

TATE on PET/CT consistently report that the pituitary

gland reliably shows high uptake, although SUVs vary

[19–21]. Indeed, pituitary uptake on 68Ga-DOTATATE

PET is so reliable that Shastry et al. [22], reported the lack

of pituitary uptake to indicate poor tracer labelling in an

otherwise technically sound study. There is little data

regarding 68Ga-DOTATATE uptake in pituitary adenomas

and no SUV cut-off can differentiate normal pituitary from

adenoma, although there are now reports of the use of68Ga-DOTATATE PET/CT to identify the location of

ectopic ACTH-secreting pituitary adenomas [23].

Peptide receptor radionuclide therapy (PRRT) using a

radiolabelled sst analogue has been used with great success in

neuroendocrine tumours (NETs), particularly gastroentero-

pancreatic (GEPNETs), but smaller case series have also

reported some successful results targeting other tumours that

express sst, including meningiomas [24–26]. There are two

promising case reports regarding the use of PRRT in pituitary

adenomas. Baldari et al. [27] described significant tumour

shrinkage and clinical improvement following administration

of a course of 111In-DTPA-octreotide in a patient with a

recurrent giant prolactinoma resistant to conventional treat-

ment and Komor et al. [28], recently reported symptomatic

improvement and long-term control ([8 years) in a patient

with an atypical non-functioning pituitary adenoma following

therapy with 177Lu-DOTATOC.

However, there are few studies out-with GEPNETS and

publication bias plagues case reports. We have found

mixed results in the three patients with advanced pituitary

tumours we treated with 177Lu-DOTATATE and report

these here, along with the first dosimetric evaluation of

absorbed dose of radiation for a pituitary adenoma.

Materials and methods

Between January 2010 and October 2011, three patients with

advanced progressive pituitary tumours were referred to our

centre for evaluation of suitability for 177Lu DOTATATE

therapy. They underwent 68Ga-DOTATATE PET/CT scan

to establish sst status. No other patients with pituitary

tumours were evaluated. All cases were discussed at the

institution’s brain tumour and nuclear medicine multi-dis-

ciplinary meetings. Treatment with 177Lu-DOTATATE in

patients with sst-positive disease was approved by the local

ethics committee. Each patient gave written informed con-

sent for treatment. Adequate haematologic, renal and hepatic

functions were required.

Patients were admitted into a dedicated in-patient radio-

isotope treatment room. 177Lu-DOTATATE was obtained

commercially (IDB, Holland) and re-constituted in-house.

The regime was administered as previously described for

GEPNETs [24]. The intention of treatment was to administer

a fixed dose of 7,400 MBq of 177Lu DOTATATE. To satu-

rate renal tubular uptake and reduce radiation to the kidneys,

an intravenous amino acid infusion (2.5 % L-Lysine HCl and

2.5 % L-arginine in water for injection 1 L over 4 h) was

commenced 30 min before intravenous administration of177Lu-DOTATATE (delivered over 30 min). Ondansetron

and a short course of oral dexamethasone (8 mg twice daily

for 3 days) were prescribed to counteract nausea and neuro-

axial oedema. An overnight stay following administration

was required for radiation protection purposes, although for

logistical reasons patients stayed 2 nights. Planned treatment

was 4 cycles separated by 8–10 weeks. Full blood count was

monitored weekly for 6 weeks because of the risk of delayed

myelosupression. Tracer uptake scans were performed fol-

lowing each administration. 68Ga-DOTATATE and MRI

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123

scans were performed prior to each cycle and 6 monthly or as

appropriate after completion.

Post-therapy imaging

Whole-body and SPECT/CT images were acquired at 24 h

following 177Lu-DOTATATE administrations. A GE Infi-

nia Hawkeye gamma camera confirmed tracer uptake. A

single bed position covering the head and neck was

acquired immediately after the whole-body image. SPECT/

CT reconstructions were performed using 3-D OSEM with

CT attenuation correction.

Dosimetry

Dosimetry was performed on cycle two for patient 2 to

calculate the mean absorbed dose in tumour for that cycle.

This was carried out according to the standard Medical

Internal Radiation Dose (MIRD) schema [29]:

DT ¼X

h

~AhS rT rSð Þ

where DT is mean absorbed dose (Gy), ~Ah is total cumu-

lated activity (Bq/s) and S is the mean absorbed dose per

unit cumulated activity (Gy/Bq/s). ~Ah incorporates char-

acteristics of both uptake and retention of activity in the

regions of interest. S includes consideration of the types

and energies of the radiations emitted, geometrical aspects

such as the size and shape of the source and target regions

and the distance between them. SPECT/CT was performed

at 19.3, 23.9 and 89.1 h post-adminstration with low-dose

CT attenuation correction. Four specific regions of tumour

uptake were defined and their volumes measured on the

pre-treatment MRI co-registered to SPECT/CT. Total

counts in each region were measured at each time point and

related to cumulated activity ( ~Ah) using a SPECT sensi-

tivity factor (counts/s/MBq) specific to our scanner (pre-

viously determined by 177Lu-DOTATATE phantom

imaging). Time-activity curves for each region were plot-

ted and a MATLAB program used to fit a biexponential to

the curves to derive cumulated activity ( ~Ah) and OLINDA/

EXM software was used to derive the relevant S factors for

the mass of each region of uptake.

Results

All patients had tumour radioisotope uptake on 68Ga-

DOTATATE PET/CT and commenced 177Lu-DOTATATE

therapy. Regions of 177Lu-DOTATATE uptake on post

administration SPECT/CT always correlated with pre-

treatment 68Ga-DOTATATE imaging (Fig. 1).

Case 1

This 63 year old man originally underwent resection of a

non-functioning pituitary adenoma followed by adjuvant

radiotherapy in 1987. He required transsphenoidal surgery

for recurrent disease in 2006. Routine MRI in 2007 dem-

onstrated meningeal thickening throughout the neuroaxis

and multiple small leptomeningeal nodules. As he was

asymptomatic, a surveillance approach was adopted. MRI

in 2009 revealed a significant increase in the number and

size of the leptomeningeal nodules and spinal disease

(Fig. 2). Excision biopsy of a leptomeningeal nodule at

T10 by laminectomy confirmed metastatic pituitary carci-

noma. Surprisingly, the Ki67 remained low at 3 % and

there was no overexpression of p53. The reporting

pathology department is a specialist tertiary referral centre

for pituitary tumours. 68Ga-DOTATATE PET-CT showed

tracer uptake in all regions of tumour identified on MRI

plus several other areas of his neuroaxis, skull and spine.18F-FDG PET CT was also performed and mirrored the68Ga-DOTATATE scan.

He remained asymptomatic and ECOG performance status

0, but there was concern regarding neurological risk from

progressive disease. The patient refused temozolomide

despite discussion regarding its acceptable side-effect profile,

but he was willing to undergo 177Lu-DOTATATE therapy.

He commenced 177Lu-DOTATATE in January 2010 and

completed the planned four cycles. Administered activity was

7,390–7,392 MBq, and the interval between treatments was

12–15 weeks. He tolerated treatment extremely well. On

week 4 of cycle 1 his platelet count dropped to 70 9 109/L

but recovered by week 5. He experienced no other toxicity

and maintained an active lifestyle. No adjustment to his

pituitary replacement therapy was required.

His disease has remained radiologically stable overall

with complete response in some nodules 40 months post

treatment induction (Fig. 3) and there has been a down-

ward trend in the PET SUVmax across the different tumour

regions with the largest bulk disease falling from SUVmax

21.7 to SUVmax 12.9 (Fig. 4). He remains symptom-free.

Case 2

This 42 year old man presented in 2008 with diplopia due

to a large GH and prolactin secreting pituitary macroade-

noma compressing the chiasm and encasing the right

internal carotid artery. Primary treatment was transphe-

noidal debulking, followed by external beam radiotherapy

(50.4 Gy in 28 fractions) to the residual mass, lanreotide

and cabergoline. His disease relentlessly progressed and,

between 2008 and September 2010, he underwent four

further debulking operations including insertion of gliadel

wafers on two occasions. Ki-67 levels increased from 6 to

Pituitary

123

22 % over this time period, p53 was overexpressed

throughout. Temozolomide chemotherapy was stopped

after 2 cycles due to disease progression in August 2010.

He had also received radiosurgery in February 2011. By

September 2011 his disease had further progressed and was

causing brainstem compression. He was effectively blind

due to complete bilateral ophthalmoplegia, chiasm com-

pression and ptosis (ECOG performance status 2). His GH

Fig. 1 a Diagnostic 68Ga

DOTATATE PET images for

each case, b corresponding177Lu uptake imaging

Pituitary

123

level was 10 mU/L with and elevated IGF-1 (he required a

full hypopituitary hormone replacement regime).

Further surgery or radiotherapy was not felt to be pos-

sible. He was transferred to our centre for evaluation of

suitability for 177Lu DOTATATE therapy. The tumour was

intensely avid on 68Ga-DOTATATE PET/CT (SUVmax

34.9). Due to the speed of his disease progression his

treatments were scheduled on a 4 weekly cycle with a stem

Fig. 2 MRI images of small

volume brain and spinal canal

metastases in patient 1

Fig. 3 MRI images of tumour changes over time in patient 1, progressive disease 2007–2009 (pre 177Lu) and stable disease 2009–2012 (after177Lu)

Pituitary

123

cell harvest prior to treatment in view of the unknown

haematological effect of accelerated cycles. He com-

menced 177Lu-DOTATATE therapy in October 2011 and

received 2 cycles (7.8 and 7.5 GBq) 4 weeks apart.

Unfortunately he deteriorated in relation to his brainstem

disease prior to cycle 3 and treatment was terminated. He

died in December 2011.

Dosimetry

As detailed in Table 1 the calculated absorbed dose for

cycle 2 varied across the different sites of tumour from 1.3

to 11.9 Gy, despite the fact that pre-treatment 68Ga-

DOTATATE imaging had shown similar SUVmax in these

regions and uptake appeared avid on the initial post treat-

ment imaging.

Case 3

This 32 year old man underwent transsphenoidal surgery in

2005 for a macroadenoma after presenting with

hypopituitarism and visual loss. Immunohistochemistry

confirmed a corticotroph adenoma (no clinical Cushing’s

disease). He underwent further transphenoidal surgery with

post-operative radiotherapy (50.4 Gy in 28 #) in 2007 for

recurrent disease. Pathology at that time showed an atyp-

ical adenoma with very high levels of Ki67 and p53

staining. These were higher than on the original tumour,

although retrospective testing of his primary disease

showed that this was also an atypical adenoma (no specific

values documented for Ki67 or p53—reported at a different

centre). His disease remained under control until 2010

when imaging revealed significant progression. Following

further debulking surgery, he received 6 cycles of tem-

ozolomide initially with good response. Further progres-

sion was noted in May 2011 and he was rechallenged with

temozolomide, but only received one cycle due to rapid

disease progression requiring further debulking surgery

(transsphenoidal plus craniotomy) for symptom control

(severe facial pain).68Ga-DOTATATE PET/CT demonstrated only mild

uptake in his pituitary tumour (SUVmax 7.2). However, in

Fig. 4 Stable 68Ga

DOTATATE PET images in

patient 1 post treatment

Pituitary

123

view of the limited therapeutic options he commenced177Lu-DOTATATE in October 2011. Post-therapy imaging

demonstrated avid uptake. He was ECOG performance

status 0 at the time of administration, but experienced a

severe increase in facial pain shortly after the first treat-

ment necessitating admission to his local hospital and

preventing travel to our centre for further PRRT. He

received PCV chemotherapy locally, but progressed

through two cycles. Further surgery was performed, but his

disease continued to progress rapidly despite temozolo-

mide rechallenge. He underwent re-irradiation (45 Gy in

25 fractions) in July 2012 and, despite a good clinical and

radiological response, he died suddenly in November 2012.

Discussion

We treated three patients with advanced progressive pitui-

tary adenoma/carcinoma using 177Lu-DOTATATE PRRT

with mixed results. Our first patient appeared to derive a

benefit. However, pathological examination of the meta-

static nodule revealed unusually benign features identical to

the original tumour (low Ki-67 index and no overexpression

of p53). Proliferation indices and p53 expression tend to be

higher in pituitary metastases than in primary disease [30].

Although, the evaluation of Ki-67 and p53 as prognostic

markers has focused upon primary pituitary tumours [31],

the low Ki-67 in the metastatic tissue would suggest that his

disease was likely to follow a relatively indolent course

without any intervention. Nonetheless, therapy had been

initiated due to the significant growth in the metastatic

lesions between 2007 and 2009 and there has been no further

growth in the 3 years since commencing therapy. Indeed,

there was regression of some tumour nodules. Temozolo-

mide had been recommended rather than PRRT, but refused

by the patient and it is very possible that temozolomide

could have also induced a response (no MGMT staining

performed). We would continue to recommend temozolo-

mide to patients in this situation.

PRRT did not benefit the other two patients in our

cohort, both of whom had much more rapidly progressive

disease than patient 1 and were considerably more symp-

tomatic. Due to the rate of disease progression, patients 2

and 3 received only one or two cycles of treatment and this

may limit judgement on treatment efficacy. However,

PRRT was clearly unable to induce disease stabilisation,

even with an accelerated regimen. It should be noted that

patient 2 had been on dexamethasone 4 mg daily for sev-

eral months. Potentially this could have influenced sstr

expression as glucocorticoids can downregulate sstr

(especially sstr2) in pituitary NET cells. Indeed, our prac-

tice of administering a 3 day course of high dose steroids

with each cycle to prevent oedema may paradoxically have

reduced uptake of the radioisotope.

PRRT was generally well tolerated. Patient 1 experienced

self-limiting asymptomatic grade 2 thrombocytopenia in

cycle 1 (week 4), but not subsequently (no dose reduction).

Patient 2 tolerated the 4 weekly treatment interval without

toxicity although he received only two cycles. Patient 3

developed an increase in facial pain following treatment, but

imaging indicated disease progression as the cause. How-

ever, there is the potential for treatment-induced oedema that

could have significant consequences when treating CNS

tumours, hence our use of prophylactic steroids.

In our limited experience, 177Lu DOTATATE did not

benefit patients with rapidly progressive disease with ele-

vated proliferation indices. It may be that patients of good

performance status with slowly progressive disease may

have more potential to benefit, although we would expect

that a positive outcome would be induction of stable dis-

ease rather than significant tumour response. This is similar

to the findings of others who have used sst-directed PRRT

to treat other intracranial tumours [25, 26], and is our own

experience in treating patients with advanced progressive

meningiomas. Regarding PRRT for pituitary adenoma, the

patient reported by Komor et al., had stable disease for

many years following PRRT and appeared to fit this profile,

although the speed of disease progression pre-treatment is

not clear. However, Baldari et al. [27], described a dra-

matic reduction in pituitary tumour volume in a patient of

very poor performance status (reduced conscious level)

with rapidly progressive disease. The patient in their case

had a giant functioning prolactinoma and was relatively

treatment naive (no previous chemotherapy and radiother-

apy had been promptly withdrawn due to worsening of

clinical condition). Of note the patient in our series who did

appear to respond, albeit less dramatically, was also che-

motherapy-naive and his radiotherapy had been given over

20 years previously. Furthermore, the majority of his cur-

rent tumour would not have been in the original treatment

Table 1 Absorbed dose of radiation following one cycle for patient 2 in different regions of tumour

Lesion Volume (mm3) Density (g/cm3) Mass (g) Accumulated activity (MBq*h) s-factor (mGy/MBq*h) Dose (Gy)

A 611 1.03 0.63 90.84 131.26 11.9

B 6,121 1.03 6.30 244.23 13.39 3.3

C 3,330 1.03 3.43 54.58 24.47 1.3

D 3,427 1.03 3.53 120.91 23.78 2.9

Pituitary

123

field. Tumours that have progressed despite recent radio-

therapy may be relatively radio-resistant and less likely to

benefit from PRRT and changes in local blood flow fol-

lowing previous radiotherapy may limit delivery of radio-

nuclide to the tumour. Bulky tumours may also be hypoxic

and this may limit the effectiveness of radiation-based

treatments whose therapeutic effect is reliant on oxygen

free radical formation, certainly the tumour-bulk in our

patient who responded was the smallest and the patient

reported by Komor et al. appeared roughly a similar size

(without metastases).

There was a reduction in the maximum uptake in 18F-FDG

and 68Ga DOTATATE PET in patient 1. A reduction in18F-FDG uptake, a marker of glycolysis, does appear to be a

surrogate for tumour response and prognosis in other tumour

types [32, 33]. There are fewer data regarding response on68Ga-DOTATATE imaging, although one group showed that

decreased 68Ga-DOTATATE uptake in tumours after the first

cycle of PRRT predicted time to progression and correlated

with an improvement in clinical symptoms among patients

with well-differentiated NETs [34]. Due to tumour progres-

sion patients 2 and 3 did not undergo sufficient PET scans to

comment on any change in isotope uptake. Further study

would be required to establish whether PET uptake values

reflect disease response in this patient group.

All patients had 68Ga-DOTATATE uptake on their pre-

treatment imaging that mirrored therapeutic 177Lu-

DOTATATE uptake, although patient 3 had weak uptake

on pre-treatment imaging with apparently avid uptake of

therapy. Again, data from more patients would be required

to establish whether the level of isotope uptake on pre-

treatment imaging correlates with therapeutic uptake in the

pituitary, as appears to be the case in patients with GEP-

NETs and possibly meningioma [25, 35, 36].

Data regarding dosimetric evaluation of absorbed dose of

radionuclide in pituitary tumours has not been previously

published and an understanding of this will help evaluate the

relative merits of radioisotope therapy. The inhomogenous

uptake in different tumour regions in our patient was surprising

as uptake on 68Ga-DOTATATE PET was relatively uniform.

This may reflect genuine differences not detected by PET or

limitations in dosimetric evaluation. A larger number of post-

treatment scans would have provided more time points to assess

cumulated activity and a more accurate dosimetry graph (but is

intensive for both patient and resources). Furthermore, the

standard software S factors do not incorporate individual

patient/tumour morphology or cross dose from tumour to organ

or vice versa, but this is probably not a significant feature in the

pituitary. Furthermore, there may have been some growth

between the pre-treatment MRI used to calculate the tumour

masses and dosimetry evaluation (causing an inappropriately

low S-factor).

We evaluated one cycle in one patient and the markedly

inhomogenous uptake restricts interpretation: at the upper

end of the spectrum 12 Gy per fraction could be considered

a useful dose, but doses \2 Gy per fraction would not be

worthwhile. It is unknown whether the uptake results for

patient 2 are typical or indeed whether uptake would

remain the same for each cycle delivered. It would have

been interesting to perform tumour dosimetry on patient 1,

but he was not available for the necessary imaging. Eval-

uation on many patients would be required as radionuclide

uptake in other tumour types appears to be highly indi-

vidualised: dose absorbed by tumour can vary between 0.9

and 42 Gy/MBq in a single administration of 90Yttrium

DOTATOC therapy in NETs [37, 38].

Several radioisotopes that emit beta rays, most commonly177Lu or 90Y, are used to treat other NETs. 111In, as used by

Baldari et al., is less commonly used as its small particle

range limits tissue penetration. 177Lu and 111In both permit

direct imaging of isotope uptake and hence evaluation of

absorbed dose (to perform 90Y dosimetry, 111In has to be

concurrently administered). However, as the maximum

energy and range of 90Y beta particles is higher theoretically

this may have higher therapeutic potential in bulkier tumours

[39]. One group has demonstrated an advantage of alternating

cycles of 90Y and 177Lu therapy for GEPNETs [40]. As

different types of pituitary adenoma have been shown to have

distinct sst expression patterns [15] and different radio iso-

topes have differing affinity for the sst subtypes, this may

influence tumour isotope uptake. Immunohistological evalu-

ation of sst subtype expression is possible on resected

tumours and this could also guide therapy.

Conclusion

There is no established therapy for patients with relent-

lessly progressive pituitary adenomas/carcinomas follow-

ing repeated surgery and radiotherapy. Temozolomide has

become generally accepted on level IV evidence. Although

the theoretical rationale for sst-directed PRRT in advanced

pituitary adenomas is elegant, we have found mixed results

in the three patients we treated. In particular patients with

rapidly progressing disease did not benefit. A more formal

prospective study may be warranted to better determine

absorbed dose and efficacy.

Conflict of interest None.

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