Radiotherapy and Oncology 98 (2011) 207212

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Radiotherapy and Oncology

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Craniopharyngiomas

Phosphorus-32 therapy for cystic craniopharyngiomas q

Robert Bryan Barriger a, Andrew Chang a, Simon S. Lo b, Robert D. Timmerman c, Colleen DesRosiers a,
Joel C. Boaz d, Achilles J. Fakiris a,
a
Department of Radiation Oncology, Indiana University School of Medicine, Indianapolis, USA; b Departments of Radiation Oncology, Arthur G. James Cancer Hospital, Columbus, USA;
c
Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, USA; d Department of Neurological Surgery, Indiana University School of Medicine,
Indianapolis, USA

a r t i c l e i n f o a b s t r a c t

Article history: Background and purpose: To examine control rates for predominantly cystic craniopharyngiomas treated
Received 30 May 2009 with intracavitary phosphorus-32 (P-32).
Received in revised form 24 March 2010 Material and methods: 22 patients with predominantly cystic craniopharyngiomas were treated at Indiana
Accepted 2 December 2010
University between October 1997 and December 2006. Nineteen patients with follow-up of at least
Available online 25 January 2011
6 months were evaluated. The median patient age was 11 years, median cyst volume was 9 ml, a median
dose of 300 Gy was prescribed to the cyst wall, and median follow-up was 62 months.
Keywords:
Results: Overall cyst control rate after the initial P-32 treatment was 67%. Complete tumor control after
Craniopharyngioma
Brachytherapy
P-32 was 42%. KaplanMeier 1-, 3-, and 5-year initial freedom-from-progression rates were 68%, 49%, and
32-Phosphorus 31%, respectively. Following salvage therapy, the KaplanMeier 1-, 3-, and 5-year ultimate freedom-from-
progression rates were 95%, 95%, and 86%, respectively. All patients were alive at the last follow-up.
Visual function was stable or improved in 81% when compared prior to P-32 therapy. Pituitary function
remained stable in 74% of patients following P-32 therapy.
Conclusions: Intracystic P-32 can be an effective and tolerable treatment for controlling cystic compo-
nents of craniopharyngiomas as a primary treatment or after prior therapies, but frequently allows for
progression of solid tumor components. Disease progression in the form of solid tumor progression,
re-accumulation of cystic uid, or development of new cysts may require further radiotherapy or surgical
intervention for optimal long-term disease control.
2011 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 98 (2011) 207212

Craniopharyngiomas are rare epithelial tumors arising from
remnants of Rathkes pouch [1]. Although considered benign tu-
mors they may cause signicant morbidity secondary to encroach-
ment on or compression of adjacent critical parasellar structures
including but not limited to the optic chiasm, pituitary gland, or
ventricular system. These tumors consist of solid and/or cystic
components, each of which may cause symptoms and respond to
different forms of therapy.
Historically, aggressive surgical resection was advocated as the
standard-of-care treatment. However, gross total resections often
are associated with neuropathies (e.g., vision loss and ocular nerve
palsies) and/or injury to eloquent brain (e.g., hypothalamic obesity
and memory problems). Recurrence rates with surgery alone are
as high as 66% [26]. Now, less aggressive surgical management
q
Presented as a poster at the 2008 American Radium Society meeting in Dana
Point, CA.
Corresponding author. Address: Department of Radiation Oncology, Indiana
University School of Medicine, 535 Barnhill Dr (RT041), Indianapolis, IN 46202, USA.
E-mail address: afakiris@iupui.edu (A.J. Fakiris).
includes sub-total resections for biopsy or decompression of adja-
cent brain and cranial nerves, aspiration or fenestration of cystic
components to relieve mass effect, and procedures to relieve
hydrocephalus.
Adjuvant radiation therapy with external beam (EBRT) or intra-
cavitary brachytherapy improves local control after sub-total resec-
tions [5,7,8]. EBRT increases control of both gross (primary therapy)
and microscopic (adjuvant therapy) disease [8,9]. A growing litera-
ture exists using stereotactic radiosurgery either as primary therapy
or as a boost [1013]. Further, preliminary data on fractionated
proton radiotherapy and combined proton and photon irradiation
have been reported [14,15].
The natural history of craniopharyngioma progression is highly
variable among individual patients, and either solid or cystic com-
ponents of this disease may progress to cause symptoms. In some
patients, the cystic component may comprise the majority of the
entire lesions volume and account for the majority of symptoms.
More localized radiation for the cystic component given via intra-
cystic injection of a colloidal radio-isotope has been successful at
controlling the cystic components of craniopharyngiomas by deliv-
ering the radiation dose in close proximity to the cyst wall [1620].

0167-8140/$ - see front matter 2011 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.radonc.2010.12.001
208 P-32 for craniopharyngiomas
The purpose of this study was to examine control rates for pre-
dominantly cystic craniopharyngiomas treated with intracystic
phosphorus-32 (P-32) at Indiana University School of Medicine in
the modern era.
Methods and materials
We identied 22 patients with craniopharyngiomas treated
with intracystic irradiation with P-32 between 1997 and 2008 at
Indiana University School of Medicine. Three patients were ex-
cluded from this analysis due to being lost to follow-up within
6 months of treatment leaving 19 patients for evaluation. This ret-
rospective review was undertaken with authorization of the IU
Institutional Review Board. The medical records were extensively
reviewed for information regarding clinical patient characteristics,
baseline presentation, treatment outcomes, and treatment related
toxicity. Intracystic therapy was indicated in all treated patients
based on documented cystic expansion or re-accumulation of uid
after aspiration of the cystic cavity.
In the 19 evaluated patients, the mean and median patient ages
were 20 years and 11 years, respectively (range 354 years). Four-
teen patients were male and 5 were female. The most common
presenting symptoms were headaches (n = 12) and visual changes
(n = 8). Less common symptoms included nausea/vomiting, endo-
crinopathies, ataxia, memory decits, seizures, lethargy, and behav-
ioral changes. Seventeen patients (89%) had a total of 24 therapeutic
interventions prior to intracystic P-32. These interventions included
13 craniotomies, 1 trans-sphenoidal resection, 7 cyst aspirations,
2 a-interferon procedures, and 1 course of external beam radio-
therapy.
The instillation of P-32 into craniopharyngioma cysts was per-
formed with a multi-disciplinary team of neurosurgeons, radiation
oncologists, and radiation physicists. All surgical procedures were
performed by neurosurgeons at Indiana University Medical Center.
The localization and puncturing of the cysts were determined by
the neurosurgeon using stereotactic techniques.
Craniopharyngioma cyst volume was estimated based on pre-
operative CT or MRI. The volume was calculated as the sum of
the areas of each cross-sectional contour multiplied by the slice
thickness (usually 3 mm) to produce a volume in cubic centime-
ters. The treating neurosurgeons and radiation oncologists con-
toured the cyst cavity on radiation therapy treatment planning
systems (generally GammaPlan). The colloidal chromic phosphate
P-32 was ordered through the radiation safety ofce. The activity
of the stock solution was based on the manufacturers calibration.
The calculation of required activity assumed uniform distribu-
tion of the colloid in the cyst and the prescription dose of typically
300 Gy to the cyst wall. The actual activity administered was deter-
mined by nomogram tables which approximately follow the
formula:
Activity 0:1365 Dose in Gy volml=0:455
The nomogram tables were based on a numerical calculation of
dose delivered to a surface element on the inner wall of a hollow
sphere lled with a homogeneous mixture of radiocolloid and
water. In all cases the activity obtained from the nomogram fell
within 5% of the calculated activity using the previous formula.
A solution was prepared for injection based on the cyst volume.
In cases where patients were experiencing nerve or brain compres-
sion symptoms, 30% of the cystic volume was extracted to relieve
the mass effect (typically 0.51.0 cc). The physicist prepared the
P-32 colloidal phosphate/saline solution to meet the appropriate
concentration of P-32 (calculated activity/extracted volume). Be-
cause the calculated activities and aliquots of colloidal phosphorus
were very small volumes and difcult to dispense even with a
tuberculin (TB) syringe, the solution prepared was typically diluted
with saline.
Using sterile technique, the cyst cavity was accessed by the
neurosurgery team using previously described methods [16]. A
predetermined amount of cystic uid was removed before the
P-32 was injected with the objective of returning the cyst to its
original volume (or 30% of the original volume in symptomatic
patients) in order to facilitate homogenous P-32 distribution around
the surface of the cyst wall. The injection needles were barbotaged to
ensure a homogenous mixture of P-32 and cystic uid.
Following the procedure, a radiation survey was performed in
the room and on all waste materials, instruments and linens. Any
contaminated material was removed and de-contaminated if pos-
sible or held for decay for 10 half-lives. The mean and median
doses of radiation prescribed were 290.5 Gy and 300 Gy, respec-
tively, (range 150312 Gy) to the cyst wall delivered over ve
half-lives of the P-32 isotope.
EBRT was delivered as a salvage or adjuvant treatment to se-
lected patients at the discretion of the treating physician. EBRT
was delivered after P-32 to 5 patients in this analysis. Three pa-
tients received EBRT as a salvage treatment for cyst recurrence
after intracystic P-32 and 2 for progression of solid tumor compo-
nents. Radiation was delivered with 15 MV photons in daily frac-
tions of 180200 cGy to a total dose of 5456 Gy. An isocentric
5-Field non-coplanar 3D conformal plan was used in these cases.
Bremstrahllung localization scans were obtained 1 week after
the procedure to ensure no leakage of radioactive materials from
the cyst. Clinical examination including interim history, physical
examination, and neuroimaging with CT or MRI was performed
at 3 month intervals for the rst year, at 4 month intervals during
the second year, and yearly thereafter. Formal ophthalmologic and
endocrine evaluations were requested.
Treatment response was based on radiographic follow-up scans.
Response was divided into progression, stable disease, partial
response, or complete response. Progression was dened as any
increase in the size of craniopharyngioma lesions or development
of a new cyst after P-32 treatment. Stable disease was dened as
no change in size. Partial response was dened as a smaller lesion
but not complete regression, and complete regression was dened
as no radiographic evidence of craniopharyngioma. Local control
was dened as stable disease, partial response, or complete re-
sponse. Time-to-failure was dened as the rst clinical evidence
of disease failure based on increase in lesion size or appearance
of a new cyst on neuroimaging studies. Initial freedom-from-
progression was dened as the absence of enlargement after the
rst P-32 treatment. Ultimate freedom-from-progression was
dened as the ultimate absence of enlargement after all salvage
therapies.
StatView software (SAS Institute, Inc, Cary, NC) was used for
statistical analysis. KaplanMeier analysis was used to calculate
the initial freedom-from-progression and ultimate freedom-from-
progression rates.
Results
Median follow-up in the study was 62 months (range
8136 months). The median cyst volume was 9 ml (range
258 ml). Fifteen tumors contained a signicant solid portion in
addition to the cystic masses. 15 lesions were monocystic and 4 were
multicystic.
Of the 19 lesions, 8 (42%) were controlled after P-32. A typical
radiographic response to P-32 treatment is shown in Fig. 1. Of
the controlled lesions, 1 completely responded with no evidence
of disease on follow-up neuroimaging, 5 had decreased in size,
and 2 remained stable. Of the 11 lesions that were not initially
 R.B. Barriger et al. / Radiotherapy and Oncology 98 (2011) 207212
Fig. 1. MRI showing craniopharyngioma cyst before and after P-32 therapy.
controlled with the aforementioned treatment, 9 had increased
size of the cyst cavity or the solid component and 2 had develop-
ment of a new cyst. Progression occurred at a median of 10 months
from the time of initial P-32 treatment (range 154 months). Sal-
vage of uncontrolled lesions was performed with cyst aspiration
in 4 patients (all of whom had a ventriculoperitoneal shunt placed),
EBRT for 5 lesions, surgical resection of 4 lesions, and repeated
intracystic P-32 in 3 lesions. Of the 3 patients who required addi-
tional P-32 for poor response to the initial treatment, 1 patient
had 4 separate treatments for a cumulative intracystic dose of
1200 Gy, 1 patient received a single repeat treatment of 300 Gy
after initial treatment with 300 Gy, and 1 patient received a single
repeat treatment with 300 Gy after initially receiving 150 Gy. Five
patients received EBRT following P-32; three patients required
EBRT for persistent cyst uid re-accumulation and 2 had EBRT
for progression of solid tumor components while the cystic portion
was controlled after P-32. Four patients had surgical resection after
P-32; two for progression of the solid tumor component and 2 for
progression of tumor cysts. Four patients required multiple cyst
aspirations prior to achieving a durable response. Of the 11
patients who received salvage treatment, 10 had no disease
progression at the time of last follow-up.
Ultimate control with salvage therapy at last follow-up was
achieved in 17/19 (89%) lesions. Crude 1-, 3-, and 5-year control
rates were 68%, 63%, and 42%, respectively. Including salvage ther-
apy, 1-, 3-, and 5-year tumor control was 95%, 95%, and 89%,
respectively. All patients were alive at a median follow-up of
62 months (range 8139 months).
Using KaplanMeier analysis, the 1-, 3-, and 5-year initial free-
dom-from-progression was 68%, 49%, and 31%, respectively. The
median initial freedom-from-progression time was 13 months.
The 1-, 3-, and 5-year ultimate freedom-from-progression was
95%, 95%, and 86%, respectively.
Of the 4 multicystic tumors, 3 (75%) progressed with a median
time-to-progression of 8 months (213 months). Eight of 15 (53%)
monocystic tumors progressed after P-32 with a median time-to-
progression of 16 months (1103 months). Three of four (75%)
completely cystic tumors were controlled after P-32 therapy and
required no salvage treatment compared to 5/15 (33%) of those
with a signicant solid component.
Sixteen patients had pre- and post-treatment visual testing re-
cords for review. Nine evaluable patients had normal pre-treat-
ment visual acuity/elds, of which 1 worsened after treatment.
209
Pre-treatment visual decits were present in 7 patients, and 2
worsened after treatment. Overall, vision was stable or improved
in 13/16 (81%) evaluable patients. 1/4 patients who received adju-
vant/salvage EBRT had worsening of visual function after treat-
ments were completed compared to 2/12 patients who did not
receive adjuvant/salvage EBRT. One patient was blind prior to
any radiotherapy due to primary surgical resection and did not
regain vision. One patient developed bilateral superior temporal
quadrantanopsia after receiving multiple salvage therapies for a
non-responding cyst including a cumulative intracystic P-32 dose
of 1200 Gy (4 treatments) and EBRT to 54 Gy.
Nineteen patients had pre- and post-treatment endocrine func-
tion data available from medical records as shown in Table 5. Five
patients had normal pre-treatment pituitary function, 9 patients
had pre-treatment partial pituitary deciency, and 5 patients had
panhypopituitarism. Of the 5 patients with normal pre-treatment
pituitary function, 2 retained stable function, 2 developed partial
pituitary deciencies, and 1 developed panhypopituitarism. Of
the 2 patients who developed partial pituitary deciencies, one
had salvage craniotomy and surgical resection for enlargement of
the solid tumor component and the other had repeat intracystic
P-32 therapy to a dose of 300 Gy and developed a growth hormone
deciency. The patient who developed panhypopituitarism re-
ceived 4 separate intracystic P-32 treatments, EBRT to 54 Gy, and
surgical resection. The 2 patients who retained stable pituitary
function did not have salvage treatment or tumor recurrence. Of
the 9 patients with a partial deciency prior to P-32 therapy, 6
had stable function at time of last follow-up and 3 developed pan-
hypopituitarism. Of the 6 patients who retained stable function, 4
did not require salvage therapy, 1 had EBRT to 56 Gy and surgical
resection, and 1 had multiple P-32 treatments, surgical resection,
and EBRT to 54 Gy. Of the 3 patients with worsened pituitary func-
tion, two had salvage treatment for uncontrolled lesions; one had
craniotomy with surgical resection followed by EBRT to 54 Gy for
recurrent tumor and the other had repeat P-32 injection for persis-
tent cyst uid accumulation. The 5 patients with non-functioning
pituitary prior to treatment did not regain function.
Three patients had cranial nerve (CN) decits: 1 developed a
unilateral CN6 decit that spontaneously resolved over the course
of 1 year, 1 patient was blind from complications of a prior surgical
procedure over 10 years before presenting with recurrent disease,
and the patient who received 4 separate P-32 procedures devel-
oped bilateral superior temporal quadrantanopsia.
 210
Table 1
Patient treatments and outcomes.

Patient Prior therapies Tumor outcome after P-32 Salvage therapy Pre-treament vision Pre-treatment endocrinopathy Visual outcome Endocrine outcome Ultimate tumor control
Cyst Control Solid tumor control
1 Craniotomy No No EBRT Normal AP deciency Stable Stable Yes
2 Craniotomy Noa Yes Decits PHP Stable Stable No
Aspiration
EBRT
3 Aspiration Yes No Craniotomy Normal AP decieny Stable Stable Yes
4 Craniotomy No No EBRT Decits PHP Stable Stable Yes
Interferon Aspiration
Aspiration Shunt
5 Craniotomy No No Aspiration Normal AP deciency Unknown Stable Yes
6 Aspiration Yes Yes Decits AP deciency Stable Stable Yes
7 Aspiration Yes Yes Decits AP deciency Improvedb Stable Yes
8 Craniotomy Yes Yes Decits Normal Improvedb,c Stable Yes
9 Aspiration Yes Yes Unknown AP deciency Unknown Worsened Yes

P-32 for craniopharyngiomas

10 Craniotomy Noa Yes P-32 Unknown DI Unknown Worsened Yes
Craniotomy
EBRT
11 AspirationCraniotomy Yes Yes Decits PHP Improvedb Stable Yes
12 Craniotomy Noa No Craniotomy Normal AP deciency Stable Stable Yes
Aspiration
Interferon
13 Craniotomy No Yes Aspiration Decits PHP Stable Stable Yes
Shunt
14 Craniotomy Yes Yes Decits PHP Worsened Stable Yes
15 No Yes EBRT Normal Normal Stable Stable Yes
16 No Yes P-32 Decits AP deciency Worsenedb,c Worsened Yes
17 Microsurgery Yes Yes Normal AP deciency Stable Stable Yes
Craniotomy
18 Aspiration Noa Yes Aspiration Normal Normal Worsenedb Worsenedd No
P-32
Shunt
EBRT
Craniotomy
19 Craniotomy No Yes P-32 Normal Normal Stable Worsenede Yes
Aspiration Shunt

Abbreviations: P-32, phosphorus-32; EBRTm, external beam radiotherapy; AP, anterior pituitary; PHP, panhypopituitarism; DI, diabetes insipidus.
a
Completely new cystic cavity developed after P-32 treatment.
b
Visual elds.
c
Visual acuity.
d
Patient developed panhypopituitarism.
e
Patient developed anterior pituitary deciency.
 R.B. Barriger et al. / Radiotherapy and Oncology 98 (2011) 207212
A more concise summary of treatment outcomes can be found
in Table 1.
Discussion
Treatment of craniopharyngiomas should be individualized to
each specic patient by considering patient age, tumor composi-
tion (i.e., solid versus cystic), and potential complications of avail-
able therapies. Surgical resection is technically difcult in many
cases due to adherence of tumor to critical neurological structures.
Recurrences can be high with surgery alone with greater recur-
rence rates for sub-total versus gross total resections. Recent surgi-
cal series report recurrence rates from 0% to 37.5% after gross total
resection and 58.5100% after sub-total resections [2,46,9,21].
Adjuvant or salvage radiation therapy can improve local control
rates. Stripp et al. reported local control of 42% with surgical resec-
tion alone and 84% with the use of salvage radiation [8]. In other
series adjuvant radiation decreased recurrence rates to 37.551%
after partial resections [4,5]. Fractionated stereotactic conformal
radiation following surgery was evaluated by Combs and Minniti
with tumor recurrence rates of 08% [22,23]. Stereotactic radiosur-
gery has been studied in order to increase tumor response and de-
crease failure rates by delivering a high dose per fraction. Gamma
Knife radiosurgery yields 14.320% recurrence rates with long-
term local control after salvage therapy of 80100% [1013].
With regards to patients treated with P-32, Pollock reported re-
sults in 30 patients in 1995. Thirteen patients had intracystic P-32
as a primary treatment and 17 patients received P-32 after surgery
or EBRT. With a mean follow-up of 39 months P-32 resulted in
regression of 88% of the treated cysts [16]. Hasegawa reported a
series of 49 patients in 2004 treating craniopharyngiomas with ste-
reotactic intracavitary P-32 either as primary or adjuvant treat-
ment with 70% actuarial cyst control at 10 years [17]. Finally,
Schefter published the Vanderbilt experience in 2002 with a series
of 25 patients. All patients received surgery as a component of the
initial therapy. Fifteen patients received EBRT and 7 patients had
intracystic P-32. Only 1/7 patients who received P-32 required fur-
ther intervention for cyst control [18]. Other radio-isotopes have
been used in intracavitary treatments of craniopharyngiomas.
Voges et al. report a 79.5% response rate with intracavitary P-32
or yttrium-90 and a 0% response rate with rhenium-186 [19]. Ju-
low reported a reduction in cyst volume of 79% on average after yt-
trium-90 intracavitary irradiation [20].
The current series reports a 42% overall tumor control rate with
P-32 as primary, adjuvant, or salvage treatment which is low com-
pared to other published data. 89% of patients in this series had
progressed after prior treatment potentially indicating a higher
propensity of recurrence in these patients. In addition we did not
separate cystic versus solid control when reporting the outcomes
as overall tumor control is the desired outcome. Because of this
the reported results include progression of both cystic and/or solid
portions of the tumors. Cyst uid reaccumulated after P-32 therapy
in 7/11 local failures, giving an overall cyst control rate of 63%.
Including salvage options of cyst aspiration for uid accumulation,
surgical resection, repeat P-32, and EBRT, 5-year tumor control
rates were 89%, more in-line with prior published results. Other
possible reasons for the lower local control rates in this series in-
clude the use of non-radical surgical resections (e.g., sub-total
decompressive resections, cyst aspirations and cyst fenestrations)
thereby avoiding some of the toxicities seen with more radical sur-
gical procedures. While EBRT was still necessary to control cranio-
pharyngiomas in some patients, it was primarily used to address
problems related to progression of solid tumor components. For
our patients, the majority of symptoms caused by cystic expansion
alone were effectively treated with less invasive surgery and intra-
cystic P-32.
211
Complications of treatment for craniopharyngiomas frequently
include visual deterioration or pituitary gland dysfunction. Wors-
ening of visual elds or visual acuity has been reported in 915%
of patients after surgical resection [36], 034% after surgery fol-
lowed by radiation [7,8,22,23], and 3.238% after Gamma Knife
radiosurgery [10,11]. Pollock reported improved or unchanged vi-
sual elds in 69% and 59% of patients undergoing primary and
adjuvant treatment of craniopharyngiomas with P-32, respectively.
There was a trend toward a greater number of patients developing
visual decits if they had prior EBRT but this was not statistically
signicant [16]. Hasegawa reported 9/40 (23%) patients to have
worsened visual function after intracystic P-32. Six of these pa-
tients developed the abnormality after further surgical procedures
and 3 developed new visual abnormalities thought to be related to
P-32 therapy even in the face of tumor progression [17]. Our re-
sults of 81% of patients having stable to improved visual function
following treatment is in-line with the published data.
Our approach of using non-radical surgery and P-32 for cystic
expansion and EBRT for progressive solid tumor facilitated our goal
to avoid the morbidities associated with radical surgery and delay
the need for EBRT. In the current series, 81% of patients had stable
or increased visual function after treatment, and 74% had stable
endocrine function. Signicant toxicity in our report was modest,
likely as a result of our approach of avoiding radical surgery and
delaying EBRT as the more severe cranial nerve toxicities occurred
in patients who had multiple recurrences and more aggressive
interventions.
Conclusion
Intracystic P-32 can be an effective and well-tolerated treat-
ment for controlling cystic components of craniopharyngiomas as
a primary treatment or after limited surgical resection, but fre-
quently allows for progression of solid tumor components. Disease
progression in the form of solid tumor progression, re-accumula-
tion of cystic uid, or development of new cysts may require
further radiotherapy or surgical intervention for optimal and
long-term disease control. Patients need to be followed long-term
by a multi-disciplinary team to monitor for chronic long-term side
effects such as endocrinopathies or visual changes.
Conict of interest statement
None of the listed authors have any actual or potential conicts
of interest to disclose.
Role of the funding source
There was no funding source in the design, collection/interpre-
tation/analysis of data, or in the decision to submit this work for
publication.
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