Interstitial Radioactive Iodine Implants for the Treatment of Pan-invasive Pituitary Macroadenomas
Phase: PHASE2
Conditions: Pituitary Macroadenoma
Sponsor: University of Texas Southwestern Medical Center

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Interstitial Radioactive Iodine Implants for the Treatment of Pan-invasive Pituitary Macroadenomas
Organizing Institution:
University of Texas Southwestern Medical Center, Dallas, TX
Principal Investigator (P.I.):
Robert D. Timmerman, MD
Department of Radiation Oncology
Co-Investigators:
Louis Whitworth, MD
Department of Neurological Surgery
Christopher Madden, MD
Department of Neurological Surgery
Barbara Schultz, MD
Department of Otolaryngology
Aaron Laine, MD, Ph.D.
Department of Radiation Oncology
Protocol Version History
Version 1
9/22/11
Version 2
5/3/2013
Version 3
7/25/13
Version 4
9/24/15

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INDEX
Schema
Eligibility Checklist
 1.0
Introduction
 2.0
Objectives
 3.0
Patient Selection
 4.0
Pretreatment Evaluations/Management
 5.0
Registration Procedures
 6.0
Radiation Therapy
 7.0
Drug Therapy
 8.0
Other Therapy
 9.0
Specimen Submission
10.0
Patient Assessments
11.0
Data Collection
12.0
Statistical Considerations
13.0
Data Safety Monitoring Plan
References
Appendix I
- Study Parameters/Study Calendar
Appendix II
- Performance Status Scoring
Appendix III
- Post-Implant Dosimetry Data Form
Appendix IV
- Neurocognitive Battery
Appendix V
- Quality of Life Assessments
Appendix VI
- Cost Effectiveness
Appendix VII
- Risks to Subjects

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STUDY SYNOPSIS
Interstitial Radioactive Iodine Implants for the Treatment of Pituitary Macroadenomas
Schema
Patient Population:  (See Section 3.0 for Eligibility)
Patients must have biopsy proven pan-invasive pituitary macroadenomas of the pituitary gland.  Pan-
invasive for the purposes of the protocol will be defined as meeting each of the following 2 major criteria:
1. tumor volume greater than 20 cc at enrollment, and
2. suprasellar extension.
In addition, a pan-invasive tumor must meet any one of the following 3 minor criteria:
a) unresectable tumor invasion into a cavernous sinus,
b) bone or bone marrow invasion into the clivus or temporal bones, or
c) tumor extension in any direction unlikely to be completely removed specifically by a transphenoidal
surgical approach.
Patients who meet the two major criteria above (1 and 2) and are medically inoperable for tumor resection
(due to confounding co-existing medical problems) are eligible without meeting any of the three minor criteria
(a, b, or c).
Patients should be immediately threatened for vision loss or other significant neurological impairment directly
related to tumor mass effect.  As such, all patients enrolled would likely benefit from tumor response
(shrinkage).
Patients with pituitary carcinomas are not eligible.
Number of patients = up to 12 in each or two cohorts listed below (total up to 24).
Patients will be divided into two cohorts depending on if they have been previously treated with radiotherapy
or not.
Eligible patents may have a functioning or non-functioning adenoma and may have previously undergone a
surgical resection for their adenoma.
The goal of the study is primarily to monitor for tumor shrinkage after seed implantation.  Additional
outcomes that will be monitored are change in visual fields, potential toxicities (acute and late) related to the
treatment, progression free survival, and changes in patient reported outcomes.
I
F
oll

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ELIGIBILITY CHECKLIST
Case #
(page 1 of 3)
(Y)  1.  Does the patient have a pathologically confirmed pituitary adenoma?
________(Y)  2. Is the patient’s tumor causing an immediate threat to vision or other significant neurological
problems due to tumor mass effect?
(Y)  3.  Is the tumor grossly visible on MRI or CT?
(Y)  4.  Is the tumor volume >20cc?
(Y)  5.  Is there suprasellar extension of the adenoma (extension above the diaphragma sellae)?
________(Y) 6.  Does the tumor extension meet any one of the following 4 criteria?
______(Y/N) 6a. Is there unresectable tumor invasion into a cavernous sinus?
______(Y/N) 6b. Is there bone or bone marrow invasion into the clivus or temporal bones?
______(Y/N) 6c. Is there tumor extension in any direction unlikely to be completely removed by specifically
a transphenoidal surgical approach?
______(Y/N) 6d. The responses to 6a, 6b, and 6c are all NO; however, the patient is medically inoperable
for tumor resection due to confounding co-existing medical problems?
______(Y/N)  7.  Has the patient previously been treated with radiotherapy to either the central skull base or
central brain?
(Y)  8.   Has the patient been medically cleared to receive general anesthesia and stereotactic seed
placement?
          (Y/NA) 9.  If female, was there a negative serum or urine pregnancy test performed within 72 hours
prior to treatment for women of childbearing potential?
(N) 10.  Does the patient’s pituitary tumor histology reveal carcinoma?
(Y)  11. Did the patient provide study-specific informed consent prior to any protocol-specified
procedure(s)?
(N) 12. Does the patient have serum creatinine > 1.2 mg/dl or a history of severe renal
dysfunction?
(N)  13.  Does the patient have uncontrolled allergy to MRI contrast dye?
(N)  14.   Does the patient have a contraindication to MRI such as iron containing particles in the
body (e.g. iron shavings in the eye), surgical implants (e.g. aneurysm clip), or implanted
electronic device (e.g. pacemaker)?
______(Y/N)  15.   Is the patient’s pituitary adenoma hormonally functional?
______(Y/N) 16.  Has the patient had a previous surgery for resection of pituitary adenoma?
________(#)  
 If yes, how many previous surgeries?
(Continued on next page)

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ELIGIBILITY CHECKLIST (page 2 of 3)
The following questions will be asked at Study Registration:
1. Name of institutional person registering this case?
(Y)
2. Has the Eligibility Checklist (above) been completed?
(Y)
3. Is the patient eligible for this study?
4. Date the study-specific Consent Form was signed? (must be prior to study entry)
5. Patient’s Initials (First Middle Last) [May 2003; If no middle initial, use hyphen]
6. Verifying Physician
7. Patient’s ID Number
8. Date of Birth
9. Race
10. Ethnic Category (Hispanic or Latino; Not Hispanic or Latino; Unknown)
11. Gender
12. Patient’s Country of Residence
13. Zip Code (U.S. Residents)
14. Patient’s Insurance Status
15. Will any component of the patient’s care be given at a military or VA facility?
 
16. Calendar Base Date
 
17. Registration/randomization date: This date will be populated automatically.
(Continued on the next page)

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ELIGIBILITY CHECKLIST
Case #
(page 3 of 3)
              (Y/N) 18.
Tissue/Urine/Blood kept for cancer research?
              (Y/N) 19.  
Tissue/Urine/Blood kept for medical research?
              (Y/N) 20.
Allow contact for future research?
Completed by
Date
Investigator Signature
Date

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INTRODUCTION
1.1
Epidemiology
1.1.1 
Pituitary adenomas constitute 10-20% of all central nervous system tumors.1,2  Patients with
secretory adenomas most frequently present with endocrinopathies; the goal of therapy in these
cases is normalizing the endocrinopathy and eliminating further lesion growth.  First-line therapy
can be either medical or surgical depending on the hormone being secreted.3  Thirty percent of
pituitary adenomas are nonsecretory and present clinically due to their progressive increase in size
and the mass effect exerted on the surrounding tissues, most commonly, the optic apparatus.4
Controlling tumor growth and preserving vision are the most important factors in the treatment of
nonsecreting adenomas.  Surgery is considered first-line treatment for these tumors.
Tumors with their greatest diameter of less than 10mm are classified as “microadenoma”, whereas
those with a diameter of 10mm or more are considered “macroadenomas”.5  Due to their benign
nature and variable clinical presentation, pituitary adenomas may become very large, a factor that
complicates treatment.  Widespread surgical and radiologic interest in these tumors has resulted in
various definitions of pan-invasive or “giant” pituitary adenomas.  Both Fisher et al.6 and Symon et
al.7 defined giant adenomas as those showing suprasellar extension of more than 40 mm in any
direction from the midline of the jugum sphenoidale.  Symon et al. also considered giant adenomas
to be tumors extending within 6 mm of the foramen of Monro.  Others considered adenomas with
suprasellar extension of Hardy grades C and D as being large or giant.8 Mohr et al. felt that having
a superior margin more than 20 mm above the jugum sphenoidale was the key to identifying giant
adenomas.9  More recently, Goel et al. defined giant adenomas as those with greater than 4 cm in
maximum diameter, further subclassifying them into four grades according to invasion and patterns
of extension.10 Despite definitional variations, all of the authors agree that very large tumors are
difficult to treat by surgery alone and that adjuvant therapy is necessary.
1.2
Standard therapy
1.2.1 
Giant or pan-invasive pituitary adenomas are a surgically challenging subset of sellar tumors.
Although both the transsphenoidal and transcranial approaches have been used to remove giant
adenomas, the transsphenoidal approach is generally favored because of decreased morbidity
and a more direct trajectory to the long axis of the tumor. In most series of giant pituitary
adenomas, the transsphenoidal approach has been the predominantly utilized operation.9-13 A
significant drawback of the standard transsphenoidal approach for giant adenomas is poor
visualization of the suprasellar components.14  The microscope lens and light source sit at the end
of the long, narrow Hardy retractor, which limits the field of view. If the suprasellar extent of the
tumor does not deliver itself into the surgeon's line of sight, then these aspects of the tumor are
often unresected.14 One option is to perform multiple staged surgeries. The staged
transsphenoidal method or open sella method was proposed by Saito et al.15 After an initial
transsphenoidal operation, a second transsphenoidal procedure is performed in a delayed fashion
with the expectation that residual suprasellar tumor may descend into the sella facilitating re-
resection. In the series by Mortini et al.11, the majority of patients that required staged procedures
underwent a transsphenoidal operation followed by a transcranial procedure. Alleyne et al.16
described their experience with a combined simultaneous transsphenoidal and transcranial
approach. The gross total resection rate of 40% in the smaller series of Alleyne et al.16 compares
favorably with the experience of larger series of giant adenomas, which have gross total resection
rates of 14.7-29.65%.  In addition, more advanced surgical techniques have been described to
better obtain a complete resection of macroadenomas.  Added exposure provided by a Le Fort I
maxillotomy has shown to facilitate a total or near total (>95%) resection of macroadenomas that
have been incompletely resected by a traditional transnasal, transspenoidal approach.17
The clinical course and surgical outcome in cases with giant pituitary adenomas have generally
been reported to be poor.8,9,18-20 Treatment of pituitary adenoma with subtotal resection alone is
associated with a risk of recurrence that approaches up to 80%.21,22 Radiotherapy is commonly

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used in cases of tumor recurrence23 or may be used prophylactically after resection if there is
evidence of residual tumor on postoperative neuroimaging. Long-term control of pituitary
adenomas after transsphenoidal resection varies from 50 to 80%.1,2,24-27
In the past, conventional fractionated radiotherapy was the most common form of radiation therapy
for pituitary adenomas. A review done by Minniti et al.28 compared 10 studies from 1989 to 2000
on conventional radiotherapy for non-secretory adenomas. This review demonstrated an overall
progression-free survival in the region of 80–90% at 10 years and 75–90% at 20 years.  Therefore,
conventional radiotherapy does offer very good local control rates.  More recently, stereotactic
techniques have been used that allow a more precise delivery of a higher dose of radiation to the
target in either a single dose as SRS, or in multiple doses as fractionated SRT. These techniques
use gamma radiation (with the Gamma Knife), a modified linear accelerator, or proton beams.
Minniti et al.29 reviewed 13 studies of SRS for non-secretory adenomas, and reported a tumor
growth control rate of 87–100% with a follow-up of 6–60 months, in line with the results seen for
conventional fractionated radiotherapy.  However, a limitation of using SRS is that the adenoma
must be small in volume and not be within 3 mm of the optic pathways.
1.3
Deficiencies with standard therapy
1.3.1 
As mentioned above, for patients’ who present with worsening symptoms secondary to mass effect
on the surrounding tissues (deterioration of visual fields, headaches, loss of consciousness),
surgical resection should be the primary intervention.  However, depending on the size and
infiltration of the adenoma, achieving a complete total resection can be difficult, therefore leading
to an increased rate of recurrence.  Extensive surgical procedures used to obtain radical removal
of large pituitary adenomas, particularly by transcranial approaches, have been associated with
brain, optic nerve, or vascular injuries, or panhypopituitarism resulting in increased surgical
morbidity and mortality.15,30,31  A higher rate of complete resection and fewer optic and other cranial
nerve complications are associated with the transphenoidal approach.  Still, in some patients the
tumor cannot be removed or surgery may be associated with untoward toxicity.
Additionally, some patients are not candidates for surgical intervention due to the presence of
certain co-morbidities.  For these patients, treatment with conventional fractionated radiotherapy is
a potential option.  Radiotherapy alone has been shown to improve visual symptoms if visual field
impairment was initially mild.32-36  However, these effects are not usually appreciated until up to 2
to 3 years following treatment.  For both surgical resection and conventional radiotherapy, the
extent of the visual function recovery mainly depends on the preoperative deficits.37
1.4
Rationale and preliminary evidence for protocol therapy
1.4.1 
Given the need to treat patients with pan-invasive macroadenomas that were experiencing
worsening symptoms secondary to mass effect on surrounding tissues and who have previously
underwent surgical resection with recurrence of disease or who were not candidates for surgical
intervention, an alternative intervention was sought to decompress the adenoma and prevent
further deteriorating symptoms or to possibly improve their symptoms.
Previous experience in the treatment of meningiomas with brachytherapy using permanent
interstitial implantation of high activity iodine-125 (I-125) seeds provided the impetus for this
current protocol.  Kumar et al.38-40 treated 13 patients with interstitial high activity I-125 seeds.
Indications for implantation included recurrence after initial surgery or as a primary modality of
treatment in patient who were not candidates for surgery.  All 13 patients were alive at a median
follow up of 25 months.  Nine of the 13 patients achieved complete resolution of the tumor, while in
the remaining four, more than 50% reduction in tumor volume was noted.  The striking finding of
this study was the time-frame in which tumor response was observed.  The minimum time to
achieve complete response was 3 months.39,40 Additionally, no acute or late complications
secondary to this technique of brachytherapy was observed.  Given these promising results, we

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sought to apply a similar technique for the treatment of pan-invasive pituitary macroadenomas that
required rapid decompression in order to prevent further deterioration of symptoms.
There are several advantages in utilizing this technique for the treatment of pituitary adenomas.
Tumors in the central nervous system are in close proximity to cranial nerves, cerebral blood
vessels, and the brain stem.  A tight dosimetry is of vital importance while treating tumors in this
region.  I-125, because of its low gamma energy, produces a steep dose gradient permitting
delivery of a high tumor dose with a low dose to adjacent structures.41 By using I-125
brachytherapy, the dose distribution can be tailored to fit the tumor shape by selecting seed
placement at desired locations.  The seeds are placed under stereotactic procedures which can be
verified with imaging, making the treatment more accurate.  Additionally, the dose rate is a key
determinant of the biological effect of a given dose of radiation such that as the dose rate is
lowered the biological effect is reduced and so are the side effects. This so called ‘dose rate effect’
is most pronounced in the range between 1 and 100 cGy/min and more so in normal vs. tumor
tissue.42  This partially accounts for the relative normal tissue sparing with brachytherapy, which
confers an increased therapeutic ratio for this treatment. The dose rate effect is explained by the
ongoing repair of sublethal radiation damage during low-dose rate exposures and the fact that this
repair is more efficient in normal tissue. Also, the neoplastic cells in a solid tumor tend to be
asynchronously scattered in all phases of the cell cycle, and under continuous low-dose rate
irradiation, they tend to synchronize to the radiosensitive G2 and M phases.43  The radiation dose
rate effect should have a profound effect on the therapeutic ratio of brachytherapy applications for
brain tumors if, in fact, there is efficient repair of sublethal damage in the brain.44  The dose rate in
the Kumar et al. study39,40 was 5 cGy to 25 cGy per hour and given that no acute or late
complications were noted in their study, proposes that this treatment modality is well tolerated.
Interstitial irradiation of pituitary adenomas has been described before.  One of the first studies
exploring the role of interstitial irradiation in the treatment of pituitary adenomas was published in
1960 by Ramsay.45 These initial attempts with the implantation of radioactive gold and yttrium
seeds unfortunately had a high incidence of complications.  However, significant advances in
localization and guidance have occurred since then.  More current studies have shown favorable
outcomes.  Kumar et al.46 presented a case-report of one patient experiencing correction of
bilateral blindness secondary to a recurrent pituitary adenoma with the implantation of a single
high-activity iodine-125 seed.
1.5
Description of protocol therapy
1.5.1 
This study is a single arm Phase II pilot trial.  Patients enrolled on the trial will undergo
implantation of high activity iodine-125 seeds into their pituitary adenoma as outlined in sections 6
and 7.  The tumor response to treatment will be monitored as well as change in visual fields,
associated adverse effects, progression free survival and patient reported outcomes.
1.6
Who would benefit from protocol therapy?
1.6.1 
Patients that would be expected to benefit from protocol therapy are those who are experiencing
worsening neurological symptoms secondary to mass effect of their macroadenoma and who have
previously undergone a surgical resection with recurrence of their disease or who are not
candidates for surgical resection.  These patients would be expected to benefit from
decompression of their adenoma and given the findings seen in the treatment of meningiomas as
stated above, we anticipate that implantation of interstitial high activity iodine-125 would lead to
regression of their adenoma over the course of a few months, thereby preventing further
deterioration of their symptoms and possibly even improvement in some cases.

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2
OBJECTIVES
2.1
Primary objective
2.1.1 
To determine if placement of interstitial radioactive iodine seeds for the treatment of pituitary
macroadenomas can lead to a partial response (reduction in 30% of tumor volume) or greater
response within 12 months from the implant procedure.
2.2
Secondary objectives
2.2.1 
To determine if treatment results in a change of the patient’s Humphrey visual field testing
2.2.1.1
Timeframe of assessment is up to 5 years post therapy
2.2.2 
To assess for potential toxicities associated with interstitial seed placement
2.2.2.1
Specific toxicities that will be monitored are cerebrospinal fluid rhinorrhea, radiation-induced
necrosis, changes in visual field deficits, changes in visual acuity, changes in auditory acuity,
worsening headaches, and development of neurocognitive and/or short-term memory deficits
2.2.2.2
 Timeframe of assessment is up to 5 years post therapy
2.2.3 
To determine the progression free survival
2.2.3.1
Timeframe of assessment is up to 5 years post therapy
2.2.4 
To determine the effect of the treatment on quality of life evaluations (patient reported outcomes)
2.2.4.1
Timeframe of assessment is up to 5 years post therapy
2.2.5 
To evaluate the cost-utility of the treatment arm (in terms of the primary outcome) in comparison
with other widely accepted cancer and non-cancer therapies
2.2.5.1
Timeframe of assessment is up to 5 years post therapy
3
PATIENT SELECTION
3.1
Inclusion Critera
3.1.1 
Pathological or radiographic diagnosis of a pan-invasive pituitary macroadenoma
3.1.2 
Pan-invasive for the purposes of the protocol will be defined as meeting each of the following 2
major criteria:  1. tumor volume greater than 20 cc at enrollment, and 2. suprasellar extension.  In
addition, a pan-invasive tumor must meet any one of the following 3 minor criteria, a) unresectable
tumor invasion into a cavernous sinus, b) bone or bone marrow invasion into the clivus or temporal
bones, or c) tumor extension in any direction unlikely to be completely removed by specifically a
transphenoidal surgical approach.
3.1.3 
Patients who meet the two major criteria above (1 and 2) and are medically inoperable for tumor
resection (due to confounding co-existing medical problems) are eligible without meeting any of
the three minor criteria (a, b, or c).
3.1.4 
Patients should be immediately threatened for vision loss or other significant neurological
impairment directly related to tumor mass effect.  As such, all patients enrolled would likely benefit
from tumor response (shrinkage).
3.1.5 
Patients must have visible tumor on imaging studies (MRI or CT)
3.1.6 
The patient’s Zubrod performance status must be 0-3.
3.1.7 
Patients must be at least 18 years of age.

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3.1.8 
Mandatory Imaging Studies: Must be done 45 or fewer days prior to study entry
3.1.8.1
MRI or CT scan of the brain including the entire skull base and all areas of tumor extension
3.2
Exclusion Criteria
3.2.1 
Patients who are unable to undergo general anesthesia
3.2.2 
Patients who are unable to undergo placement of a stereotactic head frame
3.2.3 
Patients who are unable to provide informed consent
3.2.4 
Patients who are pregnant or nursing
3.2.5 
Patients with severe kidney dysfunction
3.2.6 
Patients who have contraindications to MRI, such as implanted pacemaker device
3.2.7 
Patients with diagnosis of pituitary carcinoma
3.3
Informed consent
3.3.1 
Patients must provide study-specific informed consent prior to ANY protocol specific procedures
3.3.2 
Patients must agree to having the radioactive seeds remain permanently in place after
implantation except for rare occasions (i.e. seed migration, as listed below in section 6.8.2), due to
the potential morbidity of seed removal otherwise
3.3.3 
All patients must be willing and capable to provide informed consent to participate in the protocol
3.3.4 
Patient is available for study related assessments and management at the treating institution for
the duration of the study
4
PRETREATMENT EVALUATIONS/MANAGEMENT (This section lists baseline evaluations
needed before the initiation of protocol treatment)
4.1
Required evaluations
4.1.1 
History and physical examination to include full neurologic assessment (cranial nerve evaluation,
confrontational visual field examination, strength assessment, sensory assessment, reflex
assessment, gait and balance assessment)
4.1.2 
Zubrod performance status (Appendix III)
4.1.3 
Baseline visual acuity assessment
4.1.4 
Baseline Humphrey visual field assessment
4.1.5 
Baseline audiometry exam
4.1.6 
Baseline neurocognitive assessment using the mini-mental state examination (MMSE), the
Hopkins Verbal Learning Test-Revised (HVLT-R), Trail Making Test: parts A & B, and the
Controlled Oral Word Association Test (COWAT)

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4.1.7 
Assessment of hormone levels (ACTH, AM cortisol, TSH, free T4, testosterone, LH, FSH, IGF-1,
GH, prolactin)
4.1.8 
Serum creatinine, CBC, platelets, electrolyte panel, PT/INR, PTT
4.1.9 
Urine pregnancy test for females (if childbearing age) within one week of study entry
4.1.10 Baseline quality of life evaluation using the European Organization for Research and Treatment of
Cancer 30-item core quality of life questionnaire (EORTC QLQ C-30), the brain specific quality of
life module (EORTC QLQ BN20)
4.1.11 Baseline assessment for monitoring the cost-utility of treatment will be assessed by using the brief
five-item EuroQol (EQ-5D)
5
REGISTRATION PROCEDURES
5.1
Preregistration
5.1.1 
Diagnostic Review
5.1.1.1
There are no requirements for central review of the pathology or radiographic imaging
studies used for initial diagnosis
5.1.2 
Accreditation
5.1.2.1
Facilities
5.1.2.1.1 Facilities should be in place for performing stereotactic procedures as well as for handling
radioactive seeds
5.1.2.2
Equipment
5.1.2.2.1 MRI facilities that are ACR certified
5.1.2.3
Training of Personnel
5.1.2.3.1 Personnel should have performed a certain number of stereotactic procedures as well as
transsphenoidal surgeries.
5.2
Registration
5.2.1 
Contact information
5.2.1.1
Name of Registrar (affiliated with the Clinical Research Office, CRO)
5.2.1.2
Address
5.2.1.3
FAX
5.2.1.4
email
5.2.2 
Procedures
5.2.2.1
Enrolling investigator must review eligibility checklist and sign/date at bottom that all criteria
have been met.
5.2.2.2
FAX or carry the enrollment form to the Registrar
5.2.2.3
A unique patient participation ID will be assigned
5.2.2.4
Eligibility will be confirmed by CRO Personnel
5.2.2.5
Successful completion of preregistration activities will be confirmed by the CRO Personnel
5.2.2.6
Treatment assignments will be conveyed to the treating investigator
6
RADIATION THERAPY
6.1
Technical Factors
6.1.1 
Physical factors
6.1.1.1
Iodine-125 (1125) radioactive seeds (or available isotope with similar energy for gamma
decay (i.e. Cs131) with prior approval of study PI) will be used for interstitial implantation

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6.2
Simulation
6.2.1
Patient positioning
6.2.1.1
Patients will be positioned in a stable position supine with a headrest. A knee sponge maybe
used for comfort.  Use of a facemask for immobilization is not required.
6.2.2
Image acquisition
6.2.2.1
Formal simulation should be carried out with computed tomography (CT) scanning from the
vertex to approximately cervical vertebrae #2.  CT will be the primary image platform for targeting
and treatment planning.  The planning CT scans must be done with IV contrast unless the patient
has allergic problems with contrast or has renal insufficiency.  Contrast will allow better distinction
between tumor and adjacent vessels, or other non-involved tissues.  MRI should also be used for
tumor/target localization, as appropriate, when it is likely that they will aid in optimizing simulation
(i.e., differentiating target vs uninvolved tissues).   MRI imaging will be performed with techniques
and frequency consistent with the standard of care for evaluation and follow-up of the disease
process.  The scans will be ordered as routine pituitary fossa evaluations which include T1
weighted images with and without contrast.  Preferred MRI acquisition would also include thin cut
contrast enhanced T1 weighted 3-D SPGR images acquired in the coronal plane with fat saturation
and subsequently reconstructed in the axial and sagittal planes to better distinguish extent of
tumor in the skull base. Various T2 weighted images and/or other sequences will be per the
discretion of the supervising neuroradiologist for an optimal, patient appropriate routine study.
6.2.2.2
Axial acquisitions with gantry 0 degrees will be required with spacing ≤ 1.0 mm between
scans in the region of the tumor.  Images will be transferred to the treatment planning computers
via direct lines, disc, or tape.
6.3
Seed Calibration and Handling
6.3.1 
The seeds will be received and inventoried according to each institution’s policy and procedures in
a manner consistent with federal or state regulations.  A random sampling of at least 10% of the
seeds shall be calibrated in such a manner that there is direct traceability to either the NIST or an
AAPM ADCL for the I-125 seed, as described by AAPM Report TG 40, paragraph V. A. 2.  The
measured activity will be compared against the vendor’s statement of activity.  If the seeds in
sterile absorbable material are used, then one seed from every 5 packets will be removed and
calibrated.
6.4
Treatment planning
6.4.1 
Targets (per ICRU 62)
6.4.1.1
Gross tumor volume (GTV) is outlined to correspond to the visible tumor as seen on CT or
CT fused with other imaging platforms.  The GTV may be disjointed.
6.4.2 
Dosimetry
6.4.2.1
Pre-plan
6.4.2.1.1 
The determination of the number of seeds, their activity, and location to be implanted will be
determined by the volume of the GTV.  Implant locations that are achievable via transsphenoidal,
transcranial or transfrontal approaches will be used.
6.4.2.1.2 
A “point dose” will be defined as a dose to 0.035 cc of tissue rather than the planning
system’s definition of a point.
6.4.2.2
Prescription Dose and Volume
6.4.2.2.1 
The prescribed dose is the dose that the oncologist intends to deliver and is the dose
entered into the treatment record.  For the purposes of this protocol, the prescribed dose is 50 Gy
to the margin of the GTV.  The prescription dose must cover at least 90% of the GTV.  The
volume encompassed with prescription isodose volume should be recorded on the appropriate
data form.

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6.4.2.3
Minimum Target Dose
6.4.2.3.1 
For the purposes of this protocol, the minimum target dose will be defined as the minimum
dose to the GTV.  This can be determined by an evaluation of the dose distribution in each CT
image containing the adenoma.  The minimum dose to the GTV should be at least 80% of the
prescriptions dose (40 Gy)
6.4.2.4
Hot Spot (High Dose) Volume
6.4.2.4.1 
For the purposes of this protocol, the hot spot volume is defined as the volume enclosed by
150% of the prescribed dose (75 Gy) is the hot spot volume.  This dose level must occur within
the GTV.  The high dose volume in all axial planes shall be reported on the appropriate data form.
6.4.2.5
Low Dose Volume
6.4.2.5.1 
For the purposes of this protocol, the low dose volume will be defined as the volume
encompassed by the 50% of prescription Isodose volume (25 Gy).  The low dose volume should
be reported on the appropriate form.
6.4.2.6
Dose Volume Histograms
6.4.2.6.1 
A DVH for the GTV should be calculated in 5 Gy increments and presented in tabular form
6.4.2.6.2 
A DVH for the optic pathway, as defined in the region of the adenoma such that the high
dose volume of the implant is included, shall be calculated in 5 Gy increments and presented in
tabular form
6.4.2.6.3 
A DVH for the brain stem, as defined in the region of the adenoma such that the high dose
volume of the implant is included, shall be calculated in 5 Gy increments and presented in tabular
form
6.4.2.6.4 
A DVH for the hippocampi as defined in the region of the adenoma such that the high dose
volume of the implant is included, shall be calculated in 5 Gy increments and presented in tabular
form
6.4.3
Organs at Risk (OAR)
6.4.3.1
Optic nerve limit.  The dosimetry should be constructed so that the optic nerves, chiasm, and
proximal optic radiations receive no more than the prescription dose (50 Gy) to any point along the
optic pathway.  Exceeding this by more than 5% is a major protocol violation.
6.4.3.2
Hippocampi limit.  The dosimetry should be constructed so that the hippocampi receive no
more than the prescription dose (50 Gy) to any point.  Exceeding this by more than 5% is a major
protocol violation.
6.4.3.3
Contouring OARs
The OARs must be appropriately contoured so that dose volume histograms can be generated.
Fusion of 3D-SPGR MRI to the treatment planning CT would assist greatly in the delineation of the
OARs and is therefore highly recommended.  Contouring instructions are described in the table
Serial Tissue
Contouring Instructions
Endpoint
(≥Grade 3)
Optic Pathway
Contour as one structure including
both sides from posterior globe,
including chiasm, to proximal optic
radiations
neuritis
Hippocampi
Contour bilateral hippocampi as
one structure as per the RTOG
hippocampi sparing proctocol
memory loss
Cochlea
Each side separately, include at
least 3 CT slices
hearing loss
Brainstem (not
medulla)
Superiorly from incisura, midbrain
and pons only, one structure
cranial
neuropathy
Cerebellum
Contour entire cerebellum to
cerebellar peduncles
Ataxia

- 15 -
6.5
Radiation Therapy Treatment
6.5.1 
Radioactive seeds will be implanted via transsphenoidal, transcranial or transfrontal approach with
the assistance of a stereotactic head frame (see section 7 for more details).
6.6
Post-Operative Evaluation
6.6.1 
The post-implant CT shall be taken the same day or following day after the implant.  This scan will
also be used to assess for any bleed post-operatively.  The patient shall be positioned in a similar
position as the pre-implant planning scan.
6.6.2 
As defined above, the post-implant CT definition of the adenoma is the GTV.  As a minimum, dose
distributions shall be calculated on each image on which the GTV is defined.  The post-implant
dosimetry form shall be completed.  This form requires the determination of the minimum dose of
the GTV for each axial image on which the GTV is defined, the dimensions of the high dose area
on each axial image on which the GTV is defined, the dimensions of the low dose area on each
axial image on which the GTV is defined, and tabular DVH’s for the adenoma and high dose
regions of the optic tract, brainstem and hippocampi in 5 Gy increments.
6.6.3 
The evaluation criteria are as follows:
·
Per Protocol: greater than or equal to 90% of the GTV receives at least the prescription dose
(50 Gy) and 99% of the GTV should receive at least 40 Gy.  The maximum dose to the dense optic
pathways and hippocampi is no more than 50 Gy
·
Variation, Acceptable: greater than or equal to 70% of the GTV receives at least 50 Gy and
99% of the GTV receives between 35-40 Gy.  The dense optic pathway and hippocampi receives 50-
52 Gy.
·
Deviation, Unacceptable: The 50 Gy Isodose covers less than 70% of the target or the
minimum dose to 99% of the GTV is under 35 Gy.  The dense optic pathway and hippocampi
maximum dose is more than 52 Gy.
6.7
(Radiation Therapy Compliance)
6.7.1 
Accreditation Compliance
6.7.1.1 All criteria listed in Section 5 must be completed to the satisfaction of the Principal Investigators in
order to be accredited.  Upon completion of the criteria, a letter will be sent to institutions informing
them of accreditation for the study. No institution will be allowed to enroll patients without
accreditation.
6.8
Radiation Therapy Adverse Events
6.8.1 
General approach
6.8.1.1 Radiation associated adverse events will be categorized and scored according to the Common
Toxicity Criteria (version 4.0) available from the United States National Institutes of Health website
(http://ctep.info.nih.gov).
6.8.1.2 Relation to therapy (e.g., unrelated, possibly, probably, or definitely related) will be made.  In trials
with multiple modalities (e.g., surgery and radiation), an attempt will be made to distinguish which
therapy was causative.  However, in some circumstances this will not be possible.
6.8.2 
Seed Migration
6.8.2.1 Follow up imaging on the scheduled intervals listed below (9.1.1) will be used to monitor the
position of the implanted radioactive seeds.  There is the potential for the seeds to migrate and/or
change position in response to shrinkage of the tumor secondary to treatment.  This change in
location of the seeds could potentially cause an increased dose to OARs.  If this occurs, then
measures should be attempted to move or remove the seed which has migrated if the treating
physician determines appropriate.  Seeds that are removed will be handled and disposed of as per
institutional policy
6.8.3 
Radiation-Induced Necrosis
6.8.3.1 Radiation-induced necrosis (RIN) is part of a series of clinical syndromes related to CNS
complications of radiotherapy. These syndromes occur in a distinct chronologic order and have
characteristic pathophysiology. While the term radiation necrosis is used to refer to radiation injury,
pathology is not limited to necrosis and a spectrum of injury patterns may occur.  Clinical symptoms

- 16 -
as well as follow-up imaging studies will be used to assess for the presence of radiation-induced
necrosis.  If RIN is suspected, observation, steroids or hyperbaric oxygen therapy could be used for
treatment as determined appropriate by the treating physician.
6.9
Radiation Therapy Adverse Event Reporting
6.9.1 
Definition of an Adverse Event (AE)
6.9.1.1 Any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or
disease temporally associated with the use of a medical treatment or procedure regardless of
whether it is considered related to the medical treatment or procedure (attribution of unrelated,
unlikely, possible, probable, or definite).
6.9.2 
Definition of a Serious Adverse Event (SAE)
6.9.2.1 Any adverse experience occurring during any part of protocol treatment and 30 days after that
results in any of the following outcomes:
§ 
Death;
§ 
A life-threatening adverse experience;
§ 
Inpatient hospitalization or prolongation of existing hospitalization;
§ 
A persistent or significant disability/incapacity;
§ 
A congenital anomaly/birth defect.
6.9.2.2 Important medical events that do not result in death, are not life threatening, or do not require
hospitalization may be considered an SAE experience, when, based upon medical judgment, they
may jeopardize the patient and may require medical or surgical intervention to prevent one of the
outcomes listed in the definition.
6.9.3 
Electronic Institutional Review Board (eIRB)
6.9.3.1 eIRB constitutes a mechanism for reporting serious adverse events to the UTSW IRB for reporting
purposes.
6.9.3.2 Any adverse event equivalent to CTC V.4 grade 3, 4, or 5 or which precipitates hospitalization or
prolongs an existing hospitalization must be reported regardless of designation (expected or
unexpected) along with the attribution. This includes all deaths that occur within 30 days after the
patient was discontinued from the study regardless of attribution AND any events that occur
beyond 30 days and are considered probably related to treatment.
6.9.3.3 SAE reports must be completed (the CRF plus information describing the event, the grade, and the
attribution) within 48 hours of the investigator’s awareness of the occurrence of the event.
6.9.3.4 Attribution of an event can be categorized as:
· 
Not Related
· 
Possibly Related
· 
Probably Related
· 
Definitely Related
6.9.3.5 Adverse events (below grade 3) do not need to be submitted immediately.  Rather, they should be
documented in the Adverse Events Clinical Report Form (CRF) along with a brief description of the
event, grade, and attribution).
All SAE reports should be made via FAX transmission to:
Department of Radiation Oncology
Clinical Research Office
The University of Texas Southwestern Medical Center
Attention:  Jean Wu, Project Manager
FAX #: 214-648-5923

- 17 -
7
OTHER  THERAPY (INCLUDING SURGERY)
7.1
Surgery
7.1.1 
Transsphenoid approach for placement of radioactive seeds
7.1.1.1 The patient will be placed under general anesthesia.  The stereotactic head frame will then be
placed.  A MRI scan of the brain with gadolinium contrast will then be obtained.  A Mayfield
headholder will be used to retain the stereotactic head frame.  As this point, examination of the
nose using nasal endoscope to assess for the best route will be performed.  Good access into the
sphenoid sinus with visualization of the sella should be obtained.  Placement of the radioactive
seed will be placed using the stereotactic head frame utilizing coordinates obtained from the pre-
implant planning scan.  Lateral X-rays should be obtained to verify the correct level of the seed and
also to make sure the seed stayed in place once the introducer was removed.
7.1.2 
Transcranial approach for placement of radioactive seeds
7.1.2.1 Patient preparation and set-up will be similar as that mentioned above for a transsphenoidal
approach.  After the stereotactic coordinates are confirmed, a skin knife will be used to expose the
skull.  A hand drill is used to perforate through the bone and dura.  The radioactive seed will then
be implanted with an introducer and conformation of location as well as seed retention after
removal of the introducer should be confirmed by fluoroscopic x-ray.  The craniotomy site will then
be closed in an appropriate fashion.
7.1.3 
Following surgical placement of the seeds, the frame should be removed and the patient
monitored for an appropriate amount of time to assess for any potential acute post-operative
complications.
7.2
Permitted Supportive Therapy
7.2.1 
All supportive therapy for optimal medical care will be given during the study period at the
discretion of the attending physician(s) within the parameters of the protocol and documented on
each site’s source documents as concomitant medication including:
· 
Antiemetics
· 
Anticoagulants
· 
Antidiarrheals
· 
Analgesics
· 
Hematopoietic Growth Factors
· 
Herbal products
· 
Nutritional supplements
8
SPECIMEN SUBMISSION
8.1
Pathology review
8.1.1 
Central pathology review
8.1.1.1 A copy of the initial pathology report (if available) defining the eligible histological diagnosis must
appear in the treatment record.
8.1.1.2 No central pathology review is part of this protocol
8.2
Tissue submission for translational research
8.2.1 
Investigational nature of translational research
8.2.1.1 Initially serum will be collected in order to build proteomic profiles of treatment recurrence, control,
and toxicity, however, with time there may be other analytical methodologies that are not yet
devised.  Blood cells will be processed and RNA and DNA collected.  Ultimately, gene expression
and genotyping will be performed and correlated with treatment outcome or normal tissue
response.
8.2.2 
Tissue collection
8.2.2.1 Serum will be collected and frozen for subsequent analysis

- 18 -
8.2.2.2 Whole blood will be drawn [20 ml per collection timepoint: 10 ml from red top and 10 ml from
lavender top tubes] using standard procedure in order to collect lymphocytes as well as plasma
serum.  Blood will be processed using standard procedure immediately after it is collected and
then stored at -70 to -80 degrees C. The samples will be kept indefinitely or until exhausted.
8.2.2.3 Collection Timepoints
1. Within 1 week prior to the first treatment (baseline)
5. 6 months after completing the treatment
8.2.2.4 For serum collection, the following materials must be provided:  the date of collection of the serum,
timepoint of blood collection, type of sample, the protocol number, and the patient’s study specific
study-ID number.
8.2.2.5 Submit materials for Translational Research to:
Michael Story, Ph.D.
UT Southwestern Medical Center at Dallas
5323 Harry Hines Blvd, Dallas, Texas 75390
(214) 648-5557
Michael.Story@utsouthwestern.edu
8.2.3 
Confidentiality and Storage
8.2.3.1 Upon receipt, the specimen is labeled with the protocol number and the patient’s assigned study-
identification number only. The database only includes the following information: the number of
specimens received, the date the specimens were received, documentation of material sent to a
qualified investigator, type of material sent, and the date the specimens were sent to the
investigator. No clinical information is kept in the database.
8.2.3.2 Specimens for translational research will be stored for an indefinite period of time (or until
exhausted) and may be used for future studies. If at any time the patient withdraws consent to
store and use specimens, the material will be destroyed.
8.2.3.3 Specimen will be stored at the UT Southwestern Medical Center Division of Molecular Radiation
Biology laboratories (NC 7.206) and the UT Southwestern Tissue Repository.
9
PATIENT ASSESSMENTS
9.1
Study Parameters per Study Calendar found in Appendix II
9.1.1 
Monitor for change in size of adenoma
9.1.1.1 The pre-treatment dimensions of the pituitary adenoma will be determined by using the pre-
treatment MR images and measuring the adenoma.  The maximum craniocaudal and transverse
diameters of the adenoma will be measured on the coronal plane, while the anteroposterior
diameter will be measured on the sagittal plane. These measurements will be determined by the
radiation oncologist and the neurosurgeon and be reported in millimeters (mm) and overall volume
of the adenoma (mm3).
9.1.1.2 The schedule for follow-up MR imaging studies will be every 3 months following seed implantation
for the first two years, every six months for the next two years and then yearly afterwards.
Measurements as stated above in 9.1.1.1 will be obtained for each imaging study.
9.1.2 
Monitor for improvement in Humphrey visual field testing
9.1.2.1 Pre-treatment Humphrey visual field testing will be performed by a neuro-ophthalmologist
assessing the visual field status of each eye of the patient
9.1.2.2 Each eye will be counted as data point in which future measurements will be compared
9.1.2.3 The schedule for follow-up Humphrey visual field testing will be every 6 months following seed
implantation for the first two years, then yearly afterwards.

- 19 -
9.1.3 
Monitor for potential adverse effects
9.1.3.1
Specific toxicities that will be monitored are cerebrospinal fluid rhinorrhea, radiation-induced
necrosis, changes in visual field deficits, changes in visual acuity, changes in auditory acuity,
worsening headaches, and development of neurocognitive and/or short-term memory deficits
·
Cerebrospinal fluid rhinorrhea will be assessed for at every follow up appointment
·
Radiation-induced necrosis will be assessed for by utilizing clinical symptoms and
radiographic imaging at every follow-up appointment
·
Changes in visual field deficits will be assessed by performing confrontational visual field
testing at every follow-up appointment (a more detailed assessment of visual fields will be obtained
by using Humphrey visual field testing as outlined in 9.1.2)
·
Changes in visual acuity will be assessed in conjunction with the Humphrey visual field
testing by a neuro-ophthalmologist at the scheduled times as outlined in 9.1.2
·
The presence of worsening headaches will be assessed at every follow up appointment.  A
scale of 1-10 will be used to determine the severity of the headaches.
·
Development of neurocognitive and/or short-term memory deficits will be assessed by using
the following testing modalities: the mini-mental status exam (MMSE), the Hopkins Verbal
Learning Test-Revised (HVLT-R), Trail Making Test: parts A & B, and the Controlled Oral Word
Association Test (COWAT).  These will be administered every 12 months.
9.1.4 
Endocrinological Evaluation
9.1.4.1 Pre-treatment hormone levels will be determined for ACTH, AM cortisol, TSH, free T4,
testosterone, FSH, LH, IGF-1, GH, prolactin.  Any abnormal values will be corrected for with
appropriate supplementation.  Follow-up endocrinological evaluations will take place annually.
9.1.5 
Quality of Life Assessments
9.1.5.1 Quality of life assessments will take place prior to treatment and then every six months for the first
year and then yearly afterwards.  The following questionnaires will be utilized for this assessment:
the European Organization for Research and Treatment of Cancer 30-item core quality of life
questionnaire (EORTC QLQ C-30), the brain specific quality of life module (EORTC QLQ BN20)
and
9.1.6 
Evaluation of Cost-Utility
9.1.6.1 Evaluation the cost-utility of the treatment arm (in terms of the primary outcome) in comparison with
other widely accepted cancer and non-cancer therapies will be assessed by using the brief five-
item EuroQol group EQ-5D-3L.  Assessments will take place prior to treatment and then every six
months for the first year and then yearly afterwards.
9.2
Ongoing Toxicity Assessments
9.2.1 
All acute and late adverse events from protocol radiation therapy will be reported and scored for
severity using the NCI Common Terminology Criteria for Adverse Events (CTC) version 4.0. A
copy of the CTC v4.0 can be downloaded from the CTEP home page (http://ctep.info.nih.gov).
Please note that this study will not be using separate toxicity scales for acute and late
radiation adverse events.
10
DATA COLLECTION
10.1
Submission
10.1.1 Data should be submitted to:
Department of Radiation Oncology
Clinical Research Office
The University of Texas Southwestern Medical Center
Attention:  Jean Wu, Project Manager
5801 Forest Park Road
Dallas, Texas  75390-9183
FAX #: 214-648-5923

- 20 -
Patients will be identified only by initials (first middle last) and a unique study ID number assigned
to each study participant; if there is no middle initial, a hyphen will be used (first-last). Last names
with apostrophes will be identified by the first letter of the last name. Participating sub-sites must
remove or black-out identifiers from source documentation that is sent to UTSW.
10.1.2 Summary of Data Submission
Item
Due
Demographics
Within 2 weeks of study entry
Eligibility and Entry Characteristics including
baseline H&P and labs
Within 2 weeks of study entry
Baseline Humphrey Visual field testing
Within 2 weeks of study entry
Baseline audiometry
Within 2 weeks of study entry
Baseline Neurocognitive Assessments
Within 2 weeks of study entry
Baseline QOL Assessments
Within 2 weeks of study entry
Dosimetry information
Within 1 week after completion of post-implant
CT imaging
Follow-up H&P data
follow-up at 1, 3, 6, 9, 12 months, then every 6
months to 4 years; then annually for years 4-
10
Adenoma Measurements
follow-up at 3, 6, 9, 12 months, then every 6
months to 4 years; then annually for years 4-
10
Follow-up Humphrey Visual field testing
follow-up at every 6 months to 2 years; then
annually for years 2-10
Follow-up Endocrine Evaluation
follow-up at every 12 months to 10 years
Follow-up Neurocognitive Assessment
follow-up at every 12 months to 10 years
QOL Assessment
follow-up at every 6 months to 1 year, then
annually for years to 2-10
Adverse Event assessment
follow-up at 1, 3, 6, 9, and 12 months, then
every 6 months to 4 years; then annually for
years 4-10
11
STATISTICAL CONSIDERATIONS
11.1
Primary Endpoint
11.1.1 The primary endpoint of this study is to determine the rate of partial (>30% reduction in GTV) or
complete responses occurring within one year of therapy.  This will be assessed by measuring the
adenoma in three dimensions, as well as determining the total volume, on pre-treatment and
follow-up imaging studies.  The percent change in size and volume of the adenoma will then be
calculated by subtracting the post-treatment measurements from the pre-treatment measurements
then divided by the pre-treatment measurements and then multiplied by 100.  The mean, median
and standard deviation of the percent change will be determined.
11.2
Secondary Endpoints
11.2.1 Change in Humphrey Visual Fields
11.2.1.1
Data for each eye will be obtained before and after treatment.  Visual fields will be reviewed
by a neuro-ophthalmologist for any signs of improvement or deterioration.
11.2.2 Toxicities
11.2.2.1
Specific toxicities that will be monitored are cerebrospinal fluid rhinorrhea, radiation-induced
necrosis, changes in visual field deficits, changes in visual acuity, changes in auditory acuity,
worsening headaches, and development of neurocognitive and/or short-term memory deficits
11.2.3 Progression Free Survival
11.2.4 Change in QOL Assessments

- 21 -
11.2.4.1
Scoring of each assessment tool will be conducted as per each individual tool’s scoring
instructions
11.3
Sample Size
11.3.1 Overview: The primary goal of this study is to monitor shrinkage in adenoma size and volume
following treatment.
11.3.2 Sample Size Derivation: The predicted partial or complete response rate (PR+CR) of treated
subjects at a follow-up interval of 12 months is the determinant of sample size.  A PR + CR rate of
of 10% or less would be considered insufficiently low for further investigation of this treatment,
whereas a PR + CR probability of 50% or higher will be considered worthy of future investigation.
If the true PR + CR rate is 50%, a sample size of 10 patients will provide 87% power to detect a
significantly higher RTS than 10% with an alpha level of 0.025. To assure an adequate number of
evaluable patients, allowing for a small number of patients who would be lost to follow-up or
otherwise found non evaluable, a total of up to 12 patients will be enrolled.  This analysis applies to
both cohorts (those with and without previous radiation therapy)
The sample size of this study will not exceed 24 patients.
11.3.3 There will be an early stopping rule for unexpected toxicity. If at any point during the study more
than 1/6 of patients treated to date experience study treatment-related grade 4-5 toxicity of any
kind, study enrollment will be suspended.  Treatment related events include those related or
possibly related to therapy.
11.4
Patient Accrual and Study Duration
11.4.1 It is expected that it will take approximately three to five years to complete the study. The analysis
for tumor shrinkage will be carried out after each follow-up and collectively after each patient has
had 365 days (i.e., 12 months) of follow-up.  Study-related data will be stored for 5 years after
termination of the study when accrual is no longer taking place and all patients have discontinued
follow-up procedures. Blood drawn for translation research will be kept indefinitely or until
exhausted.
11.5
Analysis Plan
11.5.1 Interim Reports
11.5.1.1
Interim reports will be updated at least every six months until the results of the study are
published.  In general, the interim reports will contain information about patient accrual rate with
projected completion dates of the trial, status of QA review and compliance rate of treatment per
protocol, and the frequencies and severity of toxicity.
11.5.1.2
The Analysis of Tumor Shrinkage: This analysis will be carried out when each patient has
had at least 730 days (i.e., 24 months) of follow-up.  The percent change in size and volume of the
adenoma will then be calculated by subtracting the post-treatment measurements from the pre-
treatment measurements then divided by the pre-treatment measurements and then multiplied by
100.  The mean, median and standard deviation of the percent change will be determined.
11.5.1.3
Estimation of Secondary Endpoints Related to the Efficacy: Cumulative incidence approach
will be used to estimate the progression free survival. For any individual patient, progressive
disease (PD) within the treated lesion will be scored as PD for that patient
11.6
Gender and Minorities
11.6.1 In conformance with the National Institute of Health Revitalization Act of 1993 with regard to
inclusion of women and minorities in clinical research, we have also considered the possible
interaction between race and treatments.  The projected gender and minority accruals are:

- 22 -
Projected Distribution of Gender & Minorities
Ethnic Category
Sex/Gender
Females
Males
Total
Hispanic or Latino
4
 4
 8
Not Hispanic or Latino
4
 12
 16
Ethnic Category: Total of all
subjects
8
16
24
Racial Category
American Indian or Alaskan Native
0
0
0
Asian
0
2
2
Black or African American
4
6
 10
Native Hawaiian or other Pacific
Islander
0
0
0
White
4
 8
 12
More than one race
0
0
0
Racial Category: Total of all
subjects
 8
16
 24
12
DATA SAFETY MONITORING PLAN
12.1
Purpose and Scope
12.1.1 The purpose of the Radiation Oncology Data and Safety Monitoring Plan is to ensure that clinical
trial data is accurate and valid and to ensure the safety of trial participants.
12.1.2 The Radiation Oncology DSMC is charged with developing, implementing, and maintaining the
Data and Safety Monitoring Plan. The membership consists of a Medical Director of Clinical
Research as well as representation from the following groups:  clinical research, nursing,
regulatory, pharmacy, physicists, radiation therapists, and faculty. Ad hoc members are contacted
to participate as needed
12.2
Procedures
12.2.1 Clinical trials are assessed for safety on a continual basis throughout the life of the trial.  All SAE’s
and any AEs that are unexpected and possibly/likely related to study participation are reported to
UTSW IRB through an electronic research system per UTSW IRB guidelines.
12.2.2 All clinical trials are reviewed on monthly basis for enrollment.  All local SAEs are reviewed by
Radiation Oncology DSMC monthly for severity and attribution. For investigator-initiated trials, all
SAEs at affiliated institutions are monitored as local SAEs.  The principle investigator and study
coordinator will present a study treatment summary and SAEs for review.  Source documents will
be available for the DSMC members during the review. NCI Common Toxicity Criteria Version 4
will be used for grading and attributing adverse events.
12.2.3 If the SAE occurs on a multi-institutional clinical trial coordinated by the Radiation Oncology
Clinical Research Office, the Clinical Research Manager or primary coordinator ensures that all
participating sites are notified of the event and resulting action, within one (1) working day of the
determination.
12.2.4 Interim Stopping Rules - Stopping for toxicity or efficacy will be related to dose limiting toxicity as
described in the statistical section.

- 23 -
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Fahlbusch R, Buchfelder M. Transsphenoidal surgery of parasellar pituitary adenomas. Acta
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13.
Zhang X, Fei Z, Zhang J, et al. Management of nonfunctioning pituitary adenomas with suprasellar
extensions by transsphenoidal microsurgery. Surg Neurol. Oct 1999;52(4):380-385.
14.
Greenfield JP, Leng LZ, Chaudhry U, et al. Combined simultaneous endoscopic transsphenoidal and
endoscopic transventricular resection of a giant pituitary macroadenoma. Minim Invasive Neurosurg.
Oct 2008;51(5):306-309.
15.
Saito K, Kuwayama A, Yamamoto N, Sugita K. The transsphenoidal removal of nonfunctioning
pituitary adenomas with suprasellar extensions: the open sella method and intentionally staged
operation. Neurosurgery. Apr 1995;36(4):668-675; discussion 675-666.
16.
Alleyne CH, Jr., Barrow DL, Oyesiku NM. Combined transsphenoidal and pterional craniotomy
approach to giant pituitary tumors. Surg Neurol. Jun 2002;57(6):380-390; discussion 390.
17.
Mickey B, Hutchins L, Ellis E. The role of the le fort I maxillotomy in the management of incompletely
resected pituitary macroadenomas. Skull Base. Nov 2007;17(6):369-378.
18.
Goel A, Nadkarni T. Surgical management of giant pituitary tumours--a review of 30 cases. Acta
Neurochir (Wien). 1996;138(9):1042-1049.
19.
Goel A, Deogaonkar M, Desai K. Fatal postoperative 'pituitary apoplexy': its cause and management.
Br J Neurosurg. 1995;9(1):37-40.
20.
Pia HW, Grote E, Hildebrandt G. Giant pituitary adenomas. Neurosurg Rev. 1985;8(3-4):207-220.
21.
Ciric I, Mikhael M, Stafford T, Lawson L, Garces R. Transsphenoidal microsurgery of pituitary
macroadenomas with long-term follow-up results. J Neurosurg. Sep 1983;59(3):395-401.
22.
Serri O, Rasio E, Beauregard H, Hardy J, Somma M. Recurrence of hyperprolactinemia after
selective transsphenoidal adenomectomy in women with prolactinoma. N Engl J Med. Aug 4
1983;309(5):280-283.
23.
Pamir MN, Kilic T, Belirgen M, Abacioglu U, Karabekiroglu N. Pituitary adenomas treated with
gamma knife radiosurgery: volumetric analysis of 100 cases with minimum 3 year follow-up.
Neurosurgery. Aug 2007;61(2):270-280; discussion 280.
24.
Chandler WF, Schteingart DE, Lloyd RV, McKeever PE, Ibarra-Perez G. Surgical treatment of
Cushing's disease. J Neurosurg. Feb 1987;66(2):204-212.

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25.
Friedman RB, Oldfield EH, Nieman LK, et al. Repeat transsphenoidal surgery for Cushing's disease.
J Neurosurg. Oct 1989;71(4):520-527.
26.
Laws ER, Sheehan JP, Sheehan JM, Jagnathan J, Jane JA, Jr., Oskouian R. Stereotactic
radiosurgery for pituitary adenomas: a review of the literature. J Neurooncol. Aug-Sep 2004;69(1-
3):257-272.
27.
Mampalam TJ, Tyrrell JB, Wilson CB. Transsphenoidal microsurgery for Cushing disease. A report
of 216 cases. Ann Intern Med. Sep 15 1988;109(6):487-493.
28.
Minniti G, Jaffrain-Rea ML, Osti M, Cantore G, Enrici RM. Radiotherapy for nonfunctioning pituitary
adenomas: from conventional to modern stereotactic radiation techniques. Neurosurg Rev. Jul
2007;30(3):167-175; discussion 175-166.
29.
Minniti G, Traish D, Ashley S, Gonsalves A, Brada M. Risk of second brain tumor after conservative
surgery and radiotherapy for pituitary adenoma: update after an additional 10 years. J Clin
Endocrinol Metab. Feb 2005;90(2):800-804.
30.
Hattori K, Kuwayama A. [Current technical aspect in transsphenoidal pituitary adenomectomy].
Nippon Rinsho. Oct 1993;51(10):2742-2747.
31.
Teramoto A. [Sellar and parasellar tumors]. Ryoikibetsu Shokogun Shirizu. 1993(1):72-77.
32.
Rush SC, Kupersmith MJ, Lerch I, Cooper P, Ransohoff J, Newall J. Neuro-ophthalmological
assessment of vision before and after radiation therapy alone for pituitary macroadenomas. J
Neurosurg. Apr 1990;72(4):594-599.
33.
Grigsby PW, Stokes S, Marks JE, Simpson JR. Prognostic factors and results of radiotherapy alone
in the management of pituitary adenomas. Int J Radiat Oncol Biol Phys. Nov 1988;15(5):1103-1110.
34.
Rush SC, Newall J. Pituitary adenoma: the efficacy of radiotherapy as the sole treatment. Int J
Radiat Oncol Biol Phys. Jul 1989;17(1):165-169.
35.
McCollough WM, Marcus RB, Jr., Rhoton AL, Jr., Ballinger WE, Million RR. Long-term follow-up of
radiotherapy for pituitary adenoma: the absence of late recurrence after greater than or equal to
4500 cGy. Int J Radiat Oncol Biol Phys. Aug 1991;21(3):607-614.
36.
Brada M, Rajan B, Traish D, et al. The long-term efficacy of conservative surgery and radiotherapy in
the control of pituitary adenomas. Clin Endocrinol (Oxf). Jun 1993;38(6):571-578.
37.
Gnanalingham KK, Bhattacharjee S, Pennington R, Ng J, Mendoza N. The time course of visual field
recovery following transphenoidal surgery for pituitary adenomas: predictive factors for a good
outcome. J Neurol Neurosurg Psychiatry. Mar 2005;76(3):415-419.
38.
Kumar PP, Patil AA, Leibrock LG, et al. Brachytherapy: a viable alternative in the management of
basal meningiomas. Neurosurgery. Nov 1991;29(5):676-680.
39.
Kumar PP, Patil AA, Syh HW, Chu WK, Reeves MA. Role of brachytherapy in the management of
the skull base meningioma. Treatment of skull base meningiomas. Cancer. Jun 1 1993;71(11):3726-
3731.
40.
Kumar PP, Patil AA. Interstitial brachytherapy for skull base tumors. Neurosurg Clin N Am. Oct
2000;11(4):639-649.
41.
Kumar PP, Good RR, Leibrock LG, Mawk JR, Yonkers AJ, Ogren FP. High activity iodine 125
endocurietherapy for recurrent skull base tumors. Cancer. Apr 15 1988;61(8):1518-1527.
42.
Vitaz TW, Warnke PC, Tabar V, Gutin PH. Brachytherapy for brain tumors. J Neurooncol. May
2005;73(1):71-86.
43.
Gregg EC, Yau TM, Kim SC. Effect of low dose rate radiation on cell growth kinetics. Biophys J. Oct
1979;28(1):81-91.
44.
Werner-Wasik M, Scott CB, Nelson DF, et al. Final report of a phase I/II trial of hyperfractionated and
accelerated hyperfractionated radiation therapy with carmustine for adults with supratentorial
malignant gliomas. Radiation Therapy Oncology Group Study 83-02. Cancer. Apr 15
1996;77(8):1535-1543.
45.
Ramsay GS. Interstitial irradiation of the pituitary. Proc R Soc Med. Aug 1960;53:641-644.
46.
Kumar PP, Good RR, Cox TA, Leibrock LG, Skultety FM. Reversal of visual impairment after
interstitial irradiation of pituitary tumor. Neurosurgery. Jan 1986;18(1):82-84.
47.
Gondi V, Tolakanahalli R, Mehta MP, et al. Hippocampal-sparing whole-brain radiotherapy: a "how-
to" technique using helical tomotherapy and linear accelerator-based intensity-modulated
radiotherapy. Int J Radiat Oncol Biol Phys. Nov 15 2010;78(4):1244-1252.
48.
Chera BS, Amdur RJ, Patel P, Mendenhall WM. A radiation oncologist's guide to contouring the
hippocampus. Am J Clin Oncol. Feb 2009;32(1):20-22.

- 25 -
APPENDIX I
STUDY PARAMETER TABLE
Pre-
Entry
Months Following Treatment
1 
3 
6 
9 
12
15
18
21
24
30
36
42
48
Every 12
months
for years
4-10
History and
Physical Exam
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
MRI Brain
X
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
Weight
X
  
  
X 
  
  
  
  
X 
X 
X 
X 
X 
X
X
Humphrey
Visual Field Test
X
  
  
X 
  
X 
  
X 
  
X 
  
X 
  
X
X
Visual Acuity
X
  
  
X 
  
X 
  
X 
  
X 
  
X 
  
X
X
Audiometry
X
Pregnancy test
(if applicable)
X
Endocrinological
Evaluation
X
  
  
X
X
X 
  
X
X
Creatinine, CBC,
platelets,
PT/INR, PTT,
Serum
Chemistry
X
Neurocognitive
Assessment
X
  
  
X
X
X 
  
X
X
Blood Draw for
Translational
Research
Xa
Informed
consent
X
QOL
Assessment
X
  
  
X 
  
X 
  
  
  
X 
  
X 
  
X
X
Adverse event
evaluation
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
a week prior to implant

- 26 -
APPENDIX II
ZUBROD PERFORMANCE SCALE
0
Fully active, able to carry on all predisease activities without restriction
(Karnofsky 90-100).
1
Restricted in physically strenuous activity but ambulatory and able to
carry work of a light or sedentary nature.  For example, light housework,
office work (Karnofsky 70-80).
2
Ambulatory and capable of all self-care but unable to carry out any work
activities.  Up and about more than 50% of waking hours (Karnofsky 50-
60).
3
Capable of only limited self-care, confined to bed or chair 50% or more of
waking hours (Karnofsky 30-40).
4
Completely disabled. Cannot carry on self-care. Totally confined to bed or
(Karnofsky 10-20).
5
Death (Karnofsky 0).
KARNOFSKY PERFORMANCE SCALE
100
Normal; no complaints; no evidence of disease
90
Able to carry on normal activity; minor signs or symptoms of disease
80
Normal activity with effort; some sign or symptoms of disease
70
Cares for self; unable to carry on normal activity or do active work
60
Requires occasional assistance, but is able to care for most personal
needs
50
Requires considerable assistance and frequent medical care
40
Disabled; requires special care and assistance
30
Severely disabled; hospitalization is indicated, although death not
imminent
20
Very sick; hospitalization necessary; active support treatment is
necessary
10
Moribund; fatal processes progressing rapidly
0
Dead

- 27 -
APPENDIX III
Post-Implant Dosimetry Data Form
Patient:
Physician:
Source: I-125, model XXXX
Doses are based upon TG 43 Dosimetry
Date of Pre-Implant CT study:
Date of Implant:
Date of Post-Implant CT study:
Basic Dosimetry Information
1. average activity per seed as measured by institution:
· 
Activity:
mCi
Date:
2. midpoint apparent activity stated by the vendor:
· 
Activity:
mCi
Date:
3. number of seeds used:
4. number of needles used:
5. Prescribed dose:
50Gy
TG 43 dosimetry
6. Peripheral dose:
     Gy
TG 43 dosimetry
Post Implant CT Analysis
Date of Implant:
Date of Post Implant CT Study:
1.  Adenoma is defined on ____ slices.
2.  Seeds are defined on ____ slices.
Analysis of each CT image
Slice
Min Dose to Adenoma
(GTV) in Gy
Dimensions of:
High Dose Area (cm x
cm)
Low Dose Area (cm x
cm)
1
2
3
4
5
6
7
8

- 28 -
9
10
11
12
Dose Volume Histogram Analysis
Doses are based on TG 43 dosimetry
Dose/Gy
Volume/%Adenoma
Volume/%Optic
pathway
Volume/%brain
stem
Volume/%memory
pathway
10
20
30
40
50
60
70
80
90
100
110
120
130
140
150
160
170
180
190
200
210
220
230
240
250
260
270
280
290
300
310
320
330
340
350
360
370
380
390
400

- 29 -
Appendix IV
Neurocognitive Battery: Background Information and Test Instructions
There are three immediate recall responses, one delayed recall response, and one delayed recognition
response in the HVLT-R. The response is the number of words the patient can recall out of 12 words for
recall responses and the difference of the listed words correctly and incorrectly recalled for recognition
response. The response from Trail Making Test, parts A & B is the time takes to finish each test less than 3
and 5 minutes, respectively. There are three responses for the COWAT, and each response is the number of
words starting with a provided letter of the alphabet that the patient can produce in one minute.
Testing: General Information
1. Testing should be completed in one session. Test instructions must be followed verbatim with every
patient at every assessment visit.
2. Tests should be administered in the following order to every patient and at each assessment visit:
HVLTR Part A (Learning Trials); Trail Making Test Part A; Trail Making Test Part B; COWAT; HVLT-
R Part B (Delayed Recall); and the HVLT-R Part C (Delayed Recognition).
3. Follow the instructions on the Forms Packet Index before submitting the forms.
4. All test results are recorded on the Neurocognitive Evaluation Summary Form , which is found in the
Forms Packet. Study/case-specific labels must be applied to all forms.
5.
Note: Sites should keep all original test records, and test results must remain on file at the institution
as source documentation pending request for submission..
6. Patients should not be given copies of their tests to avoid learning the material between test
administrations.
7. The HVLT-R and the COWAT have alternate forms or versions in order to reduce the effects of
practice. See the test instructions below for the versions to be administered at pre-treatment and
subsequent sessions. The forms should continue to be alternated in this order for the duration of the
study. The forms packet will contain alternate versions of these neuropsychological tests.
Before dismissing the patient, thank him/her for their cooperation. Remind the patient of their next
appointment and that these tests will be repeated.
In the event that a patient cannot complete a given test, please write the reason(s) on the test form AND the
data summary form.
Testing: Specific Instructions
Note: Administer the tests in the following order to every patient at each assessment visit.
1. HOPKINS VERBAL LEARNING TEST - REVISED (HVLT-R)
This test has three parts and six alternate forms (only the first 4 forms will be used in this study):
Part A - Free Recall: Complete the three learning trials first
Part B - Delayed Recall: Complete after Trail Making Tests and COWAT
Part C - Delayed Recognition: Complete after Delayed Recall
Part A – Free Recall: Trial 1
Examiner: “I am going to read a list of words to you. Listen carefully, because when I am through, I’d
like you to tell me as many of the words as you can remember. You can tell them to me in any order.
Are you ready?”
• Read the words at the rate of one word every 2 seconds.
Examiner: “OK. Now tell me as many of those words as you can remember.”
• Check off the words the patient recalls on the form.

- 30 -
• If a word is said that is not in the list (for example, “intrusion”), do not write that word on the form and say
nothing to the patient about the word not being on the list.
• If the patient does not produce any words for 10-15 seconds, ask the patient if he/she can remember any
more words.
• If not, move on to trial 2. Later, you can record the number of words that were correctly repeated on the
summary form.
Part A – Free Recall: Trial 2
Examiner: “Now we are going to try it again. I am going to read the same list of words to you. Listen
carefully, and tell me as many of the words as you can remember, in any order, including the words
you told me the first time.”
• Read the words at the rate of one word every 2 seconds.
• Check off the words the patient recalls on the form.
If a word is said that is not in the list (for example, “intrusion”), do not write that word on the form and say
nothing to the patient about the word not being on the list.
• If the patient does not produce any words for 10-15 seconds, ask the patient if he/she can remember any
more words.
• If not, move on to trial 3. Later, you can record the number of words that were correctly repeated on the
summary form.
Part A – Free Recall: Trial 3
Examiner: “I am going to read the list one more time. As before, I’d like you to tell me as many of the
words as you can remember, in any order, including all the words you’ve already told me.”
• Read the words at the rate of one word every 2 seconds.
• Check off the words the patient recalls on the form.
• If a word is said that is not in the list (for example, “intrusion”), do not write that word on the form and say
nothing to the patient about the word not being on the list.
• If the patient does not produce any words for 10-15 seconds, ask the patient if he/she can remember any
more words.
• Do not tell the respondent that recall of the words will be tested later.
• Record the time on the clock that you complete ‘Part A – Free Recall’ (for example, 1:00 p.m.) on the
designated space on the HVLT-R form.
2. TRAIL MAKING TEST [Timed Test]
Part A – Sample: Place the Sample A worksheet flat on the table, directly in front of the patient (the bottom
of the worksheet should be approximately six inches from the edge of the table). Give the patient a black pen
and say:
Examiner: “On this page (point) are some numbers. Begin at number 1 (point to 1) and draw a line
from 1 to 2 (point to 2), 2 to 3 (point to 3), 3 to 4 (point to 4), and so on, in order, until you reach the
end (point to the circle marked END). Draw the lines as fast as you can. Ready, begin.”
If the patient completes Sample A correctly, and in a manner demonstrating that s/he understands what to
do, proceed immediately to Test A. If the patient makes a mistake on Sample A, point out the error and
explain it.
The following explanations of mistakes serve as illustrations:
• This is where you start (point to number 1).
• You skipped this circle (point to the circle omitted).
• You should go from number 1 to 2, 2 to 3, and so on, until you reach the circle marked END.
If it is clear that the patient intended to touch a circle but missed it, do not count it as an omission. Remind
the patient, however, to be sure to touch the circles. If the patient still cannot complete Sample A, take
his/her hand and guide him/her through the trail using the opposite end of the pen, lightly touching the
worksheet to avoid making marks on he copy. Then say:

- 31 -
Examiner: “Remember, begin at number 1 (point to 1) and draw a line from 1 to 2 (point to 2), 2 to 3
(point to 3), 3 to 4 (point to 4) and so on, in order, until you reach the circle marked END (point). Do
not skip around, but go from one number to the next in proper order. Remember to work as fast as
you can. Ready, begin.”
If the patient does not succeed, or it becomes evident that s/he cannot do the task, DISCONTINUE testing
and indicate the corresponding reason on the Trail Making Data Sheet. If the patient completes Sample A
correctly and appears to understand what to do, proceed immediately to Part A.
Part A – Test: After the patient has completed Sample A, place the Part A test worksheet directly in front of
the patient and say:
Examiner: “Good! Let’s try the next one. On this page are numbers from 1 to 25. Do this the same
way. Begin at number 1 (point) and draw a line from 1 to 2 (point to 2), 2 to 3 (point to 3), 3 to 4 (point
to 4) and so on, in order, until you reach the circle marked END (point). Do not skip around, but go
from one number to the next in proper order. Remember to work as fast as you can. Ready, begin.”
• Start timing as soon as the instruction is given to “begin”
• Watch closely in order to catch any errors as soon as they are made. If the patient makes an error, call it to
his/her attention immediately and have him/her proceed from the point the mistake occurred
• The patient must complete the test in 3 minutes or less.
• DO NOT STOP TIMING UNTIL HE/SHE REACHES THE CIRCLE MARKED “END”.
• Collect the worksheet and record the time to completion on the Trail Making Data Sheet in minutes and
seconds
• If the patient does not complete the test within 3 minutes terminate the testing. The test can also be
discontinued if the patient is extremely confused and is unable to perform the task. Collect the worksheet and
complete the Trail Making Data Sheet indicating the reason the test was terminated and the last correct
number reached on the test.
Part B – Sample: Place the Sample B worksheet flat on the table, directly in front of the patient (the bottom
of the worksheet should be approximately six inches from the edge of the table) and say:
Examiner: “On this page (point) are some numbers and letters. Begin at number 1 (point to 1) and
draw a line from 1 to A (point), A to 2 (point to 2), 2 to B (point to B), B to 3 (point to 3), 3 to C (point to
C) and so on, in order, until you reach the end (point to the circle marked END). Remember, first you
have a number (point to 1), then a letter (point to A), then a number (point to 2), then a letter (point to
B), and so on. Draw the lines as fast as you can. Ready, begin.”
If the patient completes Sample B correctly, and in a manner demonstrating that s/he understands what to
do, proceed immediately to Part B. If the patient makes a mistake on Sample B, point out the error and
explain it.
The following explanations of mistakes serve as illustrations:
• You started with the wrong circle. This is where you start (point to number 1)
• You skipped this circle (point to the circle omitted)
• You should go from number 1 (point) to A (point), A to 2 (point to 2), 2 to B (point to B), B to 3 (point
to 3) and so on, until you reach the circle marked END (point).
If it is clear the patient intended to touch a circle but missed it, do not count it as an omission. Remind the
patient, however, to be sure to touch the circles. If the patient still cannot complete Sample B, take their hand
and guide them through the trail using the opposite end of the pen, lightly touching the worksheet to avoid
making marks on the copy. Then say:
Examiner: “Now you try it. Remember, begin at number 1 (point to 1) and draw a line from 1 to A
(point to A), A to 2 (point to 2), 2 to B (point to B), B to 3 (point to 3) and so on, in order, until you
reach the circle marked END (point). Ready, begin.”
If the patient does not succeed or it becomes evident that s/he cannot do the task, DISCONTINUE testing
and indicate the corresponding reason on the Trail Making Data Sheet. If the patient completes Sample A
correctly and appears to understand what to do, proceed immediately to Part A.

- 32 -
Part B – Test:
After the patient has completed Sample B, place the Part B Worksheet directly in front of the patient and say:
Examiner: “Good! Let’s try the next one. On this page are both numbers and letters. Do this the same
way. Begin at number 1 (point) and draw a line from 1 to A (point to A), A to 2 (point to 2), 2 to B
(point to B), B to 3 (point to 3), 3 to C (point to C) and so on, in order, until you reach the circle
marked END (point). Remember, first you have a number (point to 1), then a letter (point to A), then a
number (point to 2), then a letter (point to B), and so on. Do not skip around, but go from one circle to
the next in the proper order. Draw the lines as fast as you can. Ready, begin.”
• Start timing as soon as the instruction is given to “begin”.
• Watch closely in order to catch any errors as soon as they are made. If the patient makes an error, call it
to his/her attention immediately and have him/her proceed from the point the mistake occurred
• The patient must complete the test in 5 minutes or less.
• DO NOT STOP TIMING UNTIL HE/SHE REACHES THE CIRCLE MARKED “END”.
• Collect the worksheet and record the time to completion on the Trail Making Data Sheet in minutes and
seconds.
• If the patient does not complete the test within 5 minutes terminate the testing. The test can also be
discontinued if the patient is extremely confused and is unable to perform the task. Collect the worksheet and
complete the Trail Making Data Sheet indicating the reason the test was terminated and the last correct number
or letter reached on the test.
3. CONTROLLED ORAL WORD ASSOCIATION TEST (COWAT) [Timed Test]
This test has three parts (letters) and two alternate forms.
Examiner: “I am going to say a letter of the alphabet, and I want you to say as quickly as you can all
of the words that you can think of that begin with that letter. You may say any words at all, except
proper names such as the names of people or places. So you would not say ‘Rochester’ or ‘Robert’.
Also, do not use the same word again with a different ending, such as ‘Eat,’ ‘Eats,’ and ‘Eating.’
“For example, if I say ‘s,’ you could say ‘sit,’ ‘shoe,’ or ‘show.’ Can you think of other words
beginning with the letter ‘s’?”
Wait for the patient to give a word. If it is a correct response, say “good”, and ask for another word
beginning with the letter “s”. If a second appropriate word is given, proceed to the test itself.
If the patient gives an inappropriate word on either occasion, correct the patient, and repeat the instructions.
If the patient then succeeds, proceed to the test.
If the patient fails to respond, repeat the instructions. If it becomes clear that the patient does not understand
the instructions or cannot associate, stop the procedure, and indicate the reason(s) on the scoring sheet.
If the patient has succeeded in giving two appropriate words beginning with the demonstration letter, say:
Examiner: “That is fine. Now I am going to give you another letter. Again, say all of the words
beginning with that letter that you can think of. Remember, no names of people or places, just
ordinary words. Also, if you should draw a blank, I want you to keep on trying until the time limit is
up and I say STOP.”
“You will have a minute for each letter. The first letter is ‘___’” (see scoring sheet).
**Allow exactly one minute for each letter.**
• If the patient discontinues before the end of the time period, encourage him/her to try to think of more
words.

- 33 -
• If he/she is silent for 15 seconds, repeat the basic instruction and the letter (e.g., “Tell me all the words
you can think of that begin with a “c”).
• No extension on the time limit is made in the event that instructions are repeated.
• Continue the evaluation with the remaining two letters, allowing one minute for each.
Recording and Scoring:
• The record sheet provides lines on which the patient’s responses can be entered (e.g., write in the word
that is said by the patient). If his/her speed of word production is too fast to permit verbatim recording, a
“+” should be entered to indicate a correct response.
• Incorrect responses either should not be recorded or, if recorded, should be struck through with a line.
• If the patient provides more responses than there are lines on the record sheet, keep writing the responses
(or a “+”) elsewhere on the record sheet.
• Count all the correct responses. The number of correct words should be indicated below each column
on the recording sheet and on the summary data form.
Comments on scoring:
• Note: It can be helpful for the first several patients and for patients known to be fast with their word
production to tape record the session for transcription at a later time.
• The instructions include a specific prohibition against giving proper names or different forms of the same
word. Therefore, inflections of the same word (e.g., eat-eating; mouse-mice; loose-loosely; ran-run-runs) are
not considered correct responses.
• Patients often give both a verb and a word derived from the verb or adjective (e.g., fun-funny; sadsadness).
These are not considered correct responses. On the other hand, if the word refers to a specific object (e.g.,
foot-footstool; hang-hanger), it would be counted as a correct answer.
• Many words have two or more meanings (e.g., foot; can; catch; hand). A repetition of the word is
acceptable IF the patient definitely indicates the alternative meaning to you.
• Slang terms are OK if they are in general use.
• Foreign words (for example, pasta; passé; lasagna) can be counted as correct if they can be considered
part of English vocabulary (for example, in general use or found in the dictionary).
• If the test is discontinued or omitted, please mark this on the bottom of the test form and indicate the reason
on the Tests Discontinued/Not Done CRF
4. HOPKINS VERBAL LEARNING TEST - REVISED (HVLT-R)
Part B – Delayed Recall
• DO NOT READ THE WORD LIST AGAIN.
• Record the time on the clock that you start ‘Part B – Delayed Recall’ (for example, 1:20 p.m.) on the
designated space on the HVLT-R form.
• Administer ‘Part B – Delayed Recall’ after completing all Trail Making Tests and the COWAT. There should
be at least 15 minutes between ‘Part A’ and ‘Part B’. If the time is too short, allow the patients to complete a
questionnaire.
Examiner: “Do you remember that list of words you tried to learn before? Tell me as many of those
words as you can remember.”
• Check the box on the corresponding line of the HVLT-R worksheet for each word the patient accurately
recalls.
• If a word is said that is not in the list (for example, “intrusion”), do not write that word on the form and say
nothing to the patient about the word not being on the list.
• If the patient does not produce any words for 10-15 seconds, ask the patient if he/she can remember any
more words.
• If not, record the number of words that were correctly recalled on the summary form.
Part C – Delayed Recognition

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Examiner: “Now I’m going to read a longer list of words to you. Some of them are words from the
original list, and some are not. After I read each word, I’d like you to say “Yes” if it was on the
original list or “No” if it was not. Was [word] on the list?”
• Check either the “Y” (Yes) or “N” (No) box next to each word to indicate the patient’s response.
• Guessing is allowed.
• If the test is discontinued or omitted, please mark this on the bottom of the test form and indicate the reason
on the Tests Discontinued/Not Done CRF.
The score for this portion of the HVLT-R is the number of list words (i.e., words that in CAPS) correctly
identified (“yes” response) minus the number of non-list words (i.e., words in lower case) incorrectly identified
(“yes” response). Therefore, the actual score can range from –12 (no list words identified and all non-list
words identified) to +12 (all list words identified and no non-list words identified).

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Appendix V
Quality of Life Assessments
The EORTC quality of life questionnaire (QLQ) is an integrated system for assessing the health related
quality of life (QoL) of cancer patients participating in international clinical trials. The core questionnaire, the
QLQ-C30, is the product of more than a decade of collaborative research.  Following its general release in
1993, the QLQ-C30 has been used in a wide range of cancer clinical trials, by a large number of research
groups.
General principles of scoring
The QLQ-C30 is composed of both multi-item scales and single-item measures. These include five functional
scales, three symptom scales, a global health status / QoL scale, and six single items.
Each of the multi-item scales includes a different set of items - no item occurs in more than one scale.
All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a
higher response level.
Thus a high score for a functional scale represents a high / healthy level of functioning, a high score for
the global health status / QoL represents a high QoL, but a high score for a symptom scale / item
represents a high level of symptomatology / problems.
The principle for scoring these scales is the same in all cases:
1. Estimate the average of the items that contribute to the scale; this is the raw score.
2. Use a linear transformation to standardise the raw score, so that scores range from 0 to 100; a higher
score represents a higher ("better") level of functioning, or a higher ("worse") level of symptoms.
For more details and statistical evaluation, please see: http://www.eortc.be/home/qol/files/SCManualQLQ-
C30.pdf

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Appendix VI
Cost Effectiveness
Almost every incremental improvement in survival or progression-free survival comes at a cost.
The cost is both financial and experienced in terms of quality of life. Measurement of primary
outcomes such as freedom from progression and the most important aspects of human functioning and
quality of life will permit a summary equation allowing for differences in quality of life, clinical outcomes, and
cost to be incorporated into one equation. This equation is the Quality Adjusted Life Year (QALY) and a
study-specific modification, the Quality Adjusted Freedom From Progression Year (QAFFPY). The QALY has
been modified in a similar manner for different treatments where survival is not the primary outcome. Much of
the work in modifying the QALY began in ophthalmology, where sight-years, not life-years, are the outcome
of interest. Examples of modifications to the QALY have included incremental cost per vision-year gained to
assess the cost effectiveness of photodynamic therapy with verteporfin for age-related macular
degeneration, costs per sight-year saved with screening for diabetic retinopathy, cost-utility analysis for
treatments of retinal detachment associated with severe proliferative vitreoretinopathy, and the cost-utility of
cataract surgery.  However, the QALY has been used in other studies where survival is not the primary
outcome of interest, such as the costeffectiveness of memantine in the treatment of patients with moderately
severe to severe cognitive impairment from Alzheimer's and cochlear implantation for patients unable to gain
effective speech recognition with hearing aids. We will model costs using Medicare reimbursement and
measure utilities with the brief five-item EuroQol (EQ-5D).
The EQ-5D is a method for obtaining valuations (utilities) of health-related quality of life (HRQOL) to be used
as an adjustment to survival and in the cost-utility analysis. Developed in 1987, the EQ-5D is used by
investigators and the pharmaceutical industry throughout the United States, Europe, and Asia. It is one of
only several measures recommended for use in cost-effectiveness analyses by the Washington Panel on
Cost Effectiveness in Health and Medicine. The EQ-5D instrument is intended to complement other forms of
QOL measures, and it has been purposefully developed to generate a generic cardinal index of health, thus
giving it considerable potential for use in economic evaluation. The argument by some that a generic
measure does not capture some of the disease- or treatment-specific concerns of a given study misses the
point. This cost-effectiveness analysis is being done for purposes of exploring the means to inform macro
(health policy, payer) decision making, not micro (individual) decision making. The findings from the disease-
specific QOL instruments and treatment-related side effect QOL instruments described above will help inform
individual decision making. The role of the EQ-5D is to measure HRQOL at a macro level, in the same metric
as it has been measured across numerous diseases, including cancer.
This instrument gives us the ability to compare across and within diseases the “big picture” of what the
experts who developed the EQ-5D considered the primary health states of interest to humans: mobility, self
care, usual activities, pain/discomfort, and anxiety/depression. Further, there is no standardized measure to
assess and compare disease-specific utilities across or within diseases. Unlike the EQ-5D, the actual content
of standard gamble (SG) and time tradeoff (TTO) methods vary widely among studies and are subject to
wide variations in amount and type of information presented, message framing, and visual aids, making
replication of utilities with the SG or TTO extremely difficult. Therefore, using the EQ-5D, an exploratory aim
is to evaluate the cost-utility of the treatment arm demonstrating the most significant benefit (in terms of the
primary outcome), in comparison to other widely accepted cancer and non-cancer therapies. We will also
assess cost-utility among the arms to assess which therapy dominates. We will assess the value added of
the summary score known as a Quality Adjusted Life Year (QALY), and for this study the Quality Adjusted
FFP Year, that combines benefits of duration of freedom from progression (FFP) and decrements of quality
of life with financial cost of increasingly aggressive and costly therapy.
The EQ-5D has been used across numerous disease sites, including cancer. For example, the EQ-5D mean
score for 95 patients with NSCLC (93% male, mean age 62 years) was 0.58 (SD 0.32) as measured by the
questionnaire and 0.58 (SD 0.20) as measured by the visual analogue scale (VAS) version. The EQ-5D has
been used to assess QALYs and the economic value of prostate cancer screening, and treatment of pain
related to prostate cancer metastasis. Further, the EQ-5D was used in a recent study to estimate the

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economic value of the welfare loss due to prostate cancer pain by estimating the extent to which pain affects
health-related quality of life among patients with prostate cancer. Health status and economic outcomes
were modeled among a well-defined population of 200,000 Swedish prostate cancer patients. Health utility
ratings (using the EQ-5D) were obtained from a subset of 1,156 of the prostate cancer patients. A descriptive
model showed that optimal treatment that would reduce pain to zero during the whole episode of disease
would add on average 0.85 quality-adjusted life years (QALY) to every man with prostate cancer; the
economic value of this welfare loss due to prostate cancer pain was approximately $121,240,000 per year.
Quality-Adjusted Survival and Freedom from Progression
Quality-adjusted survival and freedom from progression can be defined in the same manner, by the weighted
sum of different time episodes added up to a total quality-adjusted life-year or freedom from progression–
year [U= sum of quality (qi) of health states K times the duration (si) spent in each health state].
Cost-Effectiveness and Cost-Utility
Cost-utility will be analyzed for planned publication at two time points: 1) at 1 year post-therapy, looking at
initial treatment costs and quality of life and 2) at five years post-therapy. The cost-utility analysis will be
done after the primary endpoint results are published.
Measurement of Costs
Direct medical costs fall into three categories: 1) initial therapy costs; 2) costs of managing the most common
side effects as determined by this study; and 3) costs of managing recurrence. Costs for interstitial
radiotherapy will be determined using CPT coding and Medicare reimbursement rates. Costs of common
management strategies of the most common side effects documented in this study (e.g., Imodium® for
diarrhea) will be estimated from regional costs per unit. Costs for managing recurrence will assume the
following salvage therapies: hormone therapy and chemotherapy. Costs will include professional fees,
cost/inpatient day, drugs, and supplies. Direct non-medical costs such as the cost of work lost or of
transportation will not be measured. Incremental differences in costs and outcomes will be compared for the
different alternatives and for the dominant alternative to other established therapies documented in the
literature.
The EQ-5D is a two-part self-assessment questionnaire. The first part consists of 5 items covering 5 dimensions
(mobility, self care, usual activities, pain/discomfort, and anxiety/depression). Each dimension is measured by a
three point Likert scale (1-no problems, 2-moderate problems, and 3-extreme problems). There are 243 (=35)
health states. The second part is a visual analog scale (VAS) valuing the current health state measured by 100
point scale with 10 point interval (0-worst imaginable health state, 100-best imaginable health state).

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Appendix VII
Risks to Subjects
Procedure
Risks
Measures to Minimize Risks
History and physical exam
(H&P)
MR imaging / CT imaging of
the brain
Blood draws (at all study
timepoints)
Zubrod Performance status
evaluation
Neurocognitive evaluation
QOL assessment
Interstitial seed placement
FAX transmittal of case report
forms (CRFs) to primary site
Unforeseen risks
Discovery of previously unknown
condition
Discovery of previously unknown
condition/recurrence or
progression of pituitary
adenoma; discomfort
Discomfort, bleeding, bruising,
dizziness, fainting, infection
Discomfort, psychological stress
of answering personal questions
Discomfort, psychological stress
of answering personal questions
Discomfort, psychological stress
of answering personal questions
Hemorrhage, cerebral spinal
fluid leak, neurological deficits
Constitutional:
likely:  fatigue
Loss of privacy
E.g., unpredictable interaction
between radiotherapy and
concomitant medications
Will be performed by MD and/or nurse
practitioner with oncology experience.
Will be performed by nurse/technician
with radiology experience
Blood will be drawn by an experienced
phlebotomist.
Subjects informed that they may refuse to
answer, take a break, or discontinue
participation at any time
Subjects informed that they may refuse to
answer, take a break, or discontinue
participation at any time
Subjects informed that they may refuse to
answer, take a break, or discontinue
participation at any time
Participants will be educated and asked
to inform study personnel if encounter
symptoms.
Sensitive patient information will be
blacked-out.  CRFs will only be identified
by subject initials and unique, study
identification number before fax
transmittal.
Strong encouragement to report any
difficulties and keep researchers aware of
any change in medications