Proton Beam Radiotherapy for Medulloblastoma and Pineoblastoma: An Assessment of Acute Toxicity and Long Term Neurocognitive, Neuroendocrine and Ototoxicity Outcomes
Phase: NA
Conditions: Brain Tumor, Medulloblastoma, Pineoblastoma
Sponsor: Massachusetts General Hospital

Phase II Study of Proton RT for Medulloblastoma and Pineoblastoma: Acute Toxicity and Long Term 
Outcomes, T. Yock, MD
07/20/2018
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Protocol Version Date:  03/01/2022
NCI Protocol #: N/A
Local Protocol #:  DFCI 09-361
Title: 
A Phase II Study of Proton Beam Radiotherapy for Medulloblastoma and 
Pineoblastoma: An Assessment of Acute Toxicity and Long-term Neurocognitive, 
Neuroendocrine and Ototoxicity Outcomes.
Principal Investigator:  Torunn I. Yock, MD MCH - Radiation Oncology
Massachusetts General Hospital
Coordinating Center: 
Massachusetts General Hospital
CCPO Multi-center Program
ccpo-mcgroup@mgh.harvard.edu
 Co-Investigators: 
Massachusetts General Hospital (MGH):  
Nancy Tarbell, MD, Radiation Oncology
Shannon MacDonald, MD, Radiation Oncology
William Butler, MD - Neurosurgery
David H. Ebb, MD - Pediatrics
Hanne Kooy, PhD - Radiation Physics
Karen Kuhlthau, PhD - Pediatric Research Unit
Beverly LaVally, RN, MS – Pediatric Oncology
Margaret Pulsifer, PhD - Psychology Assessment Center
Helen A Shih, MD, Radiation Oncology
Dana-Farber Cancer Institute (DFCI):
Karen Marcus, MD, Radiation Oncology
MD Anderson Cancer Center (MDACC)
Arnold dela Cruz Paulino, MD, Radiation Oncology (Site Principal Investigator)
Statistician: Beow Yeap, Sc.D., Jackie Szymonifka, MA - Biostatistics Group, MGH
Study Coordinator: at MGH: Miranda Lawell
Responsible Research Nurse: at MDACC: Beth DeGracia, RN, Lerma Ukegbu, RN 
Responsible Data Manager: at MGH: Miranda Lawell; at MDACC: Nancy Philip
Agent(s): Proton Beam Radiotherapy (no IND) 
Funding:  C06CA59267, Federal Share Clinical Trial Umbrella, Thomas F. DeLaney, MD, 
Principal Investigator

Phase II Study of Proton RT for Medulloblastoma and Pineoblastoma: Acute Toxicity and Long Term 
Outcomes, T. Yock, MD
07/20/2018
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SCHEMA

Phase II Study of Proton RT for Medulloblastoma and Pineoblastoma: Acute Toxicity and Long Term 
Outcomes, T. Yock, MD
07/20/18
CONFIDENTIAL
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TABLE OF CONTENTS
Page
SCHEMA
i
1: OBJECTIVES 
5
1.1
Study Design
5
1.2
Primary Objectives
5
1.3
Secondary Objectives
5
2: BACKGROUND
6
2.1 Study Agents
                      6
2.2 Study Disease
8
2.3 Rationale
8
2.4 Correlative Studies Background
14
3: PARTICIPANT SELECTION
14
3.1 Eligibility Criteria
14
3.2 Exclusion Criteria
14
3.3 Inclusion of Women, Minorities and Other Underrepresented Populations
15
4: REGISTRATION PROCEDURES
15
4.1
General Guidelines for DF/HCC and DF/PCC Institutions
15
4.2
Registration Process for DF/HCC and DF/PCC Institutions
15
4.3
Registration Process for Other Participating Institutions
15
5:  TREATMENT PLAN
15
5.1  Pre-treatment Criteria
16
5.2 Radiation Planning Guidelines
17
5.3
General Concomitant Medication and Supportive Care Guidelines
20
5.4
Duration of Therapy
20
5.5
Criteria for Removal from Study
21
5.6
Duration of Follow Up            
21
6: EXPECTED TOXICITIES AND DOSING DELAY/DOSE MODIFICATIONS
21
6.1 Anticipated Toxicities
21
6.2 Toxicity Management
22
6.3 Dose Modifications/Delays
23
7: DRUG FORMULATION AND ADMINISTRATION
23
8: CORRELATIVE/SPECIAL STUDIES
23
9: STUDY CALENDAR
24
9.1   Acute Side Effect Assessment
25
9.2
Description of Special Studies
25

Phase II Study of Proton RT for Medulloblastoma and Pineoblastoma: Acute Toxicity and Long Term 
Outcomes, T. Yock, MD
07/20/18
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10: MEASUREMENT OF EFFECT
29
10.1 Progression-Free Survival
29
10.2 Response Review
29
11: ADVERSE EVENT REPORTING REQUIREMENTS
29
11.1 General
29
11.2 Definitions
30
11.3 Recording Adverse Events
31
11.4 Reporting Adverse Events
31
11.5 Institutional Review Board (IRB) Notification by Investigator
33
11.6 Hospital Risk Management Notification by Investigator
33
12: DATA AND SAFETY MONITORING
33
12.1 Data Reporting
33
12.2 Safety Meetings
34
12.3 Monitoring
34
13: REGULATORY CONSIDERATIONS
35
13.1 Protocol Review and Amendments
35
13.2 Informed Consent
35
13.3 Ethics and Federal Guidelines         
35
13.4 Study Documentation
36
13.5 Records Retention
36
13.6 Multi-center Guidelines
36
14: STATISTICAL CONSIDERATIONS
36
14.1 Study Design/Endpoints
37
14.2 Sample Size/Accrual Rate
38
14.3 Stratification Factors
38
14.4 Analysis of Endpoints
38
14.5 Reporting and Exclusions
38
15: PUBLICATION PLAN
38
16. REFERENCES
39
17: APPENDICES
42
Appendix A
Data and Safety Monitoring Plan
 
Appendix B
Patient Letter 
Appendix C

Phase II Study of Proton RT for Medulloblastoma and Pineoblastoma: Acute Toxicity and Long Term 
Outcomes, T. Yock, MD
07/20/18
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This document is confidential. Do not disclose or use except as authorized.
Funded Visit Letter

Phase II Study of Proton RT for Medulloblastoma and Pineoblastoma: Acute Toxicity and Long Term 
Outcomes, T. Yock, MD
7/20/18
CONFIDENTIAL
This document is confidential. Do not disclose or use except as authorized.
5
1. OBJECTIVES
To describe the acute and late complications from craniospinal and tumor bed irradiation using 
proton beam therapy in place of conventional photon beam therapy in pediatric patients with 
medulloblastoma and pineoblastoma. 
1.1 Study Design
This trial is a phase II trial that substitutes proton irradiation for photon irradiation and 
measures toxicity from treatment. Because less normal tissue is irradiated it is presumed that 
it will be a less toxic treatment.  
1.2 Primary Objectives
Analysis of primary objectives outcomes will be done separately for high risk and standard 
risk groups.
1.2.1
To estimate the incidence and severity of ototoxicity (especially in combination   
with cisplatin-based chemotherapy) at three (3) and five (5) years following the 
completion of radiation therapy.
1.2.2
To describe the incidence of endocrine dysfunction (neuroendocrine and end organ 
defects).
1.2.3
To describe the incidence and severity of neurocognitive sequelae overall and in 
subgroups based on whether or not methotrexate was used as part of the treatment 
regimen. 
1.3 Secondary Objectives
1.3.1
To determine the 3 and 5-year progression free, event free, and overall survival rate 
of pediatric medulloblastoma and pineoblastoma patients treated with proton 
radiotherapy.
1.3.2
To develop a new supine technique to improve the speed of treating patients 
requiring cranial spinal irradiation and improve the safety of treating patients under 
anesthesia.
1.3.3
To evaluate the acute side effects from CSI using proton beam therapy, including 
nausea, esophagitis, and weight loss.

Phase II Study of Proton RT for Medulloblastoma and Pineoblastoma: Acute Toxicity and Long Term 
Outcomes, T. Yock, MD
7/20/18
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2. BACKGROUND
2.1 Study Agent(s):  Proton Radiotherapy
The current focus in radiation oncology is to improve dose localization to the tumor.  
Techniques such as Intensity Modulated Radiotherapy and Tomotherapy are two 
sophisticated photon techniques that have helped improve outcome in patients, however, 
there still remains a large amount of normal tissue getting low and intermediate doses of 
radiation.   Proton radiation capitalizes on the different physical characteristics of dose 
deposition to better localize dose to the target while sparing normal tissues. Unlike photon 
radiation which entails both an entrance and exit dose to normal tissues in the process of 
treating a tumor in a given beam line, proton radiation only entails a somewhat lower 
entrance dose and eliminates exit dose to normal tissues. Proton therapy dose distributions 
are therefore superior to those of photon therapy by a factor of 2 or greater and this provides 
the potential to further improve clinical outcomes and specifically decrease toxicity 
associated with treatment. 
2.1.1 The Advantages of Protons for Delivery of Conformal Therapy
Characteristics of Proton Beams
Figure O-1. Proton (Bragg peak and modulated peak) and 10 MV depth dose 
curves.
The basis for the advantages of proton beams lies in the physical laws that determine the 
absorption of energy in tissues exposed to photon or proton beams. In a specific tissue, 
photons are absorbed exponentially whereas protons have a finite range dependent upon 
the initial proton energy. Therefore, the depth dose characteristics of the two beams are 
qualitatively different (see Figure O-1). Protons lose their energy in tissue mostly by 
coulombic interactions with electrons in the constituent atoms; however, a small fraction 
of energy is transferred through nuclear collisions. The energy loss per unit path length is 
relatively small and constant as the proton traverses the tissue until near the end of the 
proton range where the residual energy is lost over a short distance (approximately 0.7 
cm in width at 80% of the maximum dose) and the proton comes to rest, resulting in a 

Phase II Study of Proton RT for Medulloblastoma and Pineoblastoma: Acute Toxicity and Long Term 
Outcomes, T. Yock, MD
7/20/18
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distinctive sharp rise in the tissue absorbed dose (energy absorbed per unit mass) - known 
as the Bragg peak (see the curve labeled "unmodulated proton beam" in Figure O-1). In 
physical terms, the magnitude of the transfer of energy to tissue per unit path length 
traversed by the protons is inversely proportional to the square of the proton velocity. The 
low dose region between the entrance and the Bragg peak is called the plateau of the dose 
distribution and the dose there is 30-40 percent of the maximum dose. 
The Bragg peak is too narrow in extent to irradiate any but the smallest of targets, 
ablation of the pituitary gland for example. For the irradiation of larger targets/tumors the 
beam energy is modulated - several beams of closely spaced energies (ranges) are 
superimposed to create a region of uniform dose over the depth of the target. These 
extended regions of uniform dose are called "spread-out Bragg peaks" (SOBP). This is 
shown in Figure O-1 as the “modulated proton beam”. 
For comparison, Figure O-1 also shows the depth-dose curve for a 10 MV x-ray beam, an 
x-ray energy commonly used to treat deep seated tumors. Note that the x-ray beam dose 
rises to a maximum value at relatively shallow depths, then falls off exponentially to 
lower doses at the treatment depth.
                      .
 
X-RAYS
PROTONS
MEDULLOBLASTOMA
 10
Figure O-2. Posterior, single-beam treatment of the spinal axis.
A clinical comparison of single-beam proton and photon beams is shown in Figure O-2 
where a single posterior beam is used for the treatment of the spinal axis in the treatment 
of medulloblastoma. Note that, for the photon treatment, the heart, mediastinum, 
esophagus, lung and spinal cord are irradiated by the treatment beam whereas for the 
proton treatment, the beam stops abruptly distal to the target volume and there is no 
irradiation of the tissues and organs distal to the target volume.  
In the usual clinical situation, more than one radiation beam is used in both x-ray and 
proton treatments. However, the advantage shown for protons using single beams is 
present for each and every beam used. Therefore, one cannot overcome the physical 
disadvantage of x-rays by the use of multiple beams or complex beam arrangements. In 
modern proton therapy facilities, which have isocentric gantries and sophisticated beam 
delivery and control systems, proton therapy capabilities are equivalent to those for state-

Phase II Study of Proton RT for Medulloblastoma and Pineoblastoma: Acute Toxicity and Long Term 
Outcomes, T. Yock, MD
7/20/18
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of-the-art, conformal therapy using x-rays with respect to numbers of beams, beam 
directions and complex delivery techniques such as intensity modulation. 
2.2 Study Disease 
Primitive neuroectodermal tumors (PNET) are small hypercellular, round, blue cell tumors of 
embryonal origin arising from the subependymal zone of the central nervous system (CNS) 
[1].  Medulloblastoma (MB) and pineoblastoma (PB) are defined as PNET of the posterior 
fossa or pineal region respectively. These tumors tend to occur predominately in the pediatric 
population.  MB and PB account for ~25% of CNS tumors in children. They have a 
propensity to spread to other regions of the CNS by subarachnoid seeding. Deutsch reported 
46% incidence of CNS spread at presentation for pediatric MB [2].  Likewise, a 30% rate of 
positive neuraxis involvement was observed by Bloom et al [3].  Thus, approximately one-
third of these patients present as high risk medulloblastoma and two-thirds as standard risk.
2.3 Rationale
The treatment of MB and PB of the central nervous system involves a multi-disciplinary 
approach. Surgery is necessary to obtain histological confirmation and to obtain maximal 
resection of tumor when feasible as the degree of resection correlates with outcome [4].  
Patients are at risk for local and disseminated CNS recurrence even after gross total 
resection. Adjuvant therapy to the craniospinal axis is therefore essential. Craniospinal 
irradiation (CSI) is used in this setting for patients greater than 3 years of age. An additional 
boost of radiation encompassing the residual tumor and surgical bed is routinely given as this 
region is at highest risk for recurrence.
Photon CSI is associated with many possible acute and long-term sequelae:
Acute toxicity can include the following: bone marrow myelosuppression, fatigue, alopecia, 
headache, dermatitis, folliculitis, otitis externa, otitis media, anorexia, weight loss, nausea, 
vomiting, thrush, laryngitis, pharyngitis, esophagitis, gastritis, enteritis, cystitis, acute 
pericarditis, and temporary worsening of tumor associated neurological symptoms.  
Prolonged myelosuppression and decreased bone marrow reserve may limit the ability to 
give chemotherapy after CSI.  Somnolence syndrome is a subacute reaction associated with 
CSI often disabling the patient.  
Long-term complications typically occur 3 months or more following completion of photon 
CSI and tend to be permanent. Complications arising from irradiation of the cranium include 
induction of second malignancy, permanent hair loss, cataract formation, retinopathy, 
sensorineural hearing loss due to damage to cochlea apparatus in inner ear, neuroendocrine 
dysfunction, and neuro-cognitive sequelae, rarely, necrosis and associated persistent 
vasogenic edema or atrophy. Adverse long term effects from photon irradiation of the spinal 
axis include: induction of second malignancy, stunting of growth of vertebral bodies and 
hypoplasia of paraspinal muscles and connective tissue resulting in scoliosis, kyphosis and 
decreased stature, spinal cord or nerve root damage, primary hypothyroidism, 
cardiomyopathy, pneumonitis, peptic ulcer disease, small and large bowel enteritis, primary 
ovarian failure, and decreased marrow reserve.  These long-term sequelae can have 

Phase II Study of Proton RT for Medulloblastoma and Pineoblastoma: Acute Toxicity and Long Term 
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7/20/18
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devastating effects in children on their future development and quality of life. Some of these 
complications are described in further detail below.  
Ototoxicity:
Conductive hearing loss due to serous otitis media is a well-known acute reaction to RT and 
stems from mucositis causing blockage of Eustachian tube with transudation of serous fluid.  
Patients are at increased risk at doses > 40 Gy. Most cases resolve spontaneously.  
Sensorineural hearing loss (SNHL) caused by damage to the cochlea and auditory nerve is a 
late complication from RT and can result in permanent hearing loss. While high doses of 
radiation are needed in the absence of chemotherapy to invoke SNHL [5-6], it can occur with 
lower radiation doses when ototoxic platinum chemotherapy agents are used. Evidence exists 
suggesting a dose response. Schoenthlaer et al reviewed 25 patients treated with high dose 
proton beam RT for base of skull tumors.  Six patients developed decreased hearing acuity as 
a late complication.  All patients with hearing loss received more than 60 cobalt gray 
equivalent (CGE) to at least 50% of the cochlea and auditory nerve [5]. In contradistinction, 
no patient receiving less than 60 CGE had hearing loss. Grai et al observed a higher 
incidence of severe SNHL in nasopharyngeal carcinoma patients receiving > 50 Gy to the 
inner ear compared to < 50 Gy [6]. Thibadoux et al found no hearing deficits in children 
receiving prophylactic cranial irradiation for acute lymphocytic leukemia [7].  Patients 
received 24 Gy in 2 Gy fractions.  Hua et al studied the effect of cochlear dose on 
sensorineural hearing loss in children with brain tumors treated with conformal radiation 
therapy and no ototoxic chemotherapy. They found that there is significant correlation 
between radiation dose and the incidence of sensorineural hearing loss in children. Children 
with a cochlear mean dose of 30 Gy or less had a low incidence of hearing loss, while there 
was an increased risk at greater than 40-45 Gy [8]. 
Chemotherapeutic agents such as cisplatin and carboplatin can cause high frequency SNHL.  
Recent data suggests that the combination of chemotherapy (CTx) and RT can cause more 
serious ototoxicity. Packer et al from UCSF reviewed their pediatric MB patients treated with 
concurrent vincristine plus CSI followed by adjuvant cisplatin, CCNU and vincristine.  They 
found 47.6% of patients developed grade 3 to 4 ototoxicity [9]. Twenty six MB pediatric 
patients treated at the Dana-Farber Cancer Institute (DFCI) with cisplatin and vincristine 
followed by CSI.  Only 19% of patients had normal hearing and 50% of long term survivors 
required hearing aids [10].  Degree of hearing loss was inversely related to age.  Sequencing 
of CTx and RT may also play a role in ototoxicity [11].       
Neurocognitive toxicity:
Although the majority of CNS development occurs during the 1st 3 years of life, myelination 
continues until puberty. A major radiation insult on the CNS will result in demyelinization 
with subsequent white matter necrosis and leukoencephalopathy. A large number of studies 
in the literature have documented decline in intellectual and cognitive functioning in children 
who have received whole brain radiotherapy (WBRT) for conditions including 
medulloblastoma, leukemia and other brain tumors [12]. The decline in functioning can be 
significant often necessitating placement in special education and a variety of therapeutic 
interventions. The effect of radiation depends upon the age of the child, with younger 

Phase II Study of Proton RT for Medulloblastoma and Pineoblastoma: Acute Toxicity and Long Term 
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children significantly more susceptible to the effects of radiation than older children, gender, 
with girls possibly more susceptible to decline in verbal function than boys, dose of radiation, 
with higher doses having more deleterious effects than lower, and time since completion of 
WBRT. This wide variability in these factors makes it difficult to formulate a clear post-
treatment profile for children receiving WBRT.  
IQ deficits following cranial irradiation range from 17 to 50%.  The Children’s Hospital of 
Philadelphia (CHOP) experience with cerebellar astrocytoma in children compared WBRT in 
26 patients versus no RT in 21 patients. IQ declined by a median of 13 points in the 
irradiated group versus none in the observed group [13]. The volume of brain irradiated 
influences worsening of intellectual performance. Hoppe-Hirsch et al compared 59 children 
with MB who received WBRT to 37 children who received posterior fossa RT for 
ependymoma [14].  60% of children with posterior fossa only irradiation preserved an IQ > 
90 at 10 years of follow up. Conversely, only 10% with WBRT maintained an IQ > 90.  
Radiation dose also plays a role.  Silber et al observed a higher drop in IQ below standard as 
dose of WBRT increased from 18 to > 36 Gy [15]. A study from Institut Gustave Roussy 
compared the neurocognitive outcome in 3 groups of pediatric patients who received 
different doses of radiation to the craniospinal axis. Group 1 consisted of 9 patients with 
ependymoma who received PF irradiation only, group 2 consisted of 11 patients with 
standard risk MB who received 25 Gy CSI plus PF boost and group 3 consisted of 11 patients 
with high risk MB who received 35 Gy CSI plus PF boost [16]. Increasing radiation doses to 
the brain were found to be correlated with lower full-scale IQ scores with mean IQ scores of 
84.5, 76.9 and 63.7 for patients who had received 0 Gy, 25 Gy and 35 Gy to the non-PF 
brain. The Pediatric Oncology Group (POG) and Children’s Cancer Group (CCG) have also 
compared reduced dose CSI at 23.4 Gy versus the standard 36 Gy dose in low stage pediatric 
MB patients.  Chemotherapy was not used. A reduction in neuropsychologic toxicity was 
observed in the low dose arm especially in younger children [17], albeit with a higher local 
failure rate in the reduced CSI arm [18]. Packer et al compared 13 patients treated with 
WBRT plus cisplatin, CCNU, or vincristine versus 14 patients treated with surgery only for 
children with cerebellar astrocytoma [19]. WBRT dose was 36 Gy with a boost of 18-20 Gy 
for children 3 years or older. A decline in full-scale IQ was noted in the irradiated group.  
12/18 patients required special education. The effect was most pronounced in younger 
children.  
The cognitive decline in patients from CSI may also be enhanced by the addition of 
chemotherapy. Chemotherapy without radiation has been implicated as having 
neurocognitive effects. The best studied population is the ALL (acute lymphoblastic 
leukemia) population in which many children are never irradiated but still suffer 
neurocognitive effects. (Moleski, M. (2002) Neuropsychological, neuroanatomical, and 
neurophsyiological consequences of CNS chemotherapy for acute lymphoblastic leukemia. 
Archives of Clinical Neuropyschology, 15, 603-630). Methotrexate, both high dose and 
intrathecal or intraventricular have been shown to cause leukoencephalopathy without 
radiation, but the addition of radiation appears to worsen outcome (Rutkowski et al, NEJM 
352: 2005). However, the use of methotrexate chemotherapy in high doses does appear to 
improve disease free survival compared with standard regimens in infants and young children 
(Rutkowski et al, NEJM 352: 978-986, 2005; Chi et al, JCO 22: 2004) with medulloblastoma 

Phase II Study of Proton RT for Medulloblastoma and Pineoblastoma: Acute Toxicity and Long Term 
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7/20/18
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and is increasingly gaining favor in the children with the higher risk disease. The other 
promising strategy is to deliver high dose chemotherapy with thiotepa and carboplatin with 
stem cell support and both treatment intensification strategies are employed in various 
institutions and cooperative group settings around the country and world.
Pituitary and hypothalamic toxicity:
Neuroendocrine dysfunction is extremely common following cranial irradiation in children 
and adults.  Published data indicates a radiation dose response [20-22]. Littley et al showed 
that doses as low as 20 Gy to the hypothalamus and pituitary gland can cause 
hypopituitarism, primarily anterior lobe dysfunction [21]. Doses exceeding 50 CGE to the 
pituitary gland and hypothalamus using proton beam RT decreases the incidence of 
hypopituitarism [22]. Growth hormone deficiency is particularly common following cranial 
irradiation.  Hypogonadism, hypoadrenalism and hypothyroidism can also be observed.  
Patients often have more than one hormone axis involved. Life long monitoring for 
hypopituitarism and hormone replacement is often necessary.  
Precocious puberty has been described in pre-pubertal patients treated with cranial irradiation 
[23]. The critical dose for precocious puberty is not well elucidated.
Thyroid gland toxicity:
Primary hypothyroidism after photon beam spinal axis irradiation has been well documented.  
59% of patients developed elevated levels of TSH after spinal irradiation in a study by Hirsch 
et al [24]. A strong correlation between dose and incidence of hypothyroidism has also been 
demonstrated [24-26]. An incidence of 15% is noted for doses below 30 Gy; this increases to 
40-90% for doses between 30 to 44 Gy [27]. For children, a study from Stanford University 
showed an incidence of 17% for doses < 26 Gy to the thyroid gland and 78% for > 26 Gy 
[25]. Radiation to the thyroid gland can also cause hyperthyroidism, although this is an 
uncommon event with a 10 year actuarial risk of < 3.5% [28]. Patients usually present with 
symptoms of Graves’ ophthalmopathy.  
Potential Benefits of Protons:
Benefits of spinal dose:
When a proton beam is applied for spinal irradiation, a single posteriorly directed proton 
beam delivers almost no dose to structures anterior to the treated volume compared to a 
standard photon treatment plan and even an IMRT plan. As shown in Figure O-2 (above), a 
direct comparison of a conventional 4 MV posteriorly directed field versus a single 
posteriorly directed 160 MeV proton beam to treat the spinal axis was made.  Note the lack 
of exit dose to structures anterior to the vertebral bodies using protons compared to standard 
PA 4 MV photon plan. A comparative treatment plan of protons versus photons has also been 
published by Miralbell et al recently [29]. A 6 MV photon beam spinal field was compared to 
a 100 MeV proton beam spinal field.  As expected, integral dose by DVH analysis to the 
heart and liver was zero using protons.  

Phase II Study of Proton RT for Medulloblastoma and Pineoblastoma: Acute Toxicity and Long Term 
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Benefits in cranial technique:
In a separate study, the same investigators were able to demonstrate advantages of a 3 field 
(2 opposed lateral and a posterior) proton plan for whole brain irradiation in a 3 year old 
child over parallel opposed 6 MV photon fields, 6 field conformal photon plan, or a 9 field 
IMRT photon plan [30].  A reduction in dose to the eyes and “low risk” regions of the brain 
was observed.  The estimated risk of an IQ score < 90 in young children ages 4 to 8 was 
reduced using the proton plan. We have also compared lateral opposed conformal proton plan 
to standard lateral opposed photon plan and achieved similar benefit in improved dose 
distribution as noted by Mirabell et al. See figure O-3 below. The dose gradient is improved 
near the vertex of the head and decrease dose is delivered to the middle and inner ear regions 
using protons.  
Figure O-3: Dose distribution to cranial fields in the Proton and Photon planned patient.
Furthermore, we have refined our technique and use slightly posterior obliqued fields to 
better spare the lens while still achieving good coverage of the cribiform plate in the younger 
patients whose sinuses have not pneumatized yet and the brain therefore dips low and in 
between the orbits. Parallel opposed photon treatment places the child at high risk for 
cataract formation [31].
We have also demonstrated reduced normal tissue irradiation using protons for the posterior 
fossa boost field for medulloblastoma patients. A comparison between a conformal proton 
plan using 15 degree superior anterior oblique field with two 25 degree posterior oblique 
fields is compared to a comparable field set-up with conformal photons as described by 
Paulino et al [32], and to a standard lateral opposed 4 MV photon plan. As shown in table 1, 
a decrease in relative dose to the critical structures such as the cochlea, non-posterior fossa 

Phase II Study of Proton RT for Medulloblastoma and Pineoblastoma: Acute Toxicity and Long Term 
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brain, pituitary gland and hypothalamus is observed with conformal protons and conformal 
photons compared to that of conventional photons. However, extra dose is delivered to “less 
critical” normal structures such as the parotid gland and mandible using conformal photons 
as compared to conformal protons.  
Table 1. Posterior fossa irradiation: Comparison of dose to normal structures using 3 different 
techniques [36]
Organ
 % of Prescribed Dose (Dmean/Prescribed Dose)
6 MV lateral 
opposed photons 
(optimized with 
wedges)
SAO, RPO, LPO 
conformal photons
160 MeV SAO, RPO, LPO 
conformal protons
Cochlea
102.3
55.0
11.7
Non posterior fossa 
brain
47.1
40.6
26.1
Pituitary gland
80.1
91.1
57.2
Hypothalamus
15.8
47.2
35.0
Parotid Gland
38.8
32.2
0.0
Pharynx
7.3
8.9
0.0
Mandible
 6.2
15.0
0.0
TMJ
59.7
33.9
0.0
Protons summary:
Superior dose conformity is therefore achieved with protons compared to other external beam 
modalities. Advantages in dose distribution are noted for all phases of CSI including spinal, 
whole brain and posterior fossa portions of treatment. The accuracy of delivering proton 
therapy is further enhanced by advancements in treatment planning and delivery technology.  
Improved radiological imaging with CT and MRI, the availability of computer technology 
for treatment planning and dosimetric calculations (e.g. beam’s eye view planning, 3-
dimensional image reconstruction, dose volume histogram analysis) have contributed to 
enhancing the therapeutic ratio using radiation therapy. In other tumors and sites, 
comparative treatment planning using protons versus photons have shown a clear advantage 
to protons [33-35].  
We have already treated 51 patients on the precedent medulloblastoma protocol with 37 
standard risk patients and 14 high risk patients. We have found the following: acute 
esophagitis/mucositis rates are 12% which is lower than what would be expected which is 
close to 100% percent. Nausea and vomiting is still present but less severe than it would be 
for photon techniques in that we have a grade 2 rate of 26% and grade 3 rate of 12%.  With 
regards to ototoxicity, since this is a late endpoint (after 3 years) we don’t have full data yet 
but preliminary data shows that we have 35% grade 2 hearing loss and a 9% grade 3 hearing 
loss rate. We have had 3 relapses thus far, 2 in the standard risk group and 1 in the high risk 
cohort. Disease control rates are comparable to those with photons. For the neuropsych 

Phase II Study of Proton RT for Medulloblastoma and Pineoblastoma: Acute Toxicity and Long Term 
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evaluations, there are only 18 patients in the database centrally that have both baseline and 
follow up data and no conclusions can be made based on the limited follow up to date. 
Additionally, more follow up data is being entered in the database.   
2.4 Correlative Studies Background-- Not applicable  
3.  PARTICIPANT SELECTION
Laboratory tests required for eligibility must be completed within 14 days prior to study entry. 
Other non-laboratory tests must be performed within the timeframes described below.
3.1 Eligibility Criteria
Participants must meet the following criteria on screening examination to be eligible to 
participate in the study:
3.1.1 Participants must have undergone biopsy or attempted surgical resection and 
must have histologically confirmed medulloblastoma or pineoblastoma.  
Confirmation of pathology at the treating institution is preferred prior to 
beginning study treatment, but may be received two weeks after radiation start.
3.1.2 Participants may have had a gross total resection, sub-total resection or biopsy 
only.  
3.1.3 For patients with no prior chemotherapy, treatment must start within 35 days of 
definitive surgery or as indicated if enrolled on therapeutic study. 
3.1.4
Age >3 and < 25 at the time of enrollment. 
3.1.5
Life expectancy of greater than 3 months.
3.1.7 Radiation is known to be teratogenic, women of child-bearing potential must not 
be pregnant at the time of study entry. Women and men must agree to use adequate 
contraception (hormonal or barrier method of birth control; abstinence) prior to study 
entry and for the duration of study participation. Should a woman become pregnant or 
suspect she is pregnant while participating in this study, she should inform her treating 
physician immediately.
3.1.8 Signed informed consent document and assent when appropriate.
3.2       Exclusion Criteria
Participants who exhibit any of the following conditions at screening will not be eligible for 
admission into the study.
3.2.1 Patients with more than one previous chemotherapy regimen.
3.2.2 Patients with recurrent or progressive disease after one or more regimens of pre-
radiation chemotherapy.
3.2.3    Patients with prior radiation therapy will be excluded. 

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3.2.4 Any major uncontrolled or poorly controlled intercurrent illness that would limit 
compliance with study requirements.
3.2.5
Pregnant women are excluded from this study because radiation is a teratogen 
and it is not safe to the fetus to treat a patient while pregnant.
3.3   Inclusion of Women, Minorities and Other Underrepresented Populations
We do not expect the inclusion and exclusion criteria to either over or under represent 
women, minorities, or underrepresented populations.
4. REGISTRATION PROCEDURES
4.1 General Guidelines for DF/HCC and DF/PCC Institutions
Institutions will register eligible participants in the Clinical Trials Management System 
(CTMS) OnCore. Registrations must occur prior to the initiation of protocol therapy. Any 
participant not registered to the protocol before protocol therapy begins will be considered 
ineligible and registration will be denied.
A member of the study team will confirm eligibility criteria and complete the protocol-
specific eligibility checklist. 
Following registration, participants may begin protocol treatment. Issues that would cause 
treatment delays should be discussed with the Principal Investigator. If a participant does not 
receive protocol therapy following registration, the participant’s protocol status must be 
canceled. Registration cancellations must be made in OnCore as soon as possible.
4.2 Registration Process for DF/HCC and DF/PCC Institutions
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject Protocol 
Registration (SOP #: REGIST-101) must be followed.  
4.3 Registration Process for Other Participating Institutions
Eligible participants will be entered on study centrally by the MGH Coordinating Center.  
Please refer to Section 5.7 of the Data and Safety Monitoring Plan (attached as Appendix A) 
for details. If a participant does not receive protocol therapy following registration, the 
participant’s registration on the study must be canceled. The Coordinating Center should be 
notified of cancellations as soon as possible
5. TREATMENT PLAN: RADIATION THERAPY
All charged particle treatment will be given at the Francis H. Burr Proton Therapy Center or 
MD Anderson Proton Therapy Center. Film or digital images will be taken prior to each 
treatment in accordance with the proton center's standard practice for all patients. These 

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images are used to verify the position of the patient and the aperture. These images are 
permanently stored electronically for each patient. Treatment may start any day of the week 
but preferably Monday through Thursday. Expected toxicities and potential risks as well as 
dose modifications are described in Section 6 (Expected Toxicities and Dosing Delays/Dose 
Modifications). Patients with MB will be stratified into standard and high risk for treatment 
purposes.  Physicians are strongly encouraged to enroll patients onto other active protocols.  
Children’s Oncology Group (COG) has specifically designed their protocols to allow for 
proton radiation which will therefore not preclude co-enrollment.
Documentation of chemotherapy given should be submitted.  In order to assess the causes of 
any possible acute or long term side effects, the total platinum dose given to the patient 
should be tracked. The cumulative platinum dose, number of cycles, and any dose reductions 
should be recorded.
5.1 
Pre-Treatment Criteria
5.1.1 Baseline Staging Requirements:

MRI scan with contrast enhancement (with gadolinium) of the entire spinal 
axis (preferably pre-op) 

Pre-operative MRI scan or CT scan of the brain. 

Post-operative MRI of the brain (within 21 days of surgery, preferably 
within 72 hours of surgery; intra-operative MRI is allowed). 

CSF sampling for cytology if the patient appears to have M0 disease. CSF 
sampling is not required for patients with gross M2 or M3 disease by 
imaging (leptomeningeal spread of disease in the brain or the spine). CSF 
sampling can be completed any time prior to the start of protocol therapy. 
If sampling for M0 disease performed less than 10 days after surgery is 
positive, it should be repeated.  CSF sampling must be completed no later 
than ten days after the start of radiation.
5.1.2 Additional Baseline Assessments:

Endocrine evaluation to be completed no later than 2 months after the start 
of radiation. To include TSH, Free T4, Cortisol, IGF-1 and IGF-BP3, LH, 
FSH, estradiol (females), testosterone (males) (am levels preferred), 
Tanner Stage assessed by physical exam, bone age (plain film of the 
wrist), and body proportion measurements. Bone age, Tanner Stage 
assessment, and body proportion measurements collected will be at the 
discretion of the study endocrinologist. Recommended measurements 
include sitting height (sitting height preferred, but pubic symphysis to 
floor acceptable), standing height, leg span, and arm span.

Audiogram, to be completed no later than 2 months after the start of 
radiation.

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
Neurocognitive evaluation, as detailed in Section 9.2.3, to be completed 
no later than 9 months after the start of radiation 
. 
5.2 Radiation Planning Guidelines
5.2.1  Patient Set-up and Immobilization
Patient set-up and immobilization must be determined prior to planning CT scan and may 
be either prone or supine. For CSI, patient will be positioned in accordance with the 
treating institution’s accepted method of doing so. Head will be positioned such that the 
spinal cord is as straight as possible. Children unable to cooperate and remain properly 
immobilized should be sedated or anesthetized for set-up reliability on a day-to-day basis.  
A nurse anesthetist or anesthesiologist will be supervising and administrating sedation.  
Sedated patients should be under constant surveillance during treatments with cameras, 
telemetry, and other devices.
5.2.2 CT Simulation
The patient will have a planning CT scan while in the treatment position and properly 
immobilized. Physicians are encouraged to use available MRI scans to aid in target and 
normal tissue delineation. Electronic copies of MRI scans are usually available and can 
often be registered with planning CT scans to help delineate structures. 
5.2.3 Target and Normal Structure Delineation
The following structures will be outlined on planning CT scans. It is recommended that 
the radiation oncologist outline the GTV. Cumulative dose volume histogram analysis 
will be completed for structures listed below:

GTVp and surgical bed (see below for guidelines definitions)

CTV1 and CTV2 (+/- CTV x…) 

Right and left cochlea

Lenses

Optic chiasm

Pituitary gland

Hypothalamus

Esophagus

Temporal lobes

Whole brain
ICRU 50 and ICRU 78 [37] recommended terminology will be used to define radiation 
treatment parameters. 
CTV1: Cranial-Spinal Treatment: 
CTV1 shall be defined as the cranial spinal portion of the treatment and will include the 
entire cranial contents including cribiform plate and the thecal sac surrounding the spinal 
cord and nerve roots. Care should be taken to look at the sagittal spine MRI to define 

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where the thecal sac ends and an additional margin of 1-2 cm should be added to ensure 
coverage.  When imaging is degraded or incomplete, coverage should extend to S4. The 
treating physician should use their judgment about whether the target will also include 
the vertebral body or only the thecal sac. However, in patients that have a significant 
amount of growth to do it is recommended that the whole vertebral body (or nearly so) be 
covered so as to avoid uneven growth of the vertebral body resulting in spinal scoliosis.  
CTV2: Posterior Fossa or Involved Field Boost:
The GTVp is defined as any post-operative residual tumor seen on MRI or CT scan in 
addition to the collapsed resection cavity of the primary lesion.   
The CTV2 is defined as 1-1.5 cm anatomically constrained margin around the GTVp and 
any other sites the treating physician judges to be at high risk for microscopically residual 
disease. Or, if the tumor is arising in the posterior fossa, the entire posterior fossa may be 
boosted. This is up to the COG protocol or physician discretion after consultation with 
the patient (if appropriate) or/and their guardians. 
            Metastases boosts: 
Guidelines for boosting metastatic disease (ie M1, M2 or M3) will be in accordance with 
the COG guidelines and institutional practice, but are briefly outlined below. 
 
CTV 3, 4, 5, etc:  
The boosts for the gross metastatic deposits will be targeted with a 5-10 mm margin of 
CTV and include any other area the treating physician feels is at high risk for local 
recurrence.  
Planning Target Volumes (PTV): 
An additional margin for set up uncertainty and motion will be applied according to each 
institution’s regular practices. 
The irradiated volume includes normal tissue, which receives a clinically significant dose 
with respect to normal tissue effects.
5.2.4
Dosimetry Planning
Cranial spinal planning will be according to each institution’s standard protocol for this 
technique and will include moving junctions of matched fields for safety.  
5.2.5
Dose Specification and Schedule
Physicians are encouraged to enroll patients onto other active protocols (e.g. testing 
chemotherapy regimens).  The radiation dose and fractionation schedule in these cases is 
in accordance with the co-existing protocol. Patients will usually be treated once per day. 
Doses will be prescribed such that 95% of the CTV is covered by 100% of the 
prescription dose. Dose will be reported in GyRBE (where 1 GyRBE = proton dose Gy x 

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RBE, RBE = 1.1). A RBE of 1.1 has been selected for protons and is based on RBE 
determinations in animal and cell culture systems [43,44].
Cumulative dose volume histograms using nominal dose distribution will be generated 
for all structures listed in 5.2.3.  
5.2.6  Proton Beam Physical Factors
Proton treatments will be delivered at the Francis H. Burr Proton Therapy Center at the 
Massachusetts General Hospital using a 240 MeV cyclotron. At MDACC, proton 
treatments will be delivered at the MDACC Proton Therapy Center using a 250 MeV 
synchrotron. Treatments will usually be administered as one daily fraction, 5 days per 
week. 
5.2.6
Proton Beam Modification/Blocking
Beam shaping will be accomplished using primary collimation by the gantry jaws.  The 
penumbra is large and field shaping by secondary collimation will be necessary using a 
downstream custom cut brass aperture. Apertures will be constructed on brass alloy of 
sufficient thickness to attenuate 99.9% of protons. Apertures will be cut to be parallel to 
beam divergence. 3-D lucite compensators may be fabricated to conform dose to the 
target at the distal aspect.
5.2.8 Quality Assurance and Rapid Review of Treatment Plans
To ensure protocol compliance, the treatment plans for the first three patients treated at 
each site will be reviewed by the Principal Investigator and Participating Site’s PI.  As 
described in Section 12.1.3, below, plans will be submitted to the Advance Technology 
QA Center at Washington University, St Louis (ATC) for this protocol.  The plans will 
be sent to the ATC upon approval by the treating physician, and the PI and/or 
Participating Site PI will review and confirm protocol compliance within three working 
days of the start of treatment.
5.2.9 Beam Verification:
Digitally reconstructed radiography (DRR) will be done for treatment planning and 
verification and will be performed daily during treatment. 
5.2.10 Dose Uniformity
Dose gradient in CTV should remain within +7% to –5% of prescribed dose.
5.2.11 Dose Derification
A physicist co-investigator at each participating institution will be responsible for dose 
verification. 

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5.2.12 Concurrent Protocol
For patients who are enrolled on co-existing protocols such as COG, physicians will 
adhere to the radiation therapy guidelines of the companion protocol which specify their 
own guidelines for the following parameters: total dose, dose per fraction, fractionation 
schedule and sequencing with other therapy (e.g. chemotherapy).   If any questions or 
discrepancies arise, then contact Dr. Torunn Yock, MD at (617) 726-9441 
(tyock@partners.org) before beginning radiation treatments. 
5.2.13 Treatment Delay
To avoid treatment delays resulting from the machine being down, photon or electron (if 
appropriate) beam radiation can be administered.  The maximum dose for both the 
posterior fossa and spine will be 20% of the prescribed dose (e.g. 20% of the spine at 36 
Gy would be a maximum of 4 spine treatments or 7.2 Gy).   Delay in the start of CSI 
proton therapy shall not exceed 2 weeks in M0 patients and 1 week in M+ patients. 
5.2.14 Emergent Radiation Therapy
For patients who require emergent RT when a proton slot is not available, photon (or 
electron beam) therapy may be delivered at the maximum dose for the posterior fossa and 
at 20% of the maximum dose for the spine (e.g. 20% of the spine at 36 Gy would be a 
maximum of 7.2 Gy).  
5.3
General Concomitant Medication and Supportive Care Guidelines
There are no required concomitant medications in this study.  No other radiotherapy besides 
that which was outlined above may be used during study treatment.  Patients may receive all 
concomitant therapy deemed necessary to provide optimal support.  
5.4
Duration of Therapy
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse events, treatment will continue 
until the prescribed dose of radiation therapy is delivered or until one of the following criteria 
applies:

Disease progression,

Intercurrent illness that prevents further administration of treatment,

Unacceptable adverse event(s),

Participant decides to withdraw from the study, or

General or specific changes in the participant's condition render the 
participant unacceptable for further treatment in the opinion of the 
treating investigator.

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5.5
Criteria for Removal from Study 
Participants will be removed from treatment or active follow up when any of the criteria 
listed in Section 5.4 applies. Participants removed from treatment or active follow up for 
disease progression will continue to be followed for survival status only. The reason for 
removal and the date the participant was removed must be documented in the study-
specific case report form (CRF). Alternative care options will be discussed with the 
participant.
5.6
Duration of Follow Up 
Participants will be followed for at least 8 years after completion of radiation therapy or 
until death, whichever occurs first. Participants will be invited to return to the treating 
institution for annual follow up visits. Participants who do not live in the local area of their 
treating institution will be allowed to obtain follow up care at home and forward records to 
the study team at the treating institution. Once participants have reached 5 years post 
treatment, they may be compensated for a one time return visit to MGH if grant funding is 
available.
In the event of unusual or life-threatening complications, participating 
investigators must immediately notify the Principal Investigator Torunn Yock, MD 
via the Coordinating Center at ccpo-mcgroup@partners.org.
6. EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS 
Toxicity assessments will be done using the CTEP Active Version NCI Common Terminology 
Criteria for Adverse Events (CTCAE) which is available at: 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm. 
If possible, symptoms should be managed symptomatically. In the case of toxicity, appropriate 
medical treatment should be used (including anti-emetics, anti-diarrheals, etc.).
All adverse events experienced by participants will be collected from the time of the first dose of 
study treatment, through the study and until the final study visit. Participants continuing to 
experience toxicity at the off study visit may be contacted for additional assessments until the 
toxicity has resolved or is deemed irreversible. 
6.1 Anticipated Toxicities   
A list of the adverse events and potential risks associated with the agents administered in this 
study appear below and will determine whether dose delays and modifications will be made 
or whether the event requires expedited reporting in addition to routine reporting. 
Acute side effect assessment should include the following:

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
Anorexia

Nausea + vomiting (esp. with vincristine)

Weight loss

Fatigue 

Headache

Skin reactions 

Alopecia (total alopecia expected)

Thrush (fungal infection of the mouth)

Sore throat or esophagitis

Decrease in bone marrow cells

Constipation (esp. with vincristine)
Any of the above may lead to a need for treatment break or delay in finishing treatments.
Non-physical Risks:

Inability to perform at school or job
Patient monitoring should be done per usual clinical practice. 
Late Effects:

Permanent hair loss or thinning in region of boost

Decreased growth overall (GH effects)

Decreased growth of spine

Hormonal imbalance

Hearing impairment 

Neurocognitive effects

Cataracts

Hypothyroidism

Neuroendocrine effects, may lead to an inability to have children

Abnormal curvature of the spine

Scarring or damage to the esophagus

Damage to the spinal cord or brain tissue

Tumors caused by radiation

Vascular effects, either asymptomatic or causing stroke
6.2 Toxicity Management  
Toxicity that causes a delay or dose modification in radiation therapy is not expected.  Once 
radiation has started it is important to continue with radiation unless it is deemed unsafe for 
the patient (i.e. they require anesthesia and have pneumonia). If the patient experiences 
toxicity from chemotherapy, delays and dose modifications should be made according to the 
concurrent chemotherapy treatment protocol. 
6.3 Dose Modifications/Delays   

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To avoid treatment delays resulting from the proton machine being down, photon beam 
radiation can be administered. The maximum dose for both the posterior fossa and spine will 
be 20% of the dose (e.g. 20% of the spine at 36 Gy would be a max. of 4 spine treatments). 
Delay in the start of CSI proton therapy treatment should not exceed 2 weeks in M0 patients 
and 1 week in M+ patients.
Radiation treatment delays must be avoided where possible.  If a patient is unable to receive 
a CSI treatment on a given day then consideration should be made to delivering the boost 
treatment where possible.  
7. DRUG FORMULATION AND ADMINISTRATION: N/A
8. CORRELATIVE/SPECIAL STUDIES: N/A
9. STUDY CALENDAR
Baseline evaluations are to be conducted within 35 days prior to start of protocol therapy. 
Scans must be performed within 6 weeks prior to the start of therapy. CSF sampling can be 
completed any time prior to start of protocol therapy. 
Table 2: Required Data
Tests and Observations
Pre-Study/ 
Baseline
During 
Radiation
Follow Up (1)
Informed Consent and registration
X
Biopsy or attempted resection
X
Pathology Review
X
Medical History
X
X (2)
Physical Exam 
X
X (2)
X (2)
Endocrine Evaluation
X (3)
X (3)
CSF sampling if M0 disease
X (4)
CBC 
X (5)
X (5)
Serum Chemistries
X (6)
X (6)
MRI or CT of the brain
X (7)
X (7)
MRI of the entire spine
X (8)
X (8)
Audiogram
X (9)
X (9)
X (9)
Neurocognitive Testing
X (10)
X (10)
Notes:
(1) Follow up, except for neurocognitive testing, is to be completed annually (+ or – 6 months) from the 
completion of study treatment. Follow up is highly recommended, but not required.
(2) Medical history and physical exams during radiation treatment is to be completed weekly and may include 
only the acute toxicity assessment and other pertinent objective findings. Medical history and physical exams 
at follow up are recommended, but not required.

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(3) Baseline endocrine evaluation to be completed no later than 2 months after the start of radiation. Evaluation 
includes Tanner stage assessment by physical exam, bone age (plain film of the wrist), and body proportion 
measurements. Bone age, Tanner Stage assessment, and body proportion measurements collected will be at the 
discretion of the study endocrinologist. Recommended measurements include sitting height (sitting height 
preferred, but pubic symphysis to floor acceptable), standing height, leg span, and arm span.  Recommended 
labs for endocrine evaluation are TSH, Free T4, Cortisol, IGF-1, IGF-BP3, LH, FSH, estradiol (females) and 
testosterone (males) – am levels preferred,
(4) CSF sampling can be done any time prior to the start of protocol therapy. CSF sampling must be completed 
no later than ten days after the start of radiation. If sampling performed less than 10 days after surgery is 
positive, it should be repeated.  
(5) CBC required labs are ANC, Platelets, Hematocrit. CBC with diff. is required at baseline. Annual follow 
up CBC’s are suggested, but not required
(6)  Chemistries required at baseline and that are suggested, but not required, for follow up are: albumin, alk 
phos, T bili, BUN, calcium, chloride, glucose, potassium, total protein, sodium, AST, ALT, Pregnancy test (if 
applicable and at pre-study only).  
(7) Pre-Study brain MRI or CT includes pre-op and post-op imaging, post-op to be done within 21 days of 
surgery (preferably within 72 hours of surgery; intra-operative MRI as allowed). Brain MRI or CT at follow up 
is recommended, but not required.
(8) Pre-study spine MRI should be from the time of diagnosis (preferably pre-op). Spine MRI at follow up is 
recommended, but not required.
(9) Baseline audiogram must be completed within 2 months after the start of radiation. Audiograms are 
recommended, but not required, for patients receiving platinum based chemotherapy prior to the beginning of 
each cycle.  Follow up audiograms are recommended annually.  Additional audiograms, if done, will be 
collected and included in the data set.
(10) Baseline neurocognitive testing must be completed no later than 9 months after the start of radiation. 
Follow up testing is recommended starting one year after the previous exam, at one, three, and five years post-
radiation (+ or – 12 months).
Patient Assessments:
The required tests and evaluations prior to, during and following CSI are shown in table 2.
Patients will require acute side effect assessment during radiation therapy as detailed in section 
9.1 below.  Acute side effects from RT are defined as those effects that are attributable to the 
effects of radiation and occur from commencement of RT to 90 days following completion of 
RT.  
Patients will be assessed for late side effects or complications which are defined as those effects 
that are attributable to the effects of radiation and occur > 90 days following completion of RT.
9.1 Acute Side Effect Assessment
All patients shall be assessed for acute toxicity on a weekly basis during CSI. Grading of 
acute toxicity will be done per the CTEP Active Version of CTCAE.  Duration of treatment 
breaks must be recorded along with reason for break.  

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9.2 Description of special studies
Timing of special tests and assessments are outlined in table 2.
9.2.1   Endocrine
Whenever feasible, a referral to a Pediatric Endocrine specialist should be made for 
endocrine evaluation.  Otherwise, referral to a local endocrinologist should be made.   
Labs required at baseline for study are TSH, Free T4, Cortisol, IGF-1, IGF-BP3, LH, 
FSH, estradiol (females), testosterone (males) – am levels preferred. These labs are 
recommended, but not required, at annual follow up time points. Endocrine evaluation 
also includes Tanner Stage assessed by physical exam, bone age (plain film of the wrist), 
and body proportion measurements. Bone age, Tanner Stage assessment, and body 
proportion measurements collected will be at the discretion of the study endocrinologist. 
Recommended measurements include sitting height (sitting height preferred, but pubic 
symphysis to floor acceptable), standing height, leg span, and arm span.

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9.2.2  Audiology evaluation
Audiograms are required and should be done prior to start of radiation. Audiograms 
should be obtained on a yearly basis as well (see table 2). Additionally regular 
audiograms are recommended but not required to be performed at the patient’s home 
institution prior to each cycle of platinum based chemotherapy in accordance with the 
standard of care because platinum chemotherapy can cause acute hearing loss. If the 
baseline audiogram cannot be completed prior to the start of radiation, it must be 
completed within 2 months of the beginning of radiation therapy. Each ear (left and right) 
should be tested and recorded separately. 
 
Grading of sensorineural hearing loss will be according to the CTEP Active Version of 
CTCAE.
9.2.3
Neurocognitive evaluation  
Analysis of Neurocognitive Function (NCF) will be limited to English speaking 
population, as norms for most tests are only available for this population. At baseline, 
neurocognitive testing will be required for all patients without posterior fossa syndrome. 
Patients with posterior fossa syndrome will be evaluated and referred if deemed 
appropriate. Patients will be required to undergo formal NCF evaluation at the 
Psychology Assessment Center at MGH or at the home institution.   
Patients whose premorbid IQ is less than 60 (with no indication that the tumor led to an 
acute and dramatic decline in IQ) will be excluded from neuro-psychological assessment.  
Evidence for a dramatic decline will include parental report, school records, variability in 
IQ profile, gross inattention or lack of motivation/cooperation, and/or concurrent 
functional illness (e.g., depression).  
Subjects will receive a comprehensive neuropsychological evaluation at baseline.  
Whenever possible, subjects will be evaluated within 9 months of the start of radiation. 
Following the baseline evaluation, it is recommended that subjects be evaluated at 1, 3, 
and 5 years post-RT (+ or – 12 months).
The battery of tests administered will be the same at every administration, as much as 
possible, and should include the following measures:

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Function
Measure
Age Range
Administration 
Time
Intelligence
Wechsler Intelligence Scale for Children –5th 
Ed. (WISC-V) a
Wechsler Intelligence Scale for Children –4th 
Ed. (WISC-IV) a
Wechsler Preschool & Primary Scales of 
Intelligence-3rd Ed. (WPPSI-III) a
Wechsler Adult Intelligence Scale-3rd or 4th 
Edition (WAIS III or IV) a
6- 16 years
6- 15 years
2½ - 5 years
16+ years
65 minutes
60 minutes
45 minutes
60 minutes
Language
Expressive Vocabulary Test-2nd Ed. a
OR
Expressive One-Word Vocabulary Test a
Peabody Picture Vocabulary Test-4th Ed. 
(PPVT-4) b
2½+ years
2½ -25 years
2½+ years
10 minutes
10 minutes
10 minutes
Visual-
Spatial/Motor
Beery-Buktenica Developmental Test of 
Visual-Motor Integration Version 5 or 6a
Grooved Pegboard Test a
OR
Purdue Pegboard Test a
Hooper Visual Organization Test b
Rey-Osterrieth Complex Figure Test (Copy) b
3+ years
5+ years
4-15 years
5+ years
8+ years
10 minutes
5 minutes
5 minutes
10 minutes
5 minutes
Attention / 
Executive 
Functioning
Control Oral Word Association (F,A, S; 
Animals) a
Wisconsin Card Sorting Test (64 or 128) a
Trail Making Test (A and B) a
Continuous Performance Test-2nd Ed b
Children's Memory Scale - Subtests: 
Numbers; Sequences b
Wechsler Intelligence Scale for Children-4th 
Ed. Subtests: Digit Span, Letter-Number 
Sequencing b
Wechsler Adult Intelligence Scale-3rd or 4th 
Ed. Subtests:  Digit Span, Arithmetic b
6+ years
7+ years
8+ years 
8+ years
5 - 15 years
6 - 15 years
≥16 years
5 minutes
15 minutes
5 minutes
20 minutes
10 minutes
10 minutes
10 minutes

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Learning/Memory
Children's Memory Scale - Stories I &  II a
OR
Children's Memory Scale - Word Lists I & II a 
Wechsler Memory Scale-3: Family Pictures; 
Logical Memory a
OR
Wechsler Memory Scale-3: Word Lists and 
Spatial Span a
California Verbal Learning Test-Child  
version b
California Verbal Learning Test-II b
Rey-Osterrieth Complex Figure Test (Delay) b
Children's Memory Scale - Dots I & II b
6 - 15 years
6 - 15 years
16+ years
16+ years
6 – 15 years
16+ years
8+ years
6 - 15 years 
20 minutes
20 minutes
20 minutes
20 minutes
20 minutes
20 minutes
5 minutes
10 minutes
Processing Speed
Wechsler Intelligence Scale for Children- 4th 
Ed. Subtests:  Coding;  Symbol Search a
Wechsler Adult Intelligence Scale-(WAIS-III 
or WAIS-IV) Subtests:  Digit Symbol-
Coding; Symbol Search a
6 – 15 years
>16 years
5 minutes
5 minutes
Academic 
Achievement
Wechsler Individual Achievement Test-II or 
III Subtests: Word Reading, Numerical 
Operations, Spelling a
OR
Bracken Basic Concept Scale-Revisedb
5+ years
2½- 5 years 
20 minutes
10 minutes
Emotional/
Behavioral
Behavior Assessment System for Children – 2 
Parent form a, d
Behavior Rating Inventory of Executive 
     Function – Parent form a 
Behavior Assessment System for Children – 2 
Self-Report formb, d
2½ -21 years
(if in college 
to 25 years)
2+ years 
8-21 years (if 
in college to 
25 years)
15 minutes
5 minutes 
15 minutes
Adaptive/Daily 
Living
Scales of Independent Behavior- Revised 
(Short Form)-Parent formb, d
1 month +
10 minutes
Notes:     The same test version administered at Baseline should always be re-administered at follow up unless the patient has 
aged out of the norms for that given test.  
Test battery was designed to assess patients from infancy to adulthood. 
Approximate total administration time: Approximately 3-4 hours for patient measures; however, actual tests administered 
and the time required depends on the patient’s chronological and functional ages. Parent measures require approximately 
40 minutes and are completed while the patient is being evaluated.  
a.
Required test – part of core neurocognitive assessment
b.
Recommended tests
c.
Weschler Individual Achievement Test – III should be used with all patients enrolled after January 2013

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d.
If scoring program not available, results may be sent to MGH for scoring.
10. MEASUREMENT OF EFFECT
 
Tumor response is not an endpoint of this study.  Patients will be evaluated for progressive 
disease based on imaging studies obtained in follow up.
10.1 Progression-Free Survival
Progression-Free Survival (PFS) is defined as the duration of time from start of treatment to 
time of objective disease progression. 
10.2 Response Review
There is no central review of radiology assessments as response rate is not a primary 
endpoint or even a secondary endpoint of the trial. This trial measures toxicity and late 
effects and therefore central radiology review is not indicated. 
11. ADVERSE EVENT REPORTING REQUIREMENTS 
11.1 General 
Adverse event collection and reporting is a routine part of every clinical trial. This study will 
use the descriptions and grading scales found in the CTEP Active Version of the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) that is available on the CTEP 
website at:  http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.html. 
Information on all adverse events, whether reported by the participant, directly observed, or 
detected by physical examination, laboratory test or other means, will be collected, recorded, 
followed and reported as described in the following sections. 
All adverse events experienced by participants from initiation of study treatment, throughout 
the study treatment, and within 30 days of the last dose of study treatment will be collected 
and reported as per DFCI guidelines. Participants who experience an ongoing adverse event 
related to a study procedures and/or study medication beyond 30 days will continue to be 
contacted by a member of the study team until the event is resolved, stabilized, or determined 
to be irreversible by the participating investigator.  
Participants should be instructed to report any serious post-study event(s) that might 
reasonably be related to participation in this study. The investigator should notify the the PI 
and Coordinating Center, IRB, and any other applicable regulatory agency of any 
unanticipated death or adverse event occurring after a participant has discontinued or 
terminated study participation that may reasonably be related to the study. 

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11.2 Definitions 
11.2.1  Adverse Event (AE)
An adverse event is any undesirable sign, symptom or medical condition or experience 
that develops or worsens in severity after starting the first dose of study treatment or any 
procedure specified in the protocol, even if the event is not considered to be related to the 
study. 
Abnormal laboratory values or diagnostic test results constitute adverse events only if 
they induce clinical signs or symptoms or require treatment or further diagnostic tests. 
11.2.2 Serious Adverse Event (SAE)
A serious adverse event is an undesirable sign, symptom, or medical condition which:

is fatal or life-threatening;

requires or prolongs inpatient hospitalization;

results in persistent or significant disability/incapacity;

constitutes a congenital anomaly or birth defect; or

jeopardizes the participant and requires medical or surgical intervention to 
prevent one of the outcomes listed above. 
Events not considered to be serious adverse events are hospitalizations for:

routine treatment or monitoring of the studied indication, not associated with 
any deterioration in condition, or for elective procedures

elective or pre-planned treatment for a pre-existing condition that did not 
worsen

emergency outpatient treatment for an event not fulfilling the serious criteria 
outlined above and not resulting in inpatient admission

respite care
11.2.3 Expectedness 
Adverse events can be 'Expected' or 'Unexpected.' 
11.2.3.1 Expected adverse event
Expected adverse events are those that have been previously identified as 
resulting from administration of the agent. For the purposes of this study, an 
adverse event is considered expected when it appears in the current adverse event 
list, the Investigator’s Brochure, the package insert or is included in the informed 
consent document as a potential risk.  

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Refer to Section 6.1 for a listing of expected adverse events associated with the 
study radiation.  
11.2.3.2. Unexpected adverse event
For the purposes of this study, an adverse event is considered unexpected when it 
varies in nature, intensity or frequency from information provided in the current 
adverse event list, the Investigator’s Brochure, the package insert or when it is not 
included in the informed consent document as a potential risk.  
11.2.4 Attribution 
Attribution is the relationship between an adverse event or serious adverse event and the 
study treatment. Attribution will be assigned as follows:
Definite – The AE is clearly related to the study treatment.
Probable – The AE is likely related to the study treatment.
Possible – The AE may be related to the study treatment. 
Unlikely - The AE is doubtfully related to the study treatment.
Unrelated - The AE is clearly NOT related to the study treatment.
11.3 Recording Adverse Events
Adverse event information will be obtained at each contact with the participant. All adverse 
events will be recorded on the appropriate study-specific case report forms (CRFs). After 30 
days beyond completion of study treatment, only adverse events that are possibly, probably 
or definitely related to study treatment will be collected for recording on the CRFs.
11.4 Reporting Adverse Events 
For multi-site trials where a DF/HCC investigator is serving as the principal investigator, 
each participating investigator is required to abide by the reporting requirements set below. 
The study must be conducted in compliance with FDA regulations, local safety reporting 
requirements, and reporting requirements of the principal investigator. 
Each investigative site will be responsible to report SAEs that occur at that institution to their 
respective IRB. It is the responsibility of each participating investigator to report serious 
adverse events to the study sponsor and/or others as described below. 
The following severe toxicities should be reported to the principal investigator within one 
business day:
Transverse myelitis
Any other grade 4 acute toxicity except myelosuppression
Death

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Each adverse event will be assessed to determine if it meets the criteria for serious adverse 
event. If a serious adverse event occurs, expedited reporting will follow local policies, and 
federal guidelines and regulations as appropriate. 
It is the responsibility of the participating investigator to notify the Principal Investigator (or 
Protocol Chair), IRB, and others of all serious adverse events as required in the protocol. 
The Principal Investigator (or Protocol Chair) will provide information with respect to 
adverse events and safe use of the study treatment (e.g., safety reports, Action Letters) to all 
participating investigators as soon as the information becomes available. 
11.4.1  Serious Adverse Event Reporting
All serious adverse events that occur after the initial dose of study treatment, during 
treatment, or within 30 days of the last dose of treatment must be reported to the DF/HCC 
Overall Principal Investigator on the local institutional SAE form. This includes events 
meeting the criteria outlined in Section 11.2, 11.4, as well as the following:

Grade 2 (moderate) and Grade 3 (severe) events that are unexpected and at 
least possibly related/associated with the intervention.

All Grade 4 (life-threatening or disabling) events that are unexpected, 
except myelosuppression.

All Grade 5 (fatal) events while the participant is enrolled and actively 
participating in the trial OR when the event occurs within 30 days of the 
last study intervention. 
Note: If the participant is in long term follow up, report the death at the time 
of continuing review. 
Participating investigators must report each serious adverse event to the DF/HCC Overall 
Principal Investigator within one business day of learning of the occurrence. In the event 
that the participating investigator does not become aware of the serious adverse event 
immediately (e.g., participant sought treatment elsewhere), the participating investigator 
is to report the event within one business day after learning of it and document the time 
of his or her first awareness of the adverse event. Report serious adverse events by 
telephone, email or facsimile to:
Torunn Yock, MD
c/o Coordinating Center
Telephone: 643-6086
Email: ccpo-mcgroup@partners.org
Fax: 617-724-2787

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Within the following one to two business days, the participating investigator must 
provide follow up information on the serious adverse event. Follow up information 
should describe whether the event has resolved or continues, if and how the event was 
treated, and whether the participant will continue or discontinue study participation.
Non-Serious Adverse Event Reporting:
Non-serious adverse events will be reported to the DF/HCC Overall Principal 
Investigator on the toxicity Case Report Forms.
11.5 
Institutional Review Board (IRB) Notification by Investigator
Investigative sites within DF/HCC will report all serious adverse events directly to the DFCI 
Office for Human Research Studies (OHRS).
Other investigative sites should report serious adverse events to their respective IRB 
according to the local IRB’s policies and procedures in reporting adverse events. A copy of 
the submitted institutional SAE form should be forwarded to:
Torunn Yock, MD
Telephone: 617-643-6086
Email: ccpo-mcgroup@partners.org
Fax: 617-724-2787
The DF/HCC Principal Investigator will submit SAE reports from outside institutions to the 
DFCI Office for Human Research Studies (OHRS) according to DFCI IRB policies and 
procedures in reporting adverse events. 
11.6 Hospital Risk Management Notification by Investigator
The participating investigator will report to their local Risk Management Office any subject 
safety reports or sentinel events that require reporting according to institutional policy.
12. DATA AND SAFETY MONITORING
12.1 Data Reporting 
12.1.1 Method 
Data for this study will be collected and managed by the MGH Biostatistics Center.  
Electronic case report forms will be posted for use by all participating sites in TrialDB, 
and study staff at each site will be given access to enter CRF data electronically.  Data 
will be monitored as described in the attached Data and Safety Monitoring Plan 
(Appendix A). 

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12.1.2 Data Submission 
The schedule for completion and submission of electronic case report forms to the MGH 
Biostatistics Center can be found in section 5.10 in the attached Data and Safety 
Monitoring Plan (Appendix A).
The Coordinating Center is responsible for compiling and submitting data for all 
participants to the Principal Investigator for review.
12.1.3 DICOM Data
De-identified DICOM data for each study subject will be transmitted to the Advance 
Technology QA Center at Washington University, St. Louis (ATC). ATC will maintain 
the de-identified image data for analysis by investigators at all participating sites 
12.2  Safety Meetings  
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor 
toxicity and accrual data from this trial. The committee is composed of clinical specialists 
with experience in oncology and who have no direct relationship with the study. Information 
that raises any questions about participant safety will be addressed with the Principal 
Investigator and study team.
The DSMC will meet periodically as required to review toxicity and accrual data.  
Information to be provided to the committee may include:  up-to-date participant accrual; 
current dose level information; DLT information; all grade 2 or higher unexpected adverse 
events that have been reported; summary of all deaths occurring within 30 days for Phase I 
or II protocols; for gene transfer protocols, summary of all deaths while being treated and 
during active follow up; any response information; audit results, and a summary provided 
by the study team. Other information (e.g. scans, laboratory values) will be provided upon 
request. 
12.3 Monitoring
Involvement in this study as a participating investigator implies acceptance of potential 
audits or inspections, including source data verification, by representatives designated by 
the Principal Investigator or Coordinating Center. The purpose of these audits or 
inspections is to examine study-related activities and documents to determine whether these 
activities were conducted and data were recorded, analyzed, and accurately reported in 
accordance with the protocol, institutional policy, Federal Guidelines, and any applicable 
regulatory requirements. 
All data will be monitored for timeliness of submission, completeness, and adherence to 
protocol requirements. Monitoring will begin at the time of participant registration and will 
continue during protocol performance and completion. 

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13. REGULATORY CONSIDERATIONS
13.1 Protocol Review and Amendments
This protocol, the proposed informed consent and all forms of participant information related 
to the study (e.g., advertisements used to recruit participants) and any other necessary 
documents must be submitted, reviewed and approved by a properly constituted IRB 
governing each study location. 
Any changes made to the protocol must be submitted as amendments and must be approved 
by the IRB prior to implementation. Any changes in study conduct must be reported to the 
IRB. The Principal Investigator (or Protocol Chair) will disseminate protocol amendment 
information to all participating investigators. 
All decisions of the IRB concerning the conduct of the study must be made in writing.
13.2 Informed Consent
All participants must be provided a consent form describing this study and providing 
sufficient information for participants to make an informed decision about their 
participation in this study. The formal consent of a participant, using the IRB approved 
consent form, must be obtained before the participant is involved in any study-related 
procedure. The consent form must be signed and dated by the participant or the 
participant’s legally authorized representative, and by the person obtaining the consent. The 
participant must be given a copy of the signed and dated consent document. The original 
signed copy of the consent document must be retained in the medical record or research 
file. 
Children over the age of nine will be offered the opportunity to assent to study 
participation, as appropriate.  This will also be documented in the medical record.
13.3 Ethics and Federal Guidelines
This study is to be conducted according to the following considerations, which represent 
good and sound research practice:

US Code of Federal Regulations (CFR) governing clinical study conduct and 
ethical principles that have their origin in the Declaration of Helsinki

Title 21 Part 50 – Protection of Human Subjects 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr50_02.html 

Title 21 Part 54 – Financial Disclosure by Clinical Investigators 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr54_02.html 

Title 21 Part 56 – Institutional Review Boards 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr56_02.html 

Title 21 Part 312 – Investigational New Drug Application 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr312_02.html 

State laws

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
Institutional research policies and procedures 
www.dfhcc.harvard.edu/clinical-research-support/clinical-research-
operations-cro/policies-and-procedures
It is understood that deviations from the protocol should be avoided, except when 
necessary to eliminate an immediate hazard to a research participant. In such case, the 
deviation must be reported to the IRB according to the local reporting policy. 
13.4 Study Documentation
The investigator must prepare and maintain adequate and accurate case histories designed to 
record all observations and other data pertinent to the study for each research participant. 
This information enables the study to be fully documented and the study data to be 
subsequently verified.
Original source documents supporting entries in the case report forms include but are not 
limited to hospital records, clinical charts, laboratory and pharmacy records, recorded data 
from automated instruments, microfiches, photographic negatives, microfilm or magnetic 
media, and/or x-rays. 
13.5 Records Retention
All study-related documents must be retained for the maximum period required by applicable 
federal regulations and guidelines or institutional policies. 
13.6 Multi-center Guidelines  
This protocol will adhere to the policies and requirements of the Dana-Farber/Harvard 
Cancer Center. The specific responsibilities of the Principal Investigator (or Protocol Chair), 
Coordinating Center, and Participating Institutions are presented in the Dana-Farber/Harvard 
Cancer Center Multi-Center Data and Safety Monitoring Plan (see Appendix A).

The Principal Investigator/Coordinating Center is responsible for distributing all 
Safety Reports to all participating institutions for submission to their individual 
IRBs for action as required.

Mechanisms will be in place to ensure quality assurance, protocol compliance, and 
adverse event reporting at each site. 
14. STATISTICAL CONSIDERATIONS   
The primary outcomes are late complications following proton beam irradiation to the 
craniospinal axis and posterior fossa. Late complications are defined as the delayed effects 
attributable to radiation which occur > 90 days following completion of CSI, while acute effects 
are those occurring during radiotherapy or up to 90 days after the last dose. Due to a difference 

Phase II Study of Proton RT for Medulloblastoma and Pineoblastoma: Acute Toxicity and Long Term 
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in the CSI dose used for standard-risk and high-risk patients, the two groups will be analyzed 
separately and thus have separate accrual goals. 
14.1 Study Design/Endpoints
Accrual goals are 60 standard-risk and 30 high-risk patients. In the pediatric MB population 
treated with conventional photon CSI, 3-year progression-free survival of standard-risk 
patients is in the 75-80% range depending on the concurrent use of chemotherapy, while 65-
70% is reported among high-risk patients. Thus, 48 standard-risk and 20 high-risk patients 
are projected to be evaluable for late complications at 3 years following the CSI completion; 
patients who progress or die sooner will not contribute in the analysis of late complications.
The primary endpoint of ototoxicity at 3 years following completion of radiation therapy will 
be based on failure events defined by grade 3 or 4 sensorineural hearing loss (SNHL) 
according to COG criteria. They include progressive hearing decrease to grade 3 or 4 
following mild or moderate loss (grade 1 or 2) typically experienced during platinum-based 
chemotherapy. All patients who have audiology assessments prior to censorship will 
contribute to the actuarial analysis. Patients will be censored in the event of death, drop out 
or progression of disease. The historical rates of late SNHL is in the 50% range among 
pediatric MB patients [9, 10] treated with conventional CSI and cisplatin-based 
chemotherapy. We shall conclude proton therapy leads to an improvement in the high-risk 
group if 7 or fewer of 20 patients were to experience grade 3 or 4 SNHL at 3 years following 
completion of radiation therapy. The decision rule is associated with 77% power if the SNHL 
rate were truly reduced to 30% among the high-risk patients. In contrast, the probability is 
only 13% for concluding incorrectly an improvement if the underlying SNHL rate were 50%. 
In the null hypothesis for the standard-risk group, we assume conventional CSI and cisplatin-
based chemotherapy is associated with an SNHL rate less than 50% due to their lower CSI 
dose, in particular, 40%. We shall conclude proton therapy leads to an improvement in the 
standard-risk group if 14 or fewer of 48 patients were to experience grade 3 or 4 SNHL at 3 
years following completion of radiation therapy. The decision rule is associated with 80% 
power if the SNHL rate were truly reduced to 25% among the standard-risk patients. In 
contrast, the probability is only 8% for concluding incorrectly an improvement if the 
underlying SNHL rate were 40%. 
Published data on neuroendocrine dysfunction and neurocognitive functioning have been 
based on small sample sizes, varying CSI doses and heterogeneous populations not directly 
comparable to the pediatric MB and PB patients in this protocol. Therefore, analysis of these 
endpoints will be focused mainly on estimation and precision. A standard-risk group of 48 
patients will provide exact 95% confidence intervals of less than 30% for estimating the rates 
of neuroendocrine dysfunction and neurocognitive functioning, while the maximum interval 
width will be 46% based on 20 patients. Confidence intervals will be narrower in the analysis 
of acute effects, as more patients will be evaluable because very few losses will occur due to 
progression or death within 90 days following completion of CSI.

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14.2   Sample Size/Accrual Rate
Based on recent clinical experience, the protocol is projected to accrue about 18 patients per 
year combined between the two participating institutions. Enrollment is planned for 5 years 
in order to meet the overall accrual goal of 90 patients. The observed risk distribution of MB 
and PB patients has been approximately a 2:1 ratio so that 60 standard-risk and 30 high-risk 
patients will be accrued for the sample size requirements. A minimum follow up of 3 years is 
required for observing the late complications of proton beam irradiation.
14.3   Stratification Factors
Enrollment will be stratified by risk group.
14.4    Analysis of Endpoints
Progression-free survival is measured from the start of radiation therapy to the date of 
documented disease progression or death in the absence of progression. Patients who have 
not progressed or died will be censored at the time of last follow up. Progression-free 
survival will be estimated by the Kaplan-Meier method. Acute effects will be summarized 
according to specific events with exact 95% confidence intervals for binary data. The 
incidence of late complications will be based on actuarial estimates, primarily at 3 years. 
Patients who die, progress, or are lost to follow up prior to 3 years will be censored. Other 
factors which may influence late complications will be explored in multivariate models, 
including gender, age, radiation dose to the posterior fossa, dose volume histogram of the 
normal tissue as well as drugs, dosages and sequencing of the chemotherapy regimen. In 
addition, we shall control for pre-existing hearing deficits in the analysis of ototoxicity, while 
methotrexate usage will be of interest in the analysis of neurocognitive functioning among 
high-risk patients. Multivariate analyses will be primarily exploratory due to the modest 
patient numbers in each risk group.
14.5 Reporting and Exclusions  
14.5.1 Evaluation of toxicity. 
All participants will be evaluable for toxicity from the time of their first treatment.
 14.5.2   Evaluation of response
 Tumor response is not applicable in this protocol. 
15. PUBLICATION PLAN  
The results will be made public within 24 months of the end of data collection for the primary 
objective. If a report is planned to be published in a peer-reviewed journal, then that initial 
release may be an abstract that meets the requirements of the International Committee of Medical 
Journal Editors. A full report of the outcomes should be made public no later than three (3) years 
after the end of data collection. 

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Deutsch, M.   Medulloblastoma:  staging and treatment outcome.  Int J Radiat Oncol Biol 
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Bloom, H and Bessell, E.   Medulloblastoma in adults: a review of 47 patients treated 
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Grai, C, Moller, K, Overgaard, M, et al.   Sensori-neural hearing loss in patients treated 
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Thibadoux, GM, Pereira, WV, Hodges, JM, et al.   Effects of cranial radiation on hearing 
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Packer, R, Sutton, L, Elterman, R, et al.   Outcome for children with medulloblastoma 
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Dutton, SC, Neault, M, Billett, A, et al., Progressive ototoxicity after combined modality 
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Kovner, E, McHaney, V, Ayers, D, et al.   Effects of treatment sequence on ototoxicity 
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Rubin, P, Constine, L, Fajardo, L, et al.   Late effects of normal tissues consensus 
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Sutton and al, e, in Concepts Pediatric Neurosurg. 1989. p. 91-109.
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Hoppe-Hirsch, E, L, B, Laroussinie, F, et al.   Intellectual outcome in children with 
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Silber, JH, Littman, PS and Meadows, AT.   Stature loss following skeletal irradiation for 
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Grill, J, Kieffer Renaux, V, Bulteau, C, et al.   Long-term intellectual outcome in children 
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Mulhern, RK, Kepner, JL, Thomas, PR, et al.   Neuropsychologic functioning of 
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dose craniospinal irradiation:  a Pediatric Oncology Group study.  J Clin Oncol 1998. 
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Deutsch, M, Thomas, PR, Krischer, J, et al.   Results of a prospective randomized trial 
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Packer, RJ, Sutton, LN, Atkins, TE, et al.   A prospective study of cognitive function in 
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17. APPENDICES 
Appendix A: Data and Safety Monitoring Plan
Appendix B: Patient Letter 
Appendix C: Funded Visit Letter