Pilot Study of Adjuvant Proton Beam Teletherapy for Post-Hysterectomy Cancers of the Uterus and Cervix With Metastases to Regional Lymph Nodes
Phase: NA
Conditions: Uterine Cancer, Cervical Cancer
Sponsor: Massachusetts General Hospital

Protocol Version Date: 10/9/2019
NCI Protocol #: N/A
Local Protocol #: 10-269
Title: Pilot Study of Adjuvant Proton Beam Teletherapy for Post-Hysterectomy Cancers of 
the Uterus and Cervix with Metastases to Regional Lymph Nodes
Principal Investigator:
Andrea Russo, M.D.
Massachusetts General Hospital 
Phone: 617-219-1200
Department of Radiation Oncology
Fax: 617-726-3603
100 Blossom Street, Cox 3
E-mail: ALRUSSO@PARTNERS.ORG
Boston, MA  02114
Co-Investigators: 
Thomas F. DeLaney, M.D.
Hanne Kooy, Ph.D.
Michael Birrer, M.D., Ph.D.
Anthony H. Russell, M.D.
Karen De Amorim Bernstein, M.D.
Statistician: Beow Yeap, Sc.D. Biostatistics Center, Massachusetts General Hospital, Boston, 
MA  02114   
Study Coordinator: Sarah Nisbet
Responsible Research Nurse: TBN
Responsible Data Manager: Sarah Nisbet
Agent(s):  –Proton Beam Radiotherapy (no IND)
Funding Support:  Federal Share of program income earned by Massachusetts General Hospital 
on C06 CA059267, Proton Therapy Research and Treatment Center
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Pilot Study of Adjuvant Proton Beam Teletherapy for Post-Hysterectomy Cancers of the Uterus and Cervix 
With Metastasis to Regional Lymph Nodes, Andrea Russo, M.D.
Version 10/9/2019
CONFIDENTIAL
This document is confidential. Do not disclose or use except as authorized.
TABLE OF CONTENTS
Page
SCHEMA
i
1: OBJECTIVES 
1
1.1
Study Design
1
1.2
Primary Objectives
2
1.3
Secondary Objectives
2
2: BACKGROUND
2
2.1 Study Agent(s)
2
2.2 Study Disease
3
2.3 Rationale
3
3: PARTICIPANT SELECTION
4
3.1 Eligibility Criteria
5
3.2 Exclusion Criteria
7
3.3 Inclusion of Women, Minorities and Other Underrepresented Populations
7
4: REGISTRATION PROCEDURES
7
4.1
General Guidelines for DF/HCC and DF/PCC Institutions
7
4.2
Registration Process for DF/HCC and DF/PCC Institutions
8
5:  TREATMENT PLAN
8
5.1  Pre-treatment Criteria
8
5.2 Agent Administration
8
5.3 Definition of Dose- Limiting Toxicity
12
5.4 General Concomitant Medication and Supportive Care Guidelines
12
5.5 Duration of Therapy
13
5.6 Duration of Follow Up
13
5.7 Criteria for Removal from Study
13
6: EXPECTED TOXICITIES AND DOSING DELAY/DOSE MODIFICATIONS
14
6.1 Anticipated Toxicities and Toxicity Management
15
6.2
Dose Modifications/Delays
16
7: DRUG FORMULATION AND ADMINISTRATION:
17
8: CORRELATIVE/SPECIAL STUDIES: 
17
9: STUDY CALENDAR
17
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Pilot Study of Adjuvant Proton Beam Teletherapy for Post-Hysterectomy Cancers of the Uterus and Cervix 
With Metastasis to Regional Lymph Nodes, Andrea Russo, M.D.
Version 10/9/2019
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10: MEASUREMENT OF EFFECT
18
10.1 Progression-Free Survival
18
10.2 Pattern of Recurrence
19
10.3 Quality of Life
19
11: ADVERSE EVENT REPORTING REQUIREMENTS
19
11.1 General
19
11.2 Definitions
20
11.3 Recording Adverse Events
21
11.4 Reporting Adverse Events
22
11.5 Institutional Review Board (IRB) Notification by Investigator
22
11.6 Hospital Risk Management Notification by Investigator
23
12: DATA AND SAFETY MONITORING
23
12.1 Data Reporting
23
12.2 Safety Meetings
24
12.3 Monitoring
24
13: REGULATORY CONSIDERATIONS
24
13.1 Protocol Review and Amendments
24
13.2 Informed Consent
25
13.3 Ethics and Good Clinical Practice (GCP)
25
13.4 Study Documentation
26
13.5 Records Retention
26
13.6 Multi-center Guidelines
26
14: STATISTICAL CONSIDERATIONS
26
14.1 Study Design/Endpoints
27
14.2 Sample Size/Accrual Rate
27
14.3 Stratification Factors
27
14.4 Analysis of Secondary Endpoints
27
14.5 Reporting and Exclusions
28
15: PUBLICATION PLAN
28
16. REFERENCES
30
17: APPENDICES
30
Appendix 1
31
Performance Status Criteria
Appendix 2
32
    FACT-En Version 4 questionnaire for women with uterine cancer
Appendix 3
35
    FACT-Cx Version 4 questionnaire for women with cervical cancer
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Pilot Study of Adjuvant Proton Beam Teletherapy for Post-Hysterectomy Cancers of the Uterus and Cervix 
With Metastasis to Regional Lymph Nodes, Andrea Russo, M.D.
Version 10/9/2019
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Study Schema:
Eligibility and Registration
Adjuvant RT using scanned proton beam to 
conventional doses
Plus or minus chemotherapy per standard of care for 
histology being treated
Follow Up for 5 years 
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Pilot Study of Adjuvant Proton Beam Teletherapy for Post-Hysterectomy Cancers of the Uterus and Cervix 
With Metastasis to Regional Lymph Nodes, Andrea Russo, M.D.
Version 10/9/2019
CONFIDENTIAL
This document is confidential. Do not disclose or use except as authorized.
1
1. OBJECTIVES: 
The study hypotheses are that adjuvant post-hysterectomy proton teletherapy for women with 
uterine and cervical cancers and histologically confirmed metastases to regional lymph nodes 
will be efficacious (cancer control within the irradiated volume) and reduced in both acute and 
delayed toxicity when compared to treatment with conventional photon teletherapy techniques.  
The study will quantitate the magnitude of normal tissue spared with scanning proton beam 
therapy compared to 3-dimensional conformal and intensity modulated photon radiation 
techniques, and correlate acute and late toxicity outcomes to the reduced volumes of normal 
tissues irradiated.
1.1
Study Design:
Patients who undergo hysterectomy for invasive cancer of the uterus or cervix who have 
histologically confirmed metastases to one or more regional lymph nodes (parametrial, pelvic, or 
para-aortic nodal groups) conventionally undergo radiation treatment as all, or a component of 
their adjuvant post-surgical therapy. 
Such patients will be identified at the weekly Gynecologic Oncology-Pathology 
Multidisciplinary Tumor Board that routinely reviews all gynecologic cancer pathology in 
patients operated at Massachusetts General Hospital (MGH). 
Potentially eligible patients operated elsewhere and referred for adjuvant treatment to MGH 
would be identified based on pathology review of submitted histologic sections from the 
referring institution. 
After obtaining informed consent, eligible patients will receive conventional doses of adjuvant 
teletherapy conventionally scheduled (fractionated) delivered to conventional target volumes 
using scanning proton beam instead of photon beam.
Using data from the same treatment planning CT scans used to plan proton therapy, conventional 
photon plans will be generated using three dimensional conformal radiation therapy (3DCRT)  
and intensity modulated radiation therapy (IMRT) for comparison purposes to quantitate the 
extent of normal tissue sparing through the use of dose volume histograms. 
Monitoring during and after such treatment will be essentially equivalent to standard clinical 
practice at MGH with the exception that the schedule of post-treatment assessments will more 
tightly conform to the study calendar.
Assuming successful accrual and treatment of sufficient numbers of patients, a retrospective 
outcomes study will compare cancer control within the irradiated volume, acute side effects of 
teletherapy, and delayed complications of radiation treatment to a historical control population 
treated with photon teletherapy at MGH.
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Pilot Study of Adjuvant Proton Beam Teletherapy for Post-Hysterectomy Cancers of the Uterus and Cervix 
With Metastasis to Regional Lymph Nodes, Andrea Russo, M.D.
Version 10/9/2019
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1.2
Primary Objective
1.2.1 In a population of women with cancers of the cervix or endometrium with pathologically 
proven spread to regional lymph nodes, to quantitate the magnitude of the normal tissue radiation 
dose reductions achieved by comparison of dose volume histograms achieved by scanning proton
beam teletherapy with dose volume histograms of treatment plans for the same patients using 3-
dimensional conformal radiation therapy (3DCRT) and intensity modulated radiation therapy 
(IMRT).
1.2.2 To prospectively assess acute radiation side effects and delayed complications in proton 
treated patients and to compare toxicity outcomes (acute side effects and delayed complications) 
with patients historically treated with photon teletherapy using institutional historical controls 
(retrospective outcomes comparison study).
1.3 Secondary Objectives
1.3.1 To prospectively collect data on quality of life (QOL) before and after adjuvant scanning 
proton beam therapy employing contemporary, validated instruments tailored for women treated 
for gynecologic cancer.
1.3.2 To determine the progression-free survival and patterns of recurrence with this treatment.
2. BACKGROUND
2.1
Study Agent(s)
2.1.1
Proton beam radiation therapy has been employed in the clinical treatment of cancer at 
MGH since 1961. Initially patients were treated at the Harvard Cyclotron Laboratory in 
Cambridge, but since 2001 treatment has been administered on the MGH campus in the Francis 
H. Burr Proton Treatment Center. To date, over 10,000 patients have been treated using proton 
beam in MGH programs. Proton beam has equivalent biologic effects in tissue to high energy 
photon beams from linear accelerators employed at MGH and elsewhere.  The principal clinical 
advantage of proton beam lies in the nature of its energy (radiation dose) deposition in tissue. In 
contrast to photons (X-rays), protons penetrate to a depth in tissue determined by their energy, 
then deposit dose over a very narrow range (Bragg peak) transmitting minimal radiation beyond 
that point.  Exploiting this difference in physical dose deposition characteristics allows design of 
clinical treatments with more conformal dose distributions delivering proportionately much lower 
dose to normal tissues lying adjacent to the targeted malignant tissues than conventional photon 
techniques. [1] In general, this will result in milder acute treatment side effects, and potentially 
fewer and milder long-term complications of radiation treatment. 
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Pilot Study of Adjuvant Proton Beam Teletherapy for Post-Hysterectomy Cancers of the Uterus and Cervix 
With Metastasis to Regional Lymph Nodes, Andrea Russo, M.D.
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2.2
Study Disease:
2.2.1
Patients with primary cancers of the uterus conventionally undergo surgery as their initial 
intervention. Generally this will consist of open or laparoscopic total hysterectomy and bilateral 
salpingo-oophorectomy with variable sampling or full dissection of pelvic and/or para-aortic 
lymph nodes. Patients in whom cancer has spread to lymph nodes (International Federation of 
Gynecology and Obstetrics (FIGO) Stage IIIC) routinely undergo radiation treatment to the 
pelvis or extended volumes (pelvis and para-aortic nodal basins) postoperatively, either as their 
only adjuvant treatment, or more commonly following 4-6 cycles of adjuvant systemic cytotoxic 
chemotherapy with carboplatin and taxol.  Such treatment is endorsed by National 
Comprehensive Cancer Network (NCCN) guidelines.[2] Teletherapy (external radiation) is 
commonly supplemented by limited additional vaginal brachytherapy (internal vaginal 
radiation). This approach has been standard management at MGH for more than 7 years and is 
also endorsed by National Comprehensive Cancer Network (NCCN) guidelines.[2] Based on 
retrospective outcomes comparisons from M.D. Anderson Cancer Center, cancer control and 
overall survival statistics are substantially better in patients getting teletherapy/brachytherapy as 
all or a component of their treatment compared to patients getting systemic adjuvant 
chemotherapy/brachytherapy without teletherapy.[3] Additional data from Duke University and 
the University of North Carolina support this approach as well.[4]
2.2.2
Patients with primary cancer of the cervix limited to the cervix and upper vagina (FIGO 
stages IB and IIA) based on examination under anesthesia (EUA) supplemented by diagnostic 
imaging (MRI, PET/CT) will conventionally undergo modified radical or radical hysterectomy 
with therapeutic pelvic lymphadenectomy +/- sampling para-aortic lymphadenectomy as their 
initial therapeutic intervention. Patients with histologically confirmed metastasis to lymph nodes 
undergo adjuvant teletherapy to the pelvis or extended volumes (pelvis and para-aortic nodal 
basins) administered in conjunction with concurrent cisplatin-based adjuvant cytotoxic 
chemotherapy and limited intra-vaginal brachytherapy. This has been standard therapy at MGH 
for more than 7 years and is consistent with NCCN guidelines.[2]
2.3
Rationale
While combined modality therapy (surgery, radiotherapy, chemotherapy) for patients with FIGO 
Stage IIIC uterine cancer and American Joint Commission on Cancer (AJCC) pT1,2,N1,M0 cancer 
of the cervix is associated with prolonged cancer-free survival (“cure”) in many patients [3,4,5]
acute side effects and late complications of treatment can be severe with substantial impact on 
quality of life (QOL) for many subsequent years. Despite chronic toxicities of treatment being 
recognized by both patients and the physicians involved in their longitudinal care, minimal 
prospective data are available documenting the impact of such treatment on quality of life, and no 
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Pilot Study of Adjuvant Proton Beam Teletherapy for Post-Hysterectomy Cancers of the Uterus and Cervix 
With Metastasis to Regional Lymph Nodes, Andrea Russo, M.D.
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This document is confidential. Do not disclose or use except as authorized.
4
quantitative data employing contemporary assessment instruments tailored for women with 
gynecologic malignancies.
Acute toxicities associated with radiation treatment include cramps, erratic bowel movements, 
diarrhea, nausea, vomiting, dehydration, electrolyte imbalance, urinary frequency, burning, and 
fatigue.
Late complications, which occur months to years after radiation treatment, can include leg 
lymphedema, radiation insufficiency fractures in pelvic bones or lumbar spine, small or large 
bowel obstruction which can require surgery to relieve, or chronic erratic bowel function with 
varying degrees of intestinal malabsorption. In some premenopausal patients with cervical cancer, 
ovaries will be conserved, often surgically translocated to the para-colic gutters. Teletherapy is 
often a contributing factor in the premature endocrine failure of such ovaries, resulting in 
premature menopause.
Both acute side effects and late complications of radiation treatment are mostly a function of the 
volume of adjacent organs at risk (OAR), the “innocent bystanders” that are unavoidably irradiated 
when conventional photon beam techniques are employed to target potentially cancerous tissues.  
Volume of normal tissue exposed, total dose, and dose per treatment fraction all correlate with the 
severity of both acute symptomatic side effects as well as late effects in normal tissues. Each of 
these parameters could be expected to be reduced by using proton beam therapy [1] rather than 
conventional photon beam techniques, with resultant better tolerance during treatment as well as 
reduced late complications. Virtually every patient undergoing pelvic or extended volume 
teletherapy will experience some degree of acute side effects. Only a minority will experience 
major symptomatic late complications. But for those patients, the effects can last a lifetime. 
      
The hypothesis of this study is that use of proton beam teletherapy in-lieu of conventional              
photon techniques will result in reduced radiation exposure to normal tissues and reduced side 
effects and complications of treatment. Use specifically of the “pencil-beam” scanning (PBS) 
proton capability at the FHBPTC makes the treatment of these protocol patients practically feasible
by reducing the complexity of treatment planning and delivery compared to scattered proton 
fields. Due to limitations on field size and deep range of scattered proton fields, treatment of 
large, deep-seated target volumes becomes complex, time consuming, and expensive. PBS 
reduces costs incurred in the construction of field-specific hardware and provides more 
conformal dose distributions.[6,7]
3. PARTICIPANT SELECTION
Patients will be identified at the weekly Gynecologic Oncology-Pathology Multidisciplinary 
Tumor Board that routinely reviews all gynecologic cancer pathology in patients operated at 
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Pilot Study of Adjuvant Proton Beam Teletherapy for Post-Hysterectomy Cancers of the Uterus and Cervix 
With Metastasis to Regional Lymph Nodes, Andrea Russo, M.D.
Version 10/9/2019
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Massachusetts General Hospital (MGH). Potentially eligible patients operated elsewhere and 
referred for adjuvant treatment to MGH would be identified based on pathology review of 
submitted histologic sections from the referring institution.
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 histologically confirmed primary cancer of the uterus or cervix with 
histologically confirmed metastasis to one or more parametrial, pelvic, or para-aortic nodes prior to 
enrollment.   Participants diagnosed at other institutions must have pathology reviewed and 
confirmed at MGH or another DF/HCC institution.
3.1.1.a 
Uterine cancer participants will be FIGO stage IIIC and may have endometrioid cancer, 
clear cell cancer, uterine papillary serous cancer, carcinosarcoma, or endometrial stromal sarcoma.
3.1.1.b 
Cervical cancer participants will be AJCC stages pT1,2,N1,M0 with squamous carcinoma, 
adenocarcinoma, adenosquamous carcinoma, or glassy cell carcinoma histology.
3.1.2
Participants must have undergone simple, modified radical, or radical abdominal 
hysterectomy or vaginal hysterectomy and lymphadenectomy (pelvic nodes, para-aortic nodes, or 
both nodal basins) by open or laparoscopic assisted technique.
3.1.3   Participants may have undergone prior chemotherapy for their uterine malignancy or 
may undergo chemotherapy in conjunction with adjuvant proton therapy per discretion of 
treating physicians. The agents, doses, routes and schedule of administration will be 
determined by their attending Gynecologic Oncologist or Medical Oncologist. For 
participants who have undergone prior chemotherapy, protocol radiation may commence no 
sooner than 21 days after the last chemotherapy treatment. 
3.1.4   Participants with cervical cancer may undergo chemotherapy in conjunction with 
adjuvant proton therapy. The agents, doses, routes and schedule of administration will be 
determined by their attending Gynecologic Oncologist or Medical Oncologist.
3.1.5    Prior therapeutic radiation exposure to tissues for which protocol irradiation is 
anticipated is an exclusion criterion.
3.1.6   There will be no upper age limit for eligibility. Elderly patients will be eligible for 
participation provided they are competent to provide informed consent, or written consent can be 
provided by their duly appointed healthcare proxy.
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Pilot Study of Adjuvant Proton Beam Teletherapy for Post-Hysterectomy Cancers of the Uterus and Cervix 
With Metastasis to Regional Lymph Nodes, Andrea Russo, M.D.
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3.1.7
Life expectancy of greater than 18 months.
3.1.8 ECOG performance status <2 (Karnofsky >60%, see Appendix A). 
3.1.9    Baseline hematology laboratories will be performed prior to registration, the patient can 
be enrolled in the trial if laboratory values are deemed clinically acceptable by treating 
physician.
3.1.10
Participants must have no clinical, radiographic, or laboratory evidence of cancer 
dissemination to the peritoneal cavity, chest cavity, or spread via hematogenous dissemination. 
CT or PET/CT of the chest, abdomen and pelvis must have been obtained within 10 weeks of 
study entry. There must be no measurable (macroscopic) disease within the radiation target 
volume following hysterectomy and lymphadenectomy.
3.1.11
Participants must have the ability to understand and the willingness to sign a written 
informed consent document. 
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Pilot Study of Adjuvant Proton Beam Teletherapy for Post-Hysterectomy Cancers of the Uterus and Cervix 
With Metastasis to Regional Lymph Nodes, Andrea Russo, M.D.
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3.2
Exclusion Criteria
3.2.1 Inability to sign informed consent document.
3.2.2   Evidence of extra-abdominal cancer dissemination or hematogenous cancer 
dissemination.
3.2.3   Evidence of measurable (macroscopic) residual disease following hysterectomy and 
lymphadenectomy.
3.2.4
Prior therapeutic radiation to target tissues for protocol radiation.
3.2.5   Individuals with a history of a different malignancy are ineligible except for the 
following circumstances. Individuals with a history of other malignancies are eligible if they 
have been disease-free for at least 5 years or are deemed by the investigator to be at low risk for 
recurrence of that malignancy. Individuals with the following cancers are eligible if diagnosed 
and treated within the past 5 years: cervical cancer in situ, and basal cell or squamous cell 
carcinoma of the skin. 
3.2.6 Age less than 18.
3.3
  Inclusion of Women, Minorities and Other Underrepresented Populations
All participants are women. Eligibility criteria otherwise do not limit or impede participation or 
retention of minorities or underrepresented populations.
4. REGISTRATION PROCEDURES
4.1 General Guidelines for DF/HCC and DF/PCC Institutions
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Pilot Study of Adjuvant Proton Beam Teletherapy for Post-Hysterectomy Cancers of the Uterus and Cervix 
With Metastasis to Regional Lymph Nodes, Andrea Russo, M.D.
Version 10/9/2019
CONFIDENTIAL
This document is confidential. Do not disclose or use except as authorized.
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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.
5. TREATMENT PLAN
Treatment will be administered on an outpatient basis. Expected toxicities and potential 
risks as well as dose modifications for proton beam teletherapy are described in Section 6 
(Expected Toxicities and Dosing Delays/Dose Modifications). No investigational agents or 
therapies other than those described below may be administered with the intent to treat the 
participant's malignancy.
5.1
Pre-treatment Criteria
5.1.1
Day 1 proton beam teletherapy: Provided all laboratory determinations and imaging 
findings specified in section 3.1 are within the protocol eligibility requirements, no further 
pre-treatment criteria are established.
5.1.2
Subsequent proton beam teletherapy treatments 2-30:  Maintenance of platelet count >
35,000/mcL and absolute neutrophil count >800/mcL.
5.1.3
Uterine cancer patients who have received chemotherapy prior to proton therapy may 
have twice-weekly complete circulating blood counts commencing on or before treatment 
fraction 8. These labs will be ordered and monitored at the discretion of the treating 
physician.
5.1.4
Cervix cancer patients may have weekly complete blood counts commencing on or 
before treatment fraction 8. Cervix patients receiving concurrent chemotherapy will have 
weekly determination of serum electrolytes, renal function, Ca++, and Mg++. These labs will 
be ordered and monitored at the discretion of the treating physician.
5.2
Agent Administration
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Pilot Study of Adjuvant Proton Beam Teletherapy for Post-Hysterectomy Cancers of the Uterus and Cervix 
With Metastasis to Regional Lymph Nodes, Andrea Russo, M.D.
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5.2.1
Proton beam therapy will be planned based on patient supine CT simulation with 
custom immobilization per standard practice in the Department of Radiation Oncology, 
Massachusetts General Hospital.
5.2.2    Full contours will be obtained for all abdominal organs at risk including: stomach, 
duodenum, bowel (small bowel will be contoured separately if patient requires boost with 
teletherapy), rectum, liver, kidneys, spinal cord, thoraco-lumbar spine T12-L5, pelvic bone 
girdle, and proximal femurs from the femoral heads to below the lesser trochanters.
5.2.3    Comparative treatments plans for IMRT and 3DCRT will be generated for each 
participant from the same CT-simulation data set for comparison purposes and for actual 
treatment of participants in the event of the proton beam being unavailable for any reason 
longer than 2 working days.
5.2.4   Standard immobilization-stabilization procedures and treatment verification 
procedures will be employed as customarily performed for patients at the FHBPTC.
5.2.5 For participants undergoing proton beam therapy to the pelvis, the superior extent of 
the target volume will be at the interspace of the fifth lumbar vertebra and the first sacral 
segment (L5-S1).
5.2.6 For participants undergoing proton beam therapy to an extended volume (pelvic and 
para-aortic nodal basins) the superior border will be at the interspace of the twelfth thoracic 
and the first lumbar vertebrae (T12-L1).
5.2.7 For participants treated for cervical cancer the inferior extent of the target volume will 
encompass the proximal 2 cm of the vagina.
5.2.8 For participants treated for uterine cancer, the inferior extent of the target volume will 
encompass the full extent of the vagina from the apex to the introitus defined as the external 
urethral meatus.
5.2.9 All proton beam teletherapy treatments will be administered at a daily dose of 1.8 Gy 
(RBE). The RBE for proton radiation is set at 1.1. The dose unit Gy (RBE) is defined as the 
proton dose in Gy x RBE 1.1.
5.2.10 All proton beam teletherapy treatments will be administered no more than 5 treatment 
days per week. 
5.2.11 Total absorbed teletherapy dose will be 45 Gy (RBE) in 25 daily fractions of 1.8 Gy 
(RBE) over 6 weeks for all participants except as noted in 5.2.12.
5.2.12 For patients with extra-nodal extension and cancer extension to adjacent structures 
(bone, artery, vein, muscle, nerve, bladder serosa, rectal serosa) reduced volume(s) may be 
treated with proton beam to 54 Gy (RBE) in 30 fractions of 1.8 Gy (RBE) over 7 weeks.
5.2.13 Participants with cervical cancer who have more than two positive pelvic lymph nodes or 
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extranodal involvement may be treated with a pelvic and para-aortic radiation field.
5.2.14 Target coverage requirements
o
V90 ≥90% (40.5 Gy (RBE)) 
o
D97(43.65 Gy (RBE)) ≥97%
o
D99(44.55 Gy (RBE)) ≥90%
o
D110(49.5 Gy (RBE)) ≤10%
o
D115(51.75 Gy (RBE)) ≤1%
o
Dose maximum should occur within the PTV 
For patients not receiving reduced volume “boost” therapy:
Organs at risk (OAR) hard constraints: 
o
Bowel (including duodenum, large bowel): V45≤ 250 cc; Dmax ≤ 50 Gy (RBE)
o
Rectum: Dmax ≤ 50 Gy (RBE)
o
Bone Marrow: V10 ≤90%; V20 ≤75%
o
Bladder: Dmax ≤ 50 Gy (RBE)
o
Femoral Head: Dmax ≤50 Gy (RBE)
o
Spinal cord: Dmax ≤ 36 Gy (RBE)
o
Cauda: Dmax ≤ 50 Gy (RBE)
o
Stomach: Dmax ≤ 42 Gy (RBE)
o
Kidneys: V18 ≤30% and V10 ≤50% (for each kidney)
OAR soft constraints: 
o
Bowel: V45 ≤ 200 cc; V40 ≤30%; Dmax ≤ 45 Gy (RBE)
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o
Rectum: V45 ≤50%; V30 ≤60%; Dmax ≤ 50 Gy (RBE)
o
Bone Marrow: V10 ≤80%; V20 ≤66%
o
Bladder: V45 ≤50%; Dmax ≤ 50 Gy (RBE)
o
Femoral Head: V30 ≤15%; Dmax ≤ 50 Gy (RBE)
o
Cauda Equina: Dmax ≤42 Gy (RBE)
o
Kidneys: V14 ≤30% (for each kidney)
For patients receiving reduced volume supplementary “boost” radiation:
o
Small Bowel: Dmax ≤ 52 Gy (RBE)
o
Large Bowel: Dmax ≤ 56 Gy (RBE)
o
Cauda Equina: Dmax ≤ 56 Gy (RBE)
o
Rectum: Dmax ≤ 56 Gy (RBE)
o
Bladder: Dmax ≤ 56 Gy (RBE)
o
Femoral Head: Dmax ≤ 56 Gy (RBE)
The deviations in dose constraints described are considered planning deviations only and will not 
constitute protocol deviations. Treatment plans that include minor planning deviations may be 
delivered as part of this protocol.
5.2.15   Vaginal brachytherapy will be administered on an outpatient basis employing 
standard techniques with high dose rate (HDR) remote afterloading equipment.
5.2.16   Cervix cancer patients will receive 3 brachytherapy fractions of 5 Gy each (15 Gy 
total) administered to the proximal 2 cm of the residual vagina with dose specified at the 
vaginal mucosa (surface of the intra-vaginal applicator).
5.2.17   Uterine cancer patients will receive 3 brachytherapy fractions of 5 Gy each (15 Gy 
total) to the proximal vagina with dose specified at the vaginal mucosa (surface of the intra-
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vaginal applicator). The full length of the vagina will be treated employing a gradient dose 
distribution such that the distal anterior sub-urethral vagina receives 3 Gy with each 
brachytherapy treatment.
5.2.18   For patients with cystocoele or rectocoele or vaginal introital diameter <2.5 cm, 
vaginal brachytherapy will be administered in 5 fractions of 3 Gy mucosal dose to the 
proximal vagina using techniques and dose distributions as specified in 5.2.13-5.2.15. Uterine 
cancer patients will have the distal vaginal dose administered in 5 fractions of 1.8 Gy.
5.2.19   Maximum point dose to the bladder and rectum from brachytherapy will be       
calculated and recorded from CT dosimetry from one insertion with applicator in the vagina. 
These dose contributions will not be applied to dose constraints in sections 5.2.13. 
5.2.20   Other Modalities or Procedures: 
5.2.20a  Uterine cancer patients may receive conventional chemotherapy prior to proton 
radiation, with the drugs, doses and routes of administration to be selected by their attending 
Gynecologic Oncologist or Medical Oncologist. Uterine cancer patients will not receive 
concurrent chemotherapy with protocol teletherapy. All pre-radiation chemotherapy will be 
with commercially available agents approved for use with uterine cancer patients.
5.2.20b  Cervical cancer patients may receive concurrent adjuvant cytotoxic chemotherapy 
with the drugs, doses and routes of administration to be selected by their attending 
Gynecologic Oncologist or Medical Oncologist. All chemotherapy will be with commercially 
available agents approved for use with cervical cancer patients.
5.2.20c   Experimental or non-standard chemotherapy regimens will not be administered to 
study participants. All chemotherapy agents administered prior to or during study 
participation will be FDA approved agents commercially available.
5.2.20d   For patients developing cancer recurrence after protocol therapy, investigational 
agents will not be precluded from their subsequent care.
5.3
Definition of Dose-Limiting Toxicity N/A
5.4
General Concomitant Medication and Supportive Care Guidelines:
5.4.1 Standard supportive therapies currently employed for radiation side effects will be 
administered in conventional dose, including anti-diarrheal medication (Imodium, Lomotil) anti-
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emetic medication (Ativan, Zofran, Reglan, Compazine, etc.), colony stimulating factors, 
transfusions, etc. as required to provide optimal medical symptom management and support of 
study participants. No experimental medications or off-label medications will be employed.
Transfusion of red blood cells to maintain hemoglobin >10 g/dl will be employed at discretion of 
treating physician and medical team in the case of hemoglobin <10 g/dl at study entry and in the 
eventuality that hemoglobin declines during the course of protocol therapy.
5.5 Duration of Therapy
Duration of therapy will depend on evidence of disease progression and tolerance.  In the 
event of a treatment break for circulating blood counts (neutrophils, platelets) to recover, 
treatment will resume when counts have recovered per section 5.1.2.  The treatment break will 
be documented in the data set; any length of break to allow blood counts to recover is 
allowed.  In the absence of treatment delays due to adverse events, treatment may continue 
until completed or until one of the following criteria applies:
x
Disease progression outside of the radiation target volume,
x
Intercurrent illness that prevents further administration of treatment,
x
Unacceptable adverse event(s), including grade 4 thrombocytopenia 
or neutropenia; grade 3 hemoglobin, diarrhea, urinary frequency, or 
fatigue; or grade 2 weight loss.
x
Participant decides to withdraw from the study, or
x
General or specific changes in the participant's condition render the 
participant unacceptable for further treatment in the opinion of the treating 
investigator.
5.6
Duration of Follow Up
Participants will be followed for 60 months after completion of protocol therapy or 
removal from study or until death, whichever occurs first. Participants removed from study 
for unacceptable adverse events will be followed until resolution or stabilization of the adverse 
event. Participants who experience a recurrence of their disease will be followed for survival 
only after the recurrence.
5.7
Criteria for Removal from Study 
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Participants will be removed from study when any of the criteria listed in Section 5.5 applies. 
The reason for study 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.
In the event of unusual or life-threatening complications, participating investigators must 
immediately notify the Principal Investigator:
Dr. Andrea Russo at 617-219-1200 or 
6. EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS
Dose delays and modifications will be made using the following recommendations. Toxicity 
assessments will be done using NCI Common Terminology Criteria for Adverse Events (CTCAE 
v4.02 from 9/15/2009) which is available at http://ctep.cancer.gov/reporting//ctc.html). 
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. 
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6.1 Anticipated Toxicities  
Acute toxicities expected from conventional photon therapy administered alone, or with 
concurrent chemotherapy, to the pelvis or extended volume (pelvic and para-aortic nodal 
basins) are listed below. Because radiation will be administered to a smaller volume using 
proton beam, acute toxicities are expected to be delayed in onset and/or milder in severity.
Recovery from acute side effects is expected over a 3-6 week period after the last treatment 
has been administered.
Acute (temporary) effects include:
Likely (more than 50% chance this will happen):
x
Fatigue
x
Cramps
x
Frequent bowel movement 
x
Diarrhea
x
Nausea
x
Urinary frequency and urgency
x
Burning with urination
x
Vaginal irritation with itching and discharge
x
Skin reaction (radiation dermatitis)
x
Rectal irritation
Frequent (10-50% chance this will occur):
x
Nausea (mild) and vomiting (rare) that is treatable with medications.  
x
Reduction in circulating blood counts including red cells which are important for 
carrying oxygen, platelets which are important for normal blood coagulation, and 
white cells which are important in fighting infection. If severe, changes in circulating 
blood counts may require blood transfusion, hospitalization, and medication intended 
to bring blood counts to normal levels.
Occasional (Between 1-10% chance this will occur):
x
Dehydration and Electrolyte imbalances (changes in body salts) may occur in patients 
experiencing nausea, vomiting and diarrhea.  This may not cause symptoms but 
sometimes causes fatigue, muscle weakness, muscle cramps, irregular heart beat or 
seizures. This can be severe and possibly life threatening, and may require 
hospitalization and intravenous treatment.
Delayed effects which may develop after completion of Proton beam radiation 
treatment include:
Frequent (10-50% chance this will occur):
x
Leg lymphedema (swelling of legs due to a block in lymphatic flow)
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Occasional (Between 1-10% chance this will occur):
x
Bowel obstruction requiring surgery to repair. 
x
Bowel injury
x
Premature menopause: probable if ovaries have not been conserved surgically and 
removed to locations remote from the radiation target volumes.
x
Bone fractures in the pelvis or spine
x
Weight loss is slow and progressive and rarely exceeds 10% of pre-protocol treatment 
weight.
Rare (Less than a 1% chance this will occur):
x
Appearance of radiation caused cancer in or next to the radiation site: very rare and 
usually observed 20 or more years after radiation treatment.
x
Reduced bladder capacity with urinary frequency and urgency
x
Potential injury to any/all normal tissues unavoidably irradiated
x
Possible injury to liver and/or kidneys
6.1.2 Toxicity Management
Standard supportive therapies currently employed for radiation side effects will be administered in 
conventional dose, including anti-diarrheal medication (Imodium, Lomotil) anti-emetic medication 
(Ativan, Zofran, Reglan, Compazine, etc.) as required. No experimental medications or off-label 
medications will be employed.  All supportive medications will be commercially available. 
Outpatient intravenous hydration will be instituted for symptomatic dehydration or electrolyte 
imbalance induced by diarrhea (hypokalemia, hyponatremia).
6.2 Dose Modifications/Delays
6.2.1
Dose per proton teletherapy fraction will be 1.8 Gy (RBE) and will not be modified.
6.2.2
Treatment for uterine cancer patients will be suspended for thrombocytopenia with platelets 
<35,000 mcL or neutropenia with absolute neutrophil count <800/mcL or for abnormal bleeding or 
febrile neutropenia.
6.2.3
Treatment will resume at the same daily dose and fractionation schedule when circulating 
blood counts rise above these levels. Differential blood counts may be obtained twice weekly for 
uterine cancer patients, once weekly for cervix cancer patients commencing on or before fraction 8 
of teletherapy.
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6.2.4
Treatment will be suspended for symptomatic dehydration and/or hyponatremia or 
hypokalemia requiring intravenous fluids. Treatment will resume as soon as parameters have 
normalized.
6.2.5
For cervical cancer patients getting chemotherapy concurrently with proton teletherapy, 
chemotherapy will be suspended for grade 3 neutropenia or grade 2 thrombocytopenia and resume 
when circulating counts have recovered above these levels.  Daily radiation will not be suspended 
unless platelets fall below 35,000/mcL or absolute neutrophils fall less than 800/mcL.
7. DRUG FORMULATION AND ADMINISTRATION: N/A
8. CORRELATIVE/SPECIAL STUDIES: N/A
9. STUDY CALENDAR
9.1 
Baseline hematologic evaluations are to be conducted within 2-weeks prior to 
study entry. Scans must be done <10 weeks prior to study entry. 
9.2 
Patients will be interviewed and examined weekly during treatment.
9.3 
Routine surveillance follow-up will be: 3, 6, 9, 12, 15, 18, 21, 24, 28, 32, 36,
42, 48, 54 and 60 months (+/- 4 weeks) following adjuvant radiation treatment.
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9.4 
Study Calendar/Required Data
Tests and Observations
At Study Entry
During Treatment
At Follow Up (1)
Informed Consent
x
History
x
x
Concurrent Meds
x
x
x
Physical Exam (2)
x
x
x
Pelvic Exam (3)
x
x
x
CBC with diff, PLT (4)
x
x 
Serum Chemistries (5)
x
x 
Toxicity and AE evaluation
x
x
x
Radiological imaging (6)
x
x
Quality of Life (7)
x
x
Notes:
(1) Follow up schedule (+/- 4 weeks for each time point): every 3 months for 2 years; every 4 months to 
year 3; every 6 months until year 5.
(2) Physical includes, weight,  vitals, performance status required at baseline. For weekly on-treatment 
and follow up visits, physical exam will be performed as pertinent at the discretion of the treating 
physician, and includes weight. . 
(3) Pelvic Exam pre-study, during vaginal brachytherapy (typically week 6 of treatment) and at each 
follow up visit
(4) Study entry labs for pre-treatment must be done within14 days of study entry.  Labs may be repeated 
twice weekly for uterine cancer patients, once weekly for cervix cancer patients during treatment to 
ensure maintenance of platelets >35,000mcL and ANC >800mcL. These labs are ordered and 
monitored at the discretion of the treating physician.
(5) Required chemistries are: Albumin, Alk Phos, T bili, BUN, bicarbonate, chloride, creatinine, glucose, 
LDH, phosphorus, potassium, total protein, SGOT, SGPT, sodium, calcium, magnesium. These will 
be ordered and monitored at the discretion of the treating physician. 
(6) Contrast enhanced CT scan of the chest, abdomen and pelvis pre-study (≤10 weeks of study entry) and
in post treatment, twice per year to year 3. 
(7) Quality of Life will be assessed using the FACT-En Version 4 (Appendix 2) instrument for uterine 
patients and the FACT-Cx Version 4 (Appendix 3) instrument for cervix patients. QOL will be 
assessed at study entry, and at 6, 12, 24, 36, 48, and 60 months (+/- 4 weeks) after protocol therapy.
10. MEASUREMENT OF EFFECT: Participants are excluded if they have measurable disease 
following hysterectomy. (3.2.2, 3.2.3)
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 at any site as detected by symptomatic recurrence or routine 
surveillance follow-up physical examination or imaging as described in the Study Calendar 
(Section 9) .
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10.1.1 Following protocol therapy, patients will be seen in routine surveillance follow- up at 3,
6, 9, 12, 15, 18, 21, 24, 28, 32, 36, 42, 48, 54 and 60 months
10.1.2 At each follow-up interval history, weight and vital signs will be obtained, and general 
physical examination including pelvic examination will be performed.
10.1.3 CT scans of the chest, abdomen, and pelvis will be obtained twice per year post treatment
to year 3.  
10.1.4 For this protocol, routine blood work will not be obtained in asymptomatic patients 
except as required for imaging contrast administration.
10.2 
Pattern of Recurrence
Local recurrence is defined as cancer detected at any time after initiation of treatment that lies 
within the volume of target tissue undergoing adjuvant proton beam teletherapy. 
Marginal Recurrence is defined as cancer detected at any time following initiation of adjuvant 
proton beam teletherapy that lies within 1 cm of tissue that receives 90% of the daily prescribed 
radiation dose.
Distant Recurrence is defined as cancer which has spread by hematogenous dissemination or 
peritoneal dissemination to sites spatially remote from the irradiated target volume.
10.3 Quality of Life
Quality of life will be assessed at 6, 12, 24, 36, 48, 60 months following protocol therapy.
QOL will be assessed using the FACT-En Version 4 instrument for uterine patients and the 
FACT-Cx Version 4 for cervix patients.
11. ADVERSE EVENT REPORTING REQUIREMENTS 
11.1General 
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 NCI Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.02 9/15/2009 that is available at 
http://ctep.cancer.gov/reporting//ctc.html. 
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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. 
Adverse events experienced by participants will be collected and reported from initiation of 
study treatment, throughout the study, and within 60 months of the last dose of study medication. 
Participants who experience an ongoing adverse event or related to a study procedures and/or 
study medication beyond 60 months 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 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. 
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:
x
is fatal or life-threatening;
x
requires or prolongs inpatient hospitalization;
x
results in persistent or significant disability/incapacity;
x
constitutes a congenital anomaly or birth defect; or
x
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:
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x
routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition, or for elective procedures
x
elective or pre-planned treatment for a pre-existing condition that did not worsen
x
emergency outpatient treatment for an event not fulfilling the serious criteria outlined 
above and not resulting in inpatient admission
x
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 adjuvant radiation treatment. For the purposes of this study, an adverse event is 
considered expected when it is included in the informed consent document as a potential risk.  
Refer to Section 6.1 (Anticipated Toxicities) for a listing of expected adverse events 
associated with the study treatment. 
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 informed consent document or 
when it is not included in the informed consent documentation 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:
x
Definite – The AE is clearly related to the study treatment.
x
Probable – The AE is likely related to the study treatment.
x
Possible – The AE may be related to the study treatment. 
x
Unlikely - The AE is doubtfully related to the study treatment.
x
Unrelated - The AE is clearly NOT related to the study treatment.
11.3
Recording Adverse Events
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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). 
11.4
Reporting Adverse Events 
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 Requirements
All events meeting the criteria for Serious Adverse Event (see Section 11.2.2) that occur after the 
initial dose of study treatment, during treatment, or within 30 days of the last dose of treatment 
must be reported as serious adverse events. 
The participating investigator must report each serious adverse event, regardless attribution, to 
the Principal Investigator (or Protocol Chair) within 24 hours 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 24 hours after learning of it and document the time of his or her first 
awareness of the adverse event. Report serious adverse events by telephone and facsimile to:
Andrea Russo, MD  Tel: 617-219-1200 FAX: 617-726-3603
Within the following 24-48 hours, 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. 
11.4.2 Non-Serious Adverse Event Reporting Requirements
Non-serious adverse events will be reported to the Principal Investigator (or Protocol Chair) on 
the toxicity Case Report Forms.  
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11.5 Institutional Review Board (IRB) Notification by Investigator
The participating investigator will report all adverse events and serious adverse events to the 
Principal Investigator (or Protocol Chair) and to the IRB according to the local IRB’s policies 
and procedures in reporting adverse events. 
11.6 Hospital Risk Management Notification by Investigator
The participating investigator will report to the Principal Investigator (or Protocol Chair) and to 
local Risk Management 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 
The ODQ will collect, manage, and monitor data for this study. 
12.1.2 Data Submission 
The schedule for completion and submission of case report forms (paper or 
electronic) to the ODQ is as follows:
Form
Submission Timeline
Eligibility Checklist
Complete prior to registration with ODQ
On Study Form
Within 14 days of registration
Baseline Assessment Form
Within 14 days of registration
Treatment Form
Within 10 days of the last day of the treatment
Toxicity Form
Weekly during treatment; within 14 days of  
protocol defined follow-up visit
Lab Form
With Baseline assessment form and weekly 
during treatment
Adverse Event Report Form
Immediately upon detection of adverse event 
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24
during treatment. Within 14 days of adverse 
event detected during surveillance follow-up.
Off Treatment/Off Study Form
Within 14 days of being taken off study for 
any reason
Follow up/Survival Form
Within 14 days of the protocol defined follow 
up visit date or call
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 as needed to review toxicity and accrual data.  Information to be provided 
to the committee may include:  up-to-date participant accrual;; 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 Protocol Chair) or DF/HCC. 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, Good Clinical Practice (GCP), 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. 
13. REGULATORY CONSIDERATIONS
13.1 
Protocol Review and Amendments
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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. 
13.3 
Ethics and Good Clinical Practice (GCP)
This study is to be conducted according to the following considerations, which represent 
good and sound research practice:
x
ICH Consolidated Good Clinical Practice: Guidelines (E6) 
www.fda.gov/cder/guidance/iche6.htm
x
US Code of Federal Regulations (CFR) governing clinical study conduct and 
ethical principles that have their origin in the Declaration of Helsinki
x
Title 21 Part 11 – Electronic Records; Electronic Signatures 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr11_02.html
x
Title 21 Part 50 – Protection of Human Subjects 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr50_02.html
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x
Title 21 Part 54 – Financial Disclosure by Clinical Investigators 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr54_02.html
x
Title 21 Part 56 – Institutional Review Boards 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr56_02.html
x
Title 21 Part 312 – Investigational New Drug Application 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr312_02.html
x
State laws
x
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: N/A
14. STATISTICAL CONSIDERATIONS 
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The primary objective of this protocol is to determine whether the substitution of scanning 
pencil beam proton teletherapy for conventional photon teletherapy will administer less 
radiation dose to the normal tissues of organs at risk compared to conventional techniques 
(IMRT or 3-D conformal teletherapy). Additional endpoints are to determine whether 
scanning pencil beam proton teletherapy is associated with cancer control rates within the 
irradiated volumes comparable to those reported in existing literature and to determine the 
rates of acute radiation side effects and delayed radiation complications. 
14.1
Study Design/Endpoints:
The primary endpoint is the comparison of dose volume histograms (DVH) from proton 
teletherapy and conventional photon teletherapy. Structure sets contoured for proton beam 
treatment will be used to plan alternative IMRT and 3DCRT plans by the same medical physics 
team and attending physician, and DVH will be generated for each plan. It is hypothesized that the 
area under the DVH curve will be at least 25% smaller in the bowel, in favor of the proton plan, 
for virtually all patients. With a sample size of 22 patients, we will have 91% power to accept 
that the proton plan is superior for 95% of patients if at least 20 of them have a proton plan with 
an area under the DVH curve at least 25% smaller in the bowel. The decision rule is associated 
with type 1 error of 15% if only 80% of patients truly have a superior proton plan for the bowel. 
This magnitude of radiation dose difference is expected to be clinically significant with respect 
to acute GI side effects, thus GI toxicities will be a major focus of the data analysis to explore the 
correlation between DVH and radiation effects.
14.2   Sample Size/Accrual Rate:
As of October 2016, 9 node positive uterine cancer patients and 5 node positive cervical 
cancer patients have been enrolled and treated with proton beam teletherapy. We project 
another 8 patients will be enrolled and treated by the end of 2018 for a total accrual of 22
patients. Based on the tumor distribution to date, we expect the final accrual will consist of 
approximately 14 uterine cancer patients and 8 cervical cancer patients. Patients who do not 
start protocol treatment will be replaced.
All patients will be followed for a minimum of 60 months following completion of protocol 
therapy. 
14.3   Stratification Factors: N/A
14.4    Analysis of Secondary Endpoints:
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Secondary endpoints are QOL, progression-free survival and patterns of recurrence. QOL 
outcomes will be analyzed using mixed models for longitudinal data. Progression-free survival 
will be analyzed using standard methods for failure time data, primarily the Kaplan-Meier 
estimate. Progression-free survival is defined as the duration from the start of protocol treatment to 
the time of objective disease progression at any site or death in the absence of documented 
progression, while patients who have not progressed or died will be censored at the time of last 
follow-up. Differences between patient subgroups may be explored by the log-rank test, using 
exact methods as the event numbers will be modest. Patterns of recurrence will be reported 
descriptively.
14.5
Reporting and Exclusions;
All patients starting protocol therapy will be analyzed and reported for all study endpoints, 
whether or not treatment is completed.
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. N/A. Patients with measurable disease are 
ineligible. 
14.5.3   Evaluation of cancer control. At or before each scheduled follow-up 
surveillance visit patients will be categorized as clinically cancer-free, alive with 
cancer, dead from cancer, dead from complications of therapy, or dead from inter-
current illness, or cause of death unknown.
14.5.4 Pattern of cancer recurrence: In patients developing cancer recurrence, 
the pattern of recurrence will be recorded according to the criteria in 10.2 for local, 
regional and distant sites. As a patient may recur at multiple sites and at different 
times, the dates of recurrence will be recorded for each site. Progression-free survival 
will be based on the date of the earliest date of documented recurrence.
15. PUBLICATION PLAN
15.1.1 The intent of the investigators is to publish results in peer-reviewed journals.
15.1.2  A preliminary publication will compare DVH results from proton, IMRT, and 3DCRT 
plans after accrual has been completed.
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15.1.3 A second preliminary publication is anticipated when all surviving participants have 
been followed a minimum of 24 months following completion of protocol therapy, as the large 
majority of symptomatic late radiation complications will be manifest within this time window.
15.1.4 A final publication is anticipated when all patients have been followed a minimum of 5 
years or until death.
15.1.5 Primary responsibility for publication will reside with the Principal Investigator (Study 
Chair) and may be delegated to the Division of Medical Physics for preliminary publication of 
comparative dosimetric results (endpoint 1.3.1).
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16. REFERENCES
1) Levin WP, Kooy H, Loeffler JS, Delaney TF. Proton beam therapy. Brit J Cancer (2005) 93, 
849-854.
2) National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology: 
v.1.2009 Cervical Cancer v.2.2009 Uterine Neoplasms. Available on-line at: www.NCCN.org
3) Klopp AH, Jhingran A, Ramondetta L, Lu K, et al. Node-positive adenocarcinoma of the 
endometrium: outcome and patterns of recurrence with and without external beam irradiation. 
Gynecol Oncol (2009) 115, 6-11.
4) Alvarez-Secord A, Havrilesky LJ, Bae-Jump V, Chin J, et al. The role of multi-modality 
adjuvant chemotherapy and radiation in women with advanced stage endometrial cancer. Gynecol 
Oncol (2007) 107, 285-291.
5) Peters WA 3rd, Liu RJ, Stock RJ, Monk BJ, et al. Concurrent chemotherapy and pelvic radiation 
therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in 
high-risk early stage cancer of the cervix. J. Clin Oncol (2000) 18,1606-1613.
6) Kooy HM, Clasie BM, Lu H-M, Madden TM et al. A case study in proton pencil-beam scanning 
delivery. Int J Radiat Oncol Biol Phys (2010) 76, 624-30.
7) Rutz HP, Weber DC, Goitein G, Ares C, et al. Postoperative spot-scanning proton radiation 
therapy for chordoma and chondrosarcoma in children and adolescents. Initial experience at Paul 
Scherrer Institute. Int J Radiat Oncol Biol Phys (2008) 71, 220-225.
17. APPENDICES 
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Appendix 1. Performance Status Criteria
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Description
Percent
Description
0
Normal activity. Fully active, able 
to carry on all pre-disease 
performance without restriction.
100
Normal, no complaints, no 
evidence of disease.
90
Able to carry on normal activity; 
minor signs or symptoms of 
disease.
1
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or 
sedentary nature (e.g., light 
housework, office work).
80
Normal activity with effort; 
some signs or symptoms of 
disease.
70
Cares for self, unable to carry on 
normal activity or to do active 
work.
2
In bed < 50% of the time. 
Ambulatory and capable of all self-
care, but unable to carry out any 
work activities. Up and about more 
than 50% of waking hours.
60
Requires occasional assistance, 
but is able to care for most of 
his/her needs.
50
Requires considerable assistance 
and frequent medical care.
3
In bed >50% of the time. Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours.
40
Disabled, requires special care 
and assistance.
30
Severely disabled, 
hospitalization indicated. Death 
not imminent.
4
100% bedridden. Completely 
disabled. Cannot carry on any self-
care. Totally confined to bed or 
chair.
20
Very sick, hospitalization 
indicated. Death not imminent.
10
Moribund, fatal processes 
progressing rapidly. 
5
Dead.
0
Dead.
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Appendix 2: FACT-En Version 4 Quality of Life Instrument for uterine cancer patients.
Below is a list of statements that other people with your illness have said are important. 
Please circle or mark one number per line to indicate your response as it applies to 
the past 7 days.
PHYSICAL WELL-BEING
Not 
at all
A little 
bit
Some-
what
Quite
a bit
Very 
much
GP1
I have a lack of energy .......................................................
0
1
2
3
4
GP2
I have nausea ......................................................................
0
1
2
3
4
GP3
Because of my physical condition, I have trouble 
meeting the needs of my family.........................................
0
1
2
3
4
GP4
I have pain ..........................................................................
0
1
2
3
4
GP5
I am bothered by side effects of treatment .........................
0
1
2
3
4
GP6
I feel ill ...............................................................................
0
1
2
3
4
GP7
I am forced to spend time in bed........................................
0
1
2
3
4
SOCIAL/FAMILY WELL-BEING
Not 
at all
A little 
bit
Some-
what
Quite
a bit
Very 
much
GS1
I feel close to my friends....................................................
0
1
2
3
4
GS2
I get emotional support from my family ............................
0
1
2
3
4
GS3
I get support from my friends.............................................
0
1
2
3
4
GS4
My family has accepted my illness ....................................
0
1
2
3
4
GS5
I am satisfied with family communication about my 
illness..................................................................................
0
1
2
3
4
GS6
I feel close to my partner (or the person who is my main 
support) ..............................................................................
0
1
2
3
4
Q1
Regardless of your current level of sexual activity, please 
answer the following question. If you prefer not to answer it, 
please mark this box           and go to the next section.
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Please circle or mark one number per line to indicate your response as it applies to 
the past 7 days.
EMOTIONAL WELL-BEING
Not 
at all
A little 
bit
Some-
what
Quite
a bit
Very 
much
GE1
I feel sad .............................................................................
0
1
2
3
4
GE2
I am satisfied with how I am coping with my illness.........
0
1
2
3
4
GE3
I am losing hope in the fight against my illness .................
0
1
2
3
4
GE4
I feel nervous......................................................................
0
1
2
3
4
GE5
I worry about dying .............................................................
0
1
2
3
4
GE6
I worry that my condition will get worse ............................
0
1
2
3
4
FUNCTIONAL WELL-BEING
Not 
at all
A little 
bit
Some-
what
Quite
a bit
Very 
much
GF1
I am able to work (include work at home) .........................
0
1
2
3
4
GF2
My work (include work at home) is fulfilling.....................
0
1
2
3
4
GF3
I am able to enjoy life.........................................................
0
1
2
3
4
GF4
I have accepted my illness..................................................
0
1
2
3
4
GF5
I am sleeping well................................................................
0
1
2
3
4
GF6
I am enjoying the things I usually do for fun .....................
0
1
2
3
4
GF7
I am content with the quality of my life right now.............
0
1
2
3
4
GS7
I am satisfied with my sex life ............................................
0
1
2
3
4
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Please circle or mark one number per line to indicate your response as it applies to 
the past 7 days.
ADDITIONAL CONCERNS
Not at 
all
A little 
bit
Some-
what
Quite
a bit
Very 
much
O1
I have swelling in my stomach area ....................................
0
1
2
3
4
O3
I have cramps in my stomach area ......................................
0
1
2
3
4
Hep
8
I have discomfort or pain in my stomach area ...................
0
1
2
3
4
ES6
I have vaginal bleeding or spotting ....................................
0
1
2
3
4
ES4
I have vaginal discharge.....................................................
0
1
2
3
4
Hep
1
I am unhappy about a change in my appearance................
0
1
2
3
4
ES1
I have hot flashes................................................................
0
1
2
3
4
ES2
I have cold sweats................................................................
0
1
2
3
4
ES3
I have night sweats .............................................................
0
1
2
3
4
HI7
I feel fatigued......................................................................
0
1
2
3
4
ES8
I have pain or discomfort with intercourse.........................
0
1
2
3
4
En1
I have trouble digesting food..............................................
0
1
2
3
4
B1
I have been short of breath .................................................
0
1
2
3
4
Cx6
I am bothered by constipation ............................................
0
1
2
3
4
BL2
I urinate more frequently than usual...................................
0
1
2
3
4
En2
I have discomfort or pain in my pelvic area........................
0
1
2
3
4
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Appendix 3: FACT-Cx Version 4 Quality of Life instrument for cervix cancer patients.
Below is a list of statements that other people with your illness have said are important. 
Please circle or mark one number per line to indicate your response as it applies to 
the past 7 days.
PHYSICAL WELL-BEING
Not 
at all
A little 
bit
Some-
what
Quite
a bit
Very 
much
GP1
I have a lack of energy .......................................................
0
1
2
3
4
GP2
I have nausea ......................................................................
0
1
2
3
4
GP3
Because of my physical condition, I have trouble 
meeting the needs of my family.........................................
0
1
2
3
4
GP4
I have pain ..........................................................................
0
1
2
3
4
GP5
I am bothered by side effects of treatment .........................
0
1
2
3
4
GP6
I feel ill ...............................................................................
0
1
2
3
4
GP7
I am forced to spend time in bed........................................
0
1
2
3
4
SOCIAL/FAMILY WELL-BEING
Not 
at all
A little 
bit
Some-
what
Quite
a bit
Very 
much
GS1
I feel close to my friends....................................................
0
1
2
3
4
GS2
I get emotional support from my family ............................
0
1
2
3
4
GS3
I get support from my friends.............................................
0
1
2
3
4
GS4
My family has accepted my illness ....................................
0
1
2
3
4
GS5
I am satisfied with family communication about my 
illness..................................................................................
0
1
2
3
4
GS6
I feel close to my partner (or the person who is my main 
support) ..............................................................................
0
1
2
3
4
Q1
Regardless of your current level of sexual activity, please 
answer the following question. If you prefer not to answer it, 
please mark this box           and go to the next section.
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Please circle or mark one number per line to indicate your response as it applies to 
the past 7 days.
EMOTIONAL WELL-BEING
Not 
at all
A little 
bit
Some-
what
Quite
a bit
Very 
much
GE1
I feel sad .............................................................................
0
1
2
3
4
GE2
I am satisfied with how I am coping with my illness.........
0
1
2
3
4
GE3
I am losing hope in the fight against my illness .................
0
1
2
3
4
GE4
I feel nervous......................................................................
0
1
2
3
4
GE5
I worry about dying .............................................................
0
1
2
3
4
GE6
I worry that my condition will get worse ............................
0
1
2
3
4
FUNCTIONAL WELL-BEING
Not 
at all
A little 
bit
Some-
what
Quite
a bit
Very 
much
GF1
I am able to work (include work at home) .........................
0
1
2
3
4
GF2
My work (include work at home) is fulfilling.....................
0
1
2
3
4
GF3
I am able to enjoy life.........................................................
0
1
2
3
4
GF4
I have accepted my illness..................................................
0
1
2
3
4
GF5
I am sleeping well................................................................
0
1
2
3
4
GF6
I am enjoying the things I usually do for fun .....................
0
1
2
3
4
GF7
I am content with the quality of my life right now.............
0
1
2
3
4
GS7
I am satisfied with my sex life ............................................
0
1
2
3
4

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	

	
36
36

Pilot Study of Adjuvant Proton Beam Teletherapy for Post-Hysterectomy Cancers of the Uterus and Cervix With 
Metastasis to Regional Lymph Nodes, Andrea Russo, M.D.
Version 7/10/2019
37
Please circle or mark one number per line to indicate your response as it applies to 
the past 7 days.
ADDITIONAL CONCERNS
Not at 
all
A little 
bit
Some-
what
Quite
a bit
Very 
much
Cx1
I am bothered by discharge or bleeding from my vagina...
0
1
2
3
4
Cx2
I am bothered by odor coming from my vagina.................
0
1
2
3
4
Cx3
I am afraid to have sex ........................................................
0
1
2
3
4
B4
I feel sexually attractive.......................................................
0
1
2
3
4
Cx4
My vagina feels too narrow or short ..................................
0
1
2
3
4
BMT7
I have concerns about my ability to have children.............
0
1
2
3
4
Cx5
I am afraid the treatment may harm my body ....................
0
1
2
3
4
BL4
I am interested in sex..........................................................
0
1
2
3
4
C7
I like the appearance of my body ........................................
0
1
2
3
4
Cx6
I am bothered by constipation .............................................
0
1
2
3
4
C6
I have a good appetite..........................................................
0
1
2
3
4
BL1
I have trouble controlling my urine....................................
0
1
2
3
4
BL3
It burns when I urinate.........................................................
0
1
2
3
4
Cx7
I have discomfort when I urinate........................................
0
1
2
3
4
HN1
I am able to eat the foods that I like ....................................
0
1
2
3
4


	

	
37
37