Clinical trial NCT03690921
Conditions: Anal Canal Squamous Cell Carcinoma Stage I Anal Cancer AJCC v8 Stage II Anal Cancer AJCC v8 Stage IIA Anal Cancer AJCC v8 Stage IIB Anal Cancer AJCC v8 Stage III Anal Cancer AJCC v8 Stage IIIA Anal Cancer AJCC v8 Stage IIIB Anal Cancer AJCC v8 Stage IIIC Anal Cancer AJCC v8
Sponsor: M.D. Anderson Cancer Center
Start date: 2018-11-08; Completion date: 2022-06-03
Enrollment: 8 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies the side effects of LET-IMPT and standard chemotherapy, and how well they work in treating patients with newly diagnosed stage I-III anal canal squamous cell cancer. LET-IMPT is a type of radiation therapy that uses high energy proton "beamlets" to "paint" the radiation dose into the target and may help to kill tumor cells and shrink tumors. Giving LET-IMPT and standard chemotherapy may work better in treating patients with anal canal squamous cell cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. To assess physician-reported acute grade 3 or greater gastrointestinal, genitourinary and hematologic toxicities at 12 weeks post-treatment for patients treated with linear energy transfer (LET)-optimized, intensity-modulated proton therapy (IMPT) and compare to contemporary controls treated with volume modulated arc therapy (VMAT) to determine the feasibility of this outcome for a future randomized trial.

SECONDARY OBJECTIVES:

I. To assess the feasibility of enrolling patients on a prospective trial delivering LET-optimized IMPT for newly diagnosed, non-metastatic anal cancer.

II. To develop guidelines and workflow to create and deliver anal canal cancer treatments using LET-optimized IMPT.

III. To evaluate complete response rate at 12 weeks and 24 weeks post-treatment.

IV. To evaluate local progression free survival, distant metastasis-free survival and overall survival at 24 and 48 months.

V. To evaluate rates of patient-reported acute toxicity, function, distress and quality of life (QOL) at 12 weeks.

VI. To evaluate rates of patient-reported late toxicity, function, distress and QOL every 6 months for 24 months.

VII. To evaluate the value of proton therapy by comparing Time-Driven Activity-Based Costing data from the date of consultation until the date of the 12-week follow up visit post-treatment with contemporary controls treated with VMAT.

EXPLORATORY OBJECTIVES:

I. To compare dose to the pelvic bone marrow, bowel, bladder and genitalia between LET-optimized IMPT, traditionally-optimized IMPT and VMAT.

II. To assess rates of leukopenia, neutropenia and lymphopenia at 12-weeks post-treatment for patients treated with LET-optimized IMPT and compare to contemporary controls treated with VMAT.

III. To correlate white blood cell counts (WBC), absolute neutrophil counts (ANC) and absolute lymphocyte counts (ALC) with dose to the pelvic bone marrow for patients treated with LET-optimized IMPT.

OUTLINE:

Patients undergo linear energy transfer-optimized intensity modulated proton therapy 5 times per week for 5-6 weeks. Patients also receive standard cisplatin and fluorouracil intravenously (IV) weekly for up to 6 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 12 weeks.

Arms: arm 1: Patients undergo linear energy transfer-optimized intensity modulated proton therapy 5 times per week for 5-6 weeks. Patients also receive standard cisplatin and fluorouracil IV weekly for up to 6 weeks in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Cisplatin intervention 2: Fluorouracil intervention 3: Linear Energy Transfer-Optimized Intensity Modulated Proton Therapy intervention 4: Quality-of-Life Assessment intervention 5: Questionnaire Administration
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Undergo LET-IMPT intervention 4: Ancillary studies intervention 5: Ancillary studies

Protocol documents:
Prot_SAP_001.pdf: 
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TITLE:  Linear Energy Transfer (LET)-Optimized Intensity Modulated Proton Therapy (IMPT) as a 
Component of Definitive Chemoradiation for Newly Diagnosed Squamous Cell Carcinoma of the 
Anal Canal: a Feasibility Trial 
Prinicipal Investigators: 
Emma Holliday (Radiation Oncology: Gastrointestinal) 
Short Title: 
IMPT for Anal Cancer 
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Table of Contents 
 
1.0 
Trial Summary 
2.0 
Trial Design 
3.0  
Background & Rationale 
4.0 
Inclusion & Exclusion Criteria 
5.0 
Treatment Details 
6.0  
Trial Procedures 
7.0  
Statistical Analysis Plan 
8.0 
Administrative and Regulatory Details 
9.0  
References 
10.0 
Appendices  
 
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1.0 
TRIAL SUMMARY  
 
1.1 
Objectives  
1.1.1 
Primary objective:  
1.) To assess physician-reported acute grade 3 or greater gastrointestinal, genitourinary and 
hematologic toxicities at 12 weeks post-treatment for patients treated with linear energy 
transfer (LET)-optimized, intensity-modulated proton therapy (IMPT) and compare to 
contemporary controls treated with VMAT to determine the feasibility of this outcome for a 
future randomized trial. 
 
1.1.2 
Secondary objectives:  
1.) To assess the feasibility of enrolling patients on a prospective trial delivering LET-optimized 
IMPT for newly diagnosed, non-metastatic anal cancer. 
2.) To develop guidelines and workflow to create and deliver anal canal cancer treatments 
using LET-optimized IMPT. 
3.) To evaluate complete response rate at 12 weeks and 24 weeks post-treatment. 
4.) To evaluate local progression free survival, distant metastasis-free survival and overall 
survival at 24 and 48 months. 
5.) To evaluate rates of patient-reported acute toxicity, function, distress and QOL at 12 
weeks.  
6.) To evaluate rates of patient-reported late toxicity, function, distress and QOL every 6 
months for 24 months. 
7.) To evaluate the value of proton therapy by comparing Time-Driven Activity-Based 
Costing data from the date of consultation until the date of the 12-week follow up visit post-
treatment with contemporary controls treated with VMAT.  
 
1.1.3 
Exploratory objectives: 
1.) To compare dose to the pelvic bone marrow, bowel, bladder and genitalia between LET-
optimized IMPT, traditionally-optimized IMPT and VMAT.  
2.) To assess rates of leukopenia, neutropenia and lymphopenia at 12-weeks post-treatment 
for patients treated with LET-optimized IMPT and compare to contemporary controls 
treated with VMAT. 
3.) To correlate white blood cell counts (WBC), absolute neutrophil counts (ANC) and 
absolute lymphocyte counts (ALC) with dose to the pelvic bone marrow for patients treated 
with LET-optimized IMPT.   
 
 
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Abbreviated Title 
IMPT for Anal Cancer 
Trial Phase 
Feasibility 
Clinical Indication 
Newly diagnosed, non-metastatic squamous cell carcinoma of the 
anal canal dispositioned to definitive chemoradiation treatment 
Trial Type 
Treatment 
Type of control 
None  
Route of administration 
External beam proton radiation therapy with concurrent 
chemotherapy 
Trial Blinding 
NA 
Treatment Groups  
Single arm, non-randomized 
Number of trial subjects 
40 
Estimated duration of trial 
 9 years  
Duration of Participation 
 9 years  
 
 
 
2.0 
TRIAL DESIGN 
 
2.1 
Research Questions 
There are three main research questions we hope to answer with this study:  
 
2.1.1 
Is it feasible to enroll patients only a study that utilizes LET-optimized IMPT as the radiation 
modality in the delivery of definitive chemoradiation?  
2.1.2 
Can LET-optimized IMPT reduce biologically effective dose to the bone marrow, bladder, 
bowel and genitali   
2.1.3 
Can LET-optimized IMPT decrease acute and chronic gastrointestinal, genitourinary and 
hematologic toxicities compared to historical controls treated with VMAT? 
 
2.2  
Hypothesis 
Our primary hypothesis is that LET-optimized IMPT can be used to minimize both dose and 
LET to OARs, which will reduce toxicities while obtaining similar or superior tumor response 
in anal canal cancers. 
  
 
3.0 BACKGROUND & RATIONALE: 
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3.1  
Background 
 
The current standard of care for squamous cell carcinoma of the anal canal was established by RTOG 
9811 and includes definitive CRT with 5-fluorouracil (5FU) and mitomycin-C (MMC)1. However, 
studies have shown equivalent results with 5FU with cisplatin as concurrent treatment 2, so that 
regimen is also used at some centers, including MDACC3. Intensity modulated radiotherapy (IMRT) 
emerged as the new standard of care in the treatment of anal cancer when RTOG 0529, a phase II 
study, prospectively showed that IMRT was able to significantly reduce G2+ hematologic and G3+ 
dermatologic toxicity4.  
 
The landmark studies establishing CRT as the standard of care utilized 3D treatment techniques. As 
such, large volumes of bowel, bladder, external genitalia and skin received significant doses. On the 
MMC arm of RTOG 9811, G3-4 hematologic and non-hematologic acute toxicity rates were 61% and 
74%, respectively 1. Although IMRT was shown to reduce toxicity, patients receiving IMRT with 
concurrent 5FU and MMC on RTOG 0529 still experienced 77% G2+ gastrointestinal, 73% G2+ 
hematologic and 23% G3+ dermatologic toxicity. Additionally, bone marrow dose is typically higher 
with IMRT 5, and the importance of bone marrow dose in predicting the risk of hematologic toxicity 
for patients receiving CRT for anal cancer has been established. Specifically, the volume of pelvic 
bone marrow receiving 5, 10, 15 and 20 Gy were all significantly associated with decreased WBC and 
ANC nadirs6. 
 
The advantages of proton therapy (PT) arise from the physical properties of proton beams7. From a 
physical standpoint, proton beam dose deposition is highly favorable, following a Bragg curve as a 
function of its depth in tissue. The lower entrance doses and elimination of exit doses can produce 
superior conformal dose distributions to the target volume compared with radiotherapy with 
megavoltage (MV) x-rays. Thus, the rationale for using protons lies in reducing the integral dose and 
sparing surrounding healthy tissues and critical organs, minimizing treatment related complications 
and reducing the risk of radiation-induced secondary cancers 8,9. 
 
Protons are charged particles that continuously interact with tissue, slowing as they penetrate it, 
and leaving a track of ionizations in their paths, which are quantified in terms of the linear energy 
transfer (LET). The LET increases as the energy (or speed) of the proton particle decreases. 
Consequently, the LET of proton beams increases as a function of depth in tissue. At their entrance 
to the body, the LET is low (~0.6-0.9 keV/μm) and at the tumor volume and end of the proton beam 
range, the LET increases by more than an order of magnitude. The biological damage produced by 
therapeutic proton beams depends on LET in addition to absorbed dose. However, current practice 
in proton therapy assumes that the relative biological effectiveness (RBE) is independent of LET and 
equal to 1.1. This is only an approximation, and numerous studies have demonstrated the variable 
RBE within therapeutic proton beams10–14. A recent review of the available proton RBE data 
demonstrated that, although the data support an average value of ~1.1, considerable deviations 
from this value can occur with variations in LET. In particular, near the end of the proton range 
where protons have the highest LET, RBE can increase to as much as 3.511. Thus, these physical 
properties of proton beams make it possible to precisely deliver a high dose of radiation to a tumor 
volume while minimizing dose to surrounding normal tissue7.   
 
3.2 
Rationale 
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3.2.1 
Rationale for IMPT 
In the current clinical practice of PT, techniques such as passively scattered proton therapy (PSPT) 
are used. With such techniques, the distal high LET regions of beams are nearly always in normal 
tissues distal to the target volume. Intensity modulated proton therapy (IMPT) is a newer delivery 
modality in which magnetically scanned thin pristine proton “beamlets” are used to “paint” 
radiation dose into the target volumes. For treatment planning purposes,  IMPT are categorized into 
single field optimized (SFO-IMPT) or multi-field optimized (MFO-IMPT). In SFO-IMPT, inverse 
planning is employed to optimize each individual beam to individually conform to the entire target 
volume while minimizing dose outside. In MFO-IMPT there is simultaneous optimization of all 
beamlets of all incident beams to deliver the homogeneous prescription dose to the target while 
limiting the dose to critical volumes of normal tissues to within tolerance levels.  For highly complex 
target shapes and anatomic geometries, MFO-IMPT frequently allows for the optimal balancing of 
tumor coverage and normal tissue sparing. 
 
In the pelvis, IMPT has the potential to preferentially spare bone marrow from unnecessary dose, 
and potentially increase the tolerability of treatment. Additionally, IMPT has the potential to 
decrease dose to the external genitalia, bowel and bladder, which may further improve acute and 
long-term quality of life for patients receiving CRT for anal cancer. Hematologic, gastrointestinal and 
dermatologic toxicity are common reasons patients need breaks during treatment. As it has been 
demonstrated that prolonging the overall treatment duration with breaks can worsen oncologic 
outcomes15, IMPT thus has the potential to improve the efficacy of treatment. Recently we 
completed a treatment planning study of 10 consecutive patients treated with VMAT for anal 
cancer, which we generated comparison IMPT plans. We compared doses to the pelvic bone 
marrow, bowel, bladder and genitalia. We found that IMPT plans resulted in clinically signficiant 
lower doses (RBE=1.1) to the pelvic bone marrow (mean dose, V10, V20, V30, V40) as well as 
bladder (V40) and genitalia (V30 and V20) and comparable V45 doses to bowel..  
 
Two small treatment planning studies published in 2015 have also evaluated the potential benefits 
of IMPT for anal cancer16,17. The first, performed at the Mayo Clinic, compared IMPT plans for eight 
patients with squamous cell carcinoma of the anal canal. They treated the primary site and nodes 
with individual beams by using sub-target CTVs that represent primary target as anus and the right 
and left lateral nodes. These sub-target CTVs were then used to establish individual beam 
assignments. Thus, although they used a MFO algorithm, most of the target received a near-uniform 
dose from individual fields. The gross tumor volume plus margin received 54-60 Gy (RBE) while the 
elective nodal volumes received 45-50.4 Gy (RBE). They found no different between target coverage 
between IMRT and IMPT. The IMPT plans were also robust to uncertainties as evidenced by 
acceptable coverage even with the worse-case dose values. However, the mean doses to the bone 
marrow, bladder, small bowel and genitalia were all significantly lower with IMPT as compared to 
IMRT. Specifically with regard to the bone marrow, IMPT reduced the pelvic bone marrow V10 by 
54% (P=.008), V20 by 56% (P=008) and V30 by 44% (P=.008)17. Another treatment planning study 
performed at The University of Pennsylvania also compared IMRT and IMPT plans for patients with 
anal cancer. Although they used SFO-IMPT, they similarly found no difference in target coverage, but 
they showed significant reductions of doses up to 35 Gy to the small bowel (P=.008), reductions of 
doses up to 29 Gy to the genitalia (P=.008), as well as reductions of doses up to 30 Gy to the bone 
marrow (P=.008) 16. Figure 1 shows the bone marrow and anterior viscera sparing achievable with 
IMPT compared with IMRT for a patient treated in our department.  
 
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3.2.2 
Rationate for LET-opimization 
Although IMPT appears to be quite promising for normal tissue avoidance in the treatment of anal 
squamous cell carcinomna, with current MFO-IMPT techniques, location of high biological effect 
regions is uncontrollable.  To reduce the probability of normal tissue injury, the strategy is currently 
to avoid placing such regions in sensitive normal tissues, but sometimes at the cost of compromising 
tumor dose. However, with MFO-IMPT’s ability to control intensities of individual beamlets that 
incorporate LET and/or RBE, it is possible to place such highly effective regions within the tumor 
volume and away from normal critical tissues, which would effectively allow for safe prescribed and 
delivered doses, and improved normal tissue sparing.  Evaluation of safety and feasibility of such an 
approach is one of the secondary objectives of the proposed trial. We have developed novel methods 
for the incorporation of LET in to the IMPT planning process, which use Fast Monte Carlo (fMC) dose 
engine to recalculate treatment plans generated using MFO-IMPT in order to obtain LET distributions. 
In a recent treatment planning study we completed of nine patients with anal cancer treated with 
VMAT, we observed that IMPT plans reduced the exposure of pelvic bone marrow to higher LET 
regions while maintaining target coverage compared to the original VMAT plans. 
 
3.2.3 
Rationale for use of charges and Time-Driven Activity-Based Costing data to describe value 
Healthcare value can be defined as outcomes over costs, but measuring the true costs of delivering 
care can be imprecise and difficult, particularly when utilizing advanced technology. In the current 
fee-for-service model, charges and reimbursements are utilized most often utilized as proxies for 
cost17. From the perspective of the healthcare provider, the true cost of delivering a particular 
treatment is a result of the resources that are required to deliver that care, not necessarily the 
charges or the reimbursements.  
 
The field of radiation oncology has relied on the development of, sometimes costly, technology in 
order to advance the field, improve outcomes and decrease toxicities. In the treatment of anal 
cancer, the more costly IMRT technique was shown to decrease toxicity rates as compared to the 
traditional 3D conformal radiation techniques4. As mentioned above, IMPT has the potential to 
reduce dose to non-target tissues even more than IMRT and has the subsequent potential to 
decrease toxicity rates even further. Although the charges and reimbursements for IMPT are 
undisputedly higher than those for IMRT, reducing the toxicity rates and the subsequent needs and 
costs of managing those toxicities can dramatically affect the overall cost of delivering care.  
 
Time-driven activity-based costing (TDABC) is a method that has been used by several fields of 
business and medicine19,20 and can provide a “bottom-up” cost accounting methodology used to 
more accurately measure resources utilized based on the time consumption of constituent 
activities21,22. TDABC analyses require process maps to first be generated including all points of 
contact the patient has with the radiation oncology department from consultation, to treatment 
planning and delivery, to follow up and all ancillary services required for the management of 
radiation-related toxicities. Costs are then assigned to each step of the process map based on 
multiplying the adjusted average hourly rate for the particular personnel performing the task but 
the length of time typically required to complete it. Direct and indirect costs of treatment including 
depreciation of radiation therapy and imaging equipment are also integrated.  
 
Groups at this institution have pioneered the field of utilizing the TDABC method to account for and 
compare the true costs of delivering radiation therapy as a part of oncologic care. Extensive process 
mapping and radar chart analyses were performed on a cohort of 238 men treated for prostate 
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cancer at MD Anderson with prostate brachytherapy showing the true cost and value of that 
modality23.  The same group also looked at utilizing TDABC to show the true difference in cost 
between definitive chemoradiation utilizing either IMRT or IMPT in the treatment of patients with 
head and neck cancer. They showed that, for a subgroup of patients, the cost savings of reduced 
toxicity with IMPT offset the increased technical costs associated with delivering this treatment24.  
 
This study will be the first to gather TDABC data on patients treated with IMPT for squamous cell 
carcinoma of the anal canal. The radiation oncology department has already developed process 
maps for the different radiation oncology clinics, and we will be able to adapt these maps for 
patients treated on study at the proton therapy center. We hope the data collected as a part of this 
study will better account for the true costs of delivering IMPT for this population of patients so that 
we can better define the value in the future.  
 
Figure 1- shows representative axial (A & B), coronal (C & D) and sagittal (E & F) images from IMPT 
(A, C, E) and VMAT (B, D, F) comparison plans for a patient with anal canal squamous cell carcinoma 
treated definitively with chemoradiaiton.  
 
 
4.0 INCLUSION AND EXCLUSION CRITERIA 
 
4.1 
Inclusion criteria 
1.) Histologically-proven, non-metastatic invasive primary squamous cell carcinoma of the anal 
canal (Stages I, II, and III).  
2.) History/physical examination within 60 days prior to registration. 
3.) Anal examination with biopsy on either colonoscopy, sigmoidoscopy, rigid proctoscopy or 
anoscopy.  
4.) CT scan of the chest and abdomen with contrast or contrast-enhanced PET/CT scan within 
60 days of registration unless the patient has a documented contrast allergy.  
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5.) CT scan of pelvis with contrast or contrast-enhanced PET/CT scan within 60 days of 
registration unless the patient has a documented contrast allergy.  
6.) Zubrod Performance Status of 0-1 within 60 days prior to registration.  
7.) Age >/=18 years – 85 years. 
8.) Laboratory data within 30 days prior to study registration showing: 
• 
Absolute neutrophil count (ANC) >/= 1.8 K/µL 
o Cannot be achieved through GCSF use 
• 
Platelets >/= 100 K/µL 
o Cannot be achieved through transfusion. 
• 
Hemoglobin >/= 8g/dL 
o Cannot be achieved through transfusion. 
• 
Serum creatinine </= 1.5mg/dL 
• 
Bilirubin </= 1.4mg/dL 
o Except in the case of patients with Gilberts disease. 
• 
White blood cells (WBC) >/= 3000/microliter 
• 
AST/ALT < 3x the upper limit of normal 
9.) HIV test must be done within 90 days of study registration. If HIV positive, CD4 count must 
be obtained within 90 days of study registration. Note: HIV positive patients are eligible for 
this study if they have a CD4 count >400 cells/mm3.  
10.) The patient must either have insurance authorization or otherwise secure funding to cover 
IMPT.  
11.) The patient must be able to receive concurrent chemotherapy. 
 
4.2 
Exclusion criteria 
1.) Prior invasive malignancy (except non-melanomatous skin cancer), unless disease free for a 
minimum of 3 years.  
2.) Prior systemic chemotherapy for anal cancer. 
3.) Prior radiotherapy to the pelvis that would result in overlap of radiation fields.  
4.) Evidence of distant metastatic disease (M1).  
5.) Not receiving concurrent chemotherapy 
6.) Women of childbearing potential or men who do not agree to use a medically effective 
form of birth control throughout their participation in the treatment phase of the study.  
7.) Severe, active co-morbidity defined as follows:  
• 
unstable angina and/or congestive heart failure requiring hospitalization within the last 6 
months.  
• 
transmural myocardial infarction within the last 6 months.  
• 
acute bacterial or fungal infection requiring intravenous antibiotics at the time of 
registration. 
• 
Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring 
hospitalization or precluding study therapy at the time of registration. 
• 
hepatic insufficiency resulting in clinical jaundice and/or coagulation defects. 
• 
HIV positive with a CD4 count <400 cells/mm3. 
• 
other immunocompromised status. 
• 
women who are pregnant or lactating.  
• 
uncontrolled infection as deemed by the PI. 
• 
patient incarceration. 
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5.0 TREATMENT DETAILS 
 
5.1 
Radiation treatment guidelines 
 
5.1.1 
Non-contrast treatment planning CT scans will be used to delineate the gross tumor volume 
(GTV) and clinical target volume (CTV). The treatment planning CT scan will be obtained with 
the patient in our standard treatment position: supine with legs in a “frog-legged” position. 
A custom immobilization device will be created to minimize set-up variability. A radiopaque 
anal marker will be used to indicate the anal verge. A vaginal dilator will be used during 
simulation and treatment for all female patients.  
 
5.1.2 
IMPT Planning and Plan Evaluation 
 
The following is the series of steps in the IMPT planning process for each patient: 
1. An MFO-IMPT plan will be designed using a commercial (clinical) treatment planning 
system (TPS) based on the current practice of using criteria defined in terms of dose- 
and dose-volume constraints and RBE = 1.1.  (The Fixed RBE-IMPT plan.) 
2. For the LET-optimized IMPT plan, dose distribution will be optimized using dose- and 
dose-volume criteria extended to include terms that increase LET in the target and 
reduce it in normal tissues.  Such planning will require the use of an in-house TPS based 
on Monte Carlo techniques. Post-processing of scanning spots to ensure deliverability 
will also be performed as is done in the clinical TPS.   
3. Both 1) IMPT and 2)  LET-optimized IMPT will be reported in terms of three 
distributions: a) fixed RBE weighted dose (RBE=1.1), b) dose-averaged LET, and c) 
variable RBE-weighted dose (employing the RBE model of McNamara et al 2015) 
computed using Monte Carlo simulations. These distributions, dose- and LET-volume 
histograms and indices derived therefrom will be compared and presented to physicians 
to support decision making.  
4. For safety considerations and for consistency with traditional practice, all dose 
distributions expressed in terms of RBE of 1.1 will be used to make final treatment 
decisions. To accomplish this, LET-optimized IMPT plan will be imported back into the 
current clinical TPS, Plan 1) and 2) will be renormalized to require the same target 
coverage and compared.  
5. The dose distribution that best meets the dose requirements in the RBE=1.1 domain 
(Step 4) and maximizes the target LET while minimizes LET to critical structures (Step 3), 
as judged by the attending physician, will be chosen for treatment. If LET-optimzed IMPT 
plan is not deemed significantly superior, the conventional IMPT plan will be chosen. 
6. The selected plan will be approved in the clinical TPS and processed for quality 
assurance and treatment delivery. 
 
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5.1.3 
GTV and CTV should be delineated on each axial slice of the planning CT scan on which they 
appear.  
• 
GTVp includes the gross primary tumor in the anal canal as documented by physical 
exam, endoscopic exam, CT, PET and MRI.   
• 
GTVn includes all involved nodes as documented by imaging or biopsy.  
• 
CTVp includes the GTVp with a 1 cm margin except into uninvolved bone. 
• 
CTVn includes the GTVn with a 1 cm margin except into uninvolved bone, muscle, 
bowel or bladder.  
• 
CTVel includes the elective nodal regions at risk including the perirectal, presacral, 
right and left internal iliacs, right and left external iliacs and right and left inguinals 
down to the level of the lesser trochanter of the femur inferiorly.  
 
5.1.4 
Planning target volumes (PTV) will provide a margin around the CTV to compensate for 
variability in set up as well as internal motion. The PTV margin will be 5 mm added to each 
of the CTV volumes above.  
 
5.1.5 
Radiation dosing to the PTVp and PTVel will be based on primary tumor size:  
Primary tumor size 
PTVp dose/fractionation 
PTVel dose/fractionation*  
<2cm 
50Gy(RBE) in 25 fractions 
43Gy in 25 fractions 
2-5cm 
54Gy(RBE) in 27 fractions 
45Gy in 27 fractions 
>5cm 
58Gy(RBE) in 29 fractions 
47Gy in 29 fractions 
 
Nodal size 
PTVn dose/fractionation 
<2cm 
50Gy(RBE) in 25 fractions 
2-5cm 
54Gy(RBE) in 27 fractions 
>5cm 
58Gy(RBE) in 29 fractions 
 
*In the event that the gross node is larger than the primary tumor, the dose and 
fractionation chosen for the nodal size will dictate the PTVel dose and fractionation. 
 
5.1.6 
Normal structures that should be contoured prior to treatment planning include the 
bilateral femoral heads, bladder, external genitalia, bowel bag that contains both small bowel and 
large bowel outside the CTV (contoured as the entire peritoneal potential space per Kavanaugh BD, 
Pan CC, Dawson LA, et al. Radiation dose-volume effects in the stomach and small bowel. IJROBP 
2010;76:S101-107)25, and pelvic bone marrow (contoured per Mell LK, Kochanski JD, Roeske JC, et al. 
Dosimetric predictors of acute hematologic toxicity in cervical cancer patients treated with 
concurrent cisplatin and intensity-modulated pelvic radiotherapy. IJROBP 2006;66:1356-1365)26.  
 
5.1.7 
Treatment planning directives used for inverse planning should include the following goals 
and normal tissue constraints. These constraints are only a guideline and the final decision 
will be made by the treating physician based on individual patient anatomy. 
• 
PTV coverage: V100%>95%, V95%>99%, V105%<10%, Dmax<120% (ideal; the 
treating MD may accept a plan with less coverage or higher heterogeneity based on 
individual patient anatomy and proximity to organs at risk).  
• 
Bowel bag: point dose Dmax <54Gy (ideal) V54Gy<1cc (acceptable), V45Gy<195cc 
(ideal; higher doses are acceptable at treating MD’s discretion).  
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• 
Femoral heads: V45Gy<20% (ideal; higher doses are acceptable at treating MD’s 
discretion) 
• 
Bladder: V50Gy<30% (ideal; higher doses are acceptable at treating MD’s 
discretion).  
• 
External genitalia: V30Gy<20%, V20Gy<67% (ideal; higher doses are acceptable at 
treating MD’s discretion).  
• 
Pelvic bone marrow: V10Gy <90% (ideal; higher doses are acceptable at treating 
MD’s discretion).  
 
5.1.8 
Daily image guidance is required for set-up verification and should include daily orthogonal 
images utilizing the bony anatomy for daily alignment. At least one verification CT 
simulations will be obtained in the treatment setup position during treatment to verify 
setup, dose to targets, and dose to normal organs.  
 
5.1.9 
Treatment breaks during radiation therapy are discouraged. Treatment breaks may be 
considered at the discretion of the treating physicians in the case of acute toxicity.   
 
5.2  
Chemotherapy details  
 
5.2.1  Cisplatin 
• 
Chemistry: Cisplatin (cis-diamminedichloroplatinum II ) has the empiric formula 
H6Cl2N2Pt. It is a planar inorganic compound with a molecular weight of 300; soluble in 
water at a concentration of 1 mg/ml. The (II) nomenclature denotes the (active) valence 
state of the platinum. The interatomic distance of the chlorides is 3.3 A which is different 
from the 5-7 A interatomic distance of the classic alkylating agents. Only the cis-isomer is 
therapeutically active. 
• 
Mechanism of Action: Primarily causes inhibition of DNA synthesis, and to a lesser degree 
inhibition of RNA and protein. It has not been shown to be cell cycle specific. 
• 
Human Pharmacology: Highest concentrations were found in kidney, liver, and spleen; 
lowest concentrations were found in the brain. Plasma contained less than 10% of dose at 
1 hour and the peak urinary excretion was 22-32% in 48 hours. It has a biphasic mode 
half-life, the initial phase of 25-49 minutes, and the secondary, 58-73 hours. The drug was 
79% protein bound with intracellular leukocyte levels 6.1% of plasma levels. 
• 
Side Effects: Impairment of renal function, myelosuppression, high-frequency hearing loss, 
nausea and vomiting. 
 
5.2.1  5-Fluorouracil 
• 
Chemistry: 5-fluorouracil is has the empiric forumla C4H3FN2O2. It is a pyrimidine analog 
and blocks thymidylate synthetase conversion of deoxyuridylic acid to thymidylic acid. 
• 
Mechanism of action: 5-fluorouracil (5-FU) is a pyrimidine analog antimetabolite that 
interferes with DNA and RNA synthesis; after activation, F-UMP (an active metabolite) is 
incorporated into RNA to replace uracil and inhibit cell growth; the active metabolite F-
dUMP, inhibits thymidylate synthetase, depleting thymidine triphosphate (a necessary 
component of DNA synthesis). 
• 
Human pharmacology: 5-FU Penetrates extracellular fluid, CSF, and third space fluids (eg, 
pleural effusions and ascitic fluid), marrow, intestinal mucosa, liver and other tissues. It 
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exhibits primarily Hepatic metabolism (90%) via a dehydrogenase enzyme; FU must be 
metabolized to be active metabolites, 5-fluoroxyuridine monophosphate (F-UMP) and 5-
5-fluoro-2’-deoxyuridine-5’-O-monophosphate (F-dUMP). Half life elimination is 16 
minutes (range: 8-20 minutes); two metabolites, F-dUMP and F-UMP, have prolonged 
half-lives depending on the type of tissue. 5-FU is excreted in lung (as expired CO2) and 
urine (7% to 20% as unchanged drug within 6 hours; also as metabolites within 9-10 
hours). 
• 
Side effects: Primary side effects include nausea, diarrhea, and maculopapular rash. 
Cardiovascular and hematologic side effects are rare. 
 
 
6.0 TRIAL PROCEDURES*    
Figure 2- 
 
    Table 1-  
 
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Trial Period: 
Screening 
Phase 
On-Treatment Monitoring Visit 
Post-
Treatment 
 
Study 
Screening Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 
Survival 
Follow-Up 
Scheduling Window 
(Days): 
4 weeks 
to 0 days 
prior to 
beginning 
of CRT 
Fraction 
1-5 of 
CRT 
Fraction 
6-10 of 
CRT 
Fraction 
11-15 
of CRT 
Fraction 
16-20 
of CRT 
Fraction 
20-25 
of CRT  
Fraction 
26-29 of 
CRT if 
applicable  
12+/-4 
wks after 
end of 
CRT and 
then per 
SOC FU 
algorithm 
(Table 2) 
Administrative Procedures 
Informed Consent 
X 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Survival Status 
 
 
 
 
 
 
 
Xc 
Clinical Procedures/Assessments 
Directed Physical 
Examination 
Xa 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG Performance 
Status 
X 
X 
X 
X 
X 
X 
X 
X 
Radiation CT-
Simulation 
Xb 
Xb 
Xb 
Xb 
Xb 
Xb 
Xb 
 
Physician-assessed 
CTCAE v4 
 
X 
X 
X 
X 
X 
X 
Xc 
Patient-reported PRO-
CTCAE 
 
X 
X 
X 
X 
X 
X 
X 
Chemoradiation 
Treatment 
 
X 
X 
X 
X 
X 
X 
 
Laboratory/Imaging/Assessments 
Pregnancy Test – 
Urine or Serum HCG 
X 
 
 
 
 
 
 
 
CBC with Differential 
including ANC and 
ALC 
X 
X 
X 
X 
X 
X 
X 
X 
Quality of Life 
Questionnaires 
Xd 
 
 
 
 
 
 
Xd 
PET/CT + contrast or 
CT 
chest/abdomen/pelvis 
with contrast 
X 
 
 
 
 
 
 
X 
Anoscopy or Flexible 
Sigmoidoscopy 
X 
 
 
 
 
 
 
Xe 
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Trial Period: 
Screening 
Phase 
On-Treatment Monitoring Visit 
Post-
Treatment 
 
Study 
Screening Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 
Survival 
Follow-Up 
Scheduling Window 
(Days): 
4 weeks 
to 0 days 
prior to 
beginning 
of CRT 
Fraction 
1-5 of 
CRT 
Fraction 
6-10 of 
CRT 
Fraction 
11-15 
of CRT 
Fraction 
16-20 
of CRT 
Fraction 
20-25 
of CRT  
Fraction 
26-29 of 
CRT if 
applicable  
12+/-4 
wks after 
end of 
CRT and 
then per 
SOC FU 
algorithm 
(Table 2) 
*All are standard-of-care tests/procedures/charges. 
a. 
The first physical examination during the screening period will be a full examination, all subsequent 
examinations will be directed 
b.      Patients will be simulated followed approximately one week or more prior to starting radiation 
therapy. Initial CT simulation is required for treatment planning, and at least one verification CT 
simulation is required during treatment, but verification CT simulations can be done as often as 
weekly at the discretion of the treating physician.   
c.      In lieu of an in person visit, all subsequent follow ups after the first follow up can be conducted over 
the phone. In these instances a directed physical examination will not be required and appropriate 
outside imaging scans must be utilized to assess response. 
d.     EQ-5D, EORTC QLQ -C30, Perceived Stress Scale, FSFI (women) and IIEF (men). 
e.     Baseline and 12 week follow up endoscopy must be performed at MD Anderson. Schedule of follow up 
endoscopies after the 12 week follow up will be decided by the managing team based on findings.  
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Figure 2 and Table 1 above summarize the trial procedures to be performed at each visit. Individual trial 
procedures are described in detail below. Patients are strongly encouraged to maintain follow up at MD 
Anderson. If unable to do so due to unexpected logistical or financial consideration, patients will be 
advised to maintain the follow up schedule with an outside oncologist as per the current standard of 
care- and have all imaging and clinical documentation forwarded to MD Anderson. Additional history 
and/or QOL instrumens will be emailed via REDCap or collected over the phone as needed by the study 
team. The first follow up study visit as well as all required tests at 12+/-4 weeks after compleition of CRT 
will be required to be at MD Anderson.  
 
6.1 
Pretreatment Procedures 
 
6.1.1  Patients will be screened for eligibility from 30 days prior to the start of CRT to the day of the 
start of CRT (provided that consents are signed before radiation treatment starts) (see section 
4.0).  A medical history will be obtained by the investigator or qualified designee. Medical 
history will include all active conditions, and any condition diagnosed that are considered to be 
clinically significant by the Investigator.  Details regarding the disease for which the subject has 
enrolled in this study will be recorded separately and not listed as medical history.   
 
6.1.2 
The treating physician  or qualified designee will perform a full physical examination at the first 
pretreatment evaluation including documentation of the primary anal lesion size and distance 
from the anal verge up to 30 days prior to registration.  
6.1.3 
The treating physician or qualified designee will record weight at the first pretreatment 
evaluation, weekly clinic visits and during follow-up).  
6.1.4 
The investigator or qualified designee will assess performance status using the Eastern 
Cooperative Oncology Group (ECOG) Performance Scale at screening and at every subsequent 
study visit. 
6.1.5 
Informed consent: the investigator must obtain document informed consent from each 
potential subject prior to participating in a clinical trial (Appendix).  
 
6.1.6 
MD Anderson pathology review of the biopsy specimen (if not performed at this institution) for 
histologic confirmation of squamous cell carcinoma. Human Papilloma Virus (HPV) 
determination  will be noted from the biopsy specimen if available.  
 
6.1.7  Endoscopic examination of the anal canal on either sigmoidoscopy or rigid proctoscopy will be 
completedprior to initiation of CRT and 7 days after initiation of CRT (although endoscopic 
examination prior to the start of CRT is strongly encouraged).  
 
6.1.8  Contrast-enhanced PET/CT scan or CT scan of the chest, abdomen and pelvis with contrast up to 
60 days prior to initiation of CRT unless the patient has a documented contrast allergy.  
 
6.1.9 
Baseline labs will be obtained, including complete blood count (CBC: hemoglobin, hematocrit, 
WBC with differential blood cell counts (neutrophils, bands, lymphocytes, monocytes, 
eosinophils, basophils) and platelets. Women of child-bearing potential require a urine 
pregnancy test (beta-hCG) prior to simulation.  
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6.1.10 Patients will report baseline symptoms and quality of life with the following instruments as 
outlined below. Questionnaires will be administered electronically and paper copies of the 
questionnaires will be available if necessary.  
• 
The EQ-5D-5L  
• 
The EORTC QLQ-C30 will be utilized to report GI-specific quality of life 
• 
The Perceived Stress Scale 
• 
For female patients:  
Female Sexual Function Index (FSFI)- 19 question survey validated in cancer survivors.  
• 
For male patients: 
Individual Items of International Index of Erectile Function Questionnaire (IIEF).  
 
6.2 
On-treatment Procedures 
6.2.1 
Radiation treatment will be precede approximately 1 week or more by radiation treatment 
planning simulation consisting of a non-contrast CT scan in the treatment position. At least one 
verification CT scan in the treatment poision is required after the initiation of treatment. The 
treating radiation oncologist should review the internal anatomy on the verification scan with 
respect to the initial treatment planning scan and review the target coverage as well as doses 
to normal organs on the verifcations scan with respect to the initial treatment plan. Adaptive 
plans can be generated if deemed clinically necessary by the treating radiation oncologist. 
Additional verifaction scans can be obtained up to weekly if deemed necessary by the treating 
radiation oncologist.  See section 5.1 for further details on radiation treatment.  
6.2.2 
Chemoradiation will be administered using doses of both radiation and chemotherapy 
consistent with the current institutional standard of care (further details provided in sections 5.1 
and 5.2). 
 
6.2.3 
On-treatment evaluation consists of weekly clinic visits with the treating radiation oncologist 
who will assign CTCAE v4 toxicity grades of hematologic, gastrointestinal, genitourinary and 
dermatologic side effects GI: nausea, vomiting, diarrhea, constipation, anal pain, proctitis, and 
fecal incontinence; GU: urinary frequency, urinary urgency, urinary tract pain, urinary 
incontinence, vaginal pain (women only), and perineal pain; Dermatological: radiation 
dermatitis). Patients will also report toxicity using the PRO-CTCAE. Weekly blood work will be 
monitored by both the treating medical and radiation oncologists including: complete blood 
count (CBC: hemoglobin, hematocrit, WBC with differential blood cell counts (neutrophils, 
bands, lymphocytes, monocytes, eosinophils, basophils, platelets, and febrile neutropenia). A 
focused physical examination, weight and ECOG performance status will be assessed at each 
weekly visit.   
 
6.2.4  For all patients enrolled on study, charges and TDABC data will be collected from the date of 
initial consultation until the 12 week follow up. Data will capture all visits, treatments, 
procedures, interventions, emergency room visits and hospital admissions within the MDACC 
system. Total cost of care will be calculated for each enrolled patient. Total professional and 
technical charges will also be calculated for each enrolled patient with the assistance of the 
billing department. 
 
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6.3 
Post-treatment Follow-up Procedures 
6.3.1 
The treating physician  or qualified designee will perform a focused physical examination at the 
first follow-up evaluation including documentation of clinical response to treatment (complete 
clinical response, partial clinical response/residual disease, or progressive disease). .  
6.3.2 
The treating physician or qualified designee will record weight at the first follow-up evaluation.   
6.3.3 
The investigator or qualified designee will assess performance status using the Eastern 
Cooperative Oncology Group (ECOG) Performance Scale at the first follow-up evaluation. 
6.3.4  Endoscopic examination of the anal canal on either anoscopy, sigmoidoscopy or rigid 
proctoscopy at the time of the first follow-up evaluation (12+/-4 weeks from completion of 
CRT).   
 
6.3.5  Contrast-enhanced CT scan of the chest, abdomen and pelvis with contrast at the time of the 
first follow-up evaluation (12+/-4 weeks from completion of CRT) unless the patient has a 
documented contrast allergy or inadequate renal function. The CT will be read by a staff 
radiologist as per the current standard of care. Dimensions of any residual tumor should be 
recorded where applicable.  
 
6.3.6 
Labs will be obtained at the first follow-up evaluation including complete blood count (CBC: 
hemoglobin, hematocrit, WBC with differential blood cell counts (neutrophils, bands, 
lymphocytes, monocytes, eosinophils, basophils) and platelets.  
 
6.3.7 
At the first follow-up evaluation, patients will report symptoms and quality of life with the 
following instruments as outlined below. Questionnaires will be administered electronically and 
paper copies of the questionnaires will be available if necessary.  
• 
The PRO-CTCAE 
• 
The EQ-5D. 
• 
The EORTC QLQ-C30 will be utilized to report GI-specific quality of life 
• 
The Perceived Stress Scale 
• 
For female patients:  
Female Sexual Function Index (FSFI)- 19 question survey validated in cancer survivors.  
• 
For male patients: 
Individual Items of International Index of Erectile Function Questionnaire (IIEF).  
 
6.3.8 
Patients should be followed every 12+/-4 weeks for the first two years per the current 
standard of care with physical exam, labs, imaging and endoscopy at the discretion of the 
treating physicians (See Table 2). Only the first follow-up visit will be required on study. 
However, the questionnaires mentioned in 6.3.7 above will be sent via email using REDCap at 6 
month intervals for voluntary participation for 24 months after treatment completion. Patients 
returning for follow up at MD Anderson will have their medical records queried for response 
rate, local progression free survival, distant metastasis-free survival and overall survival at each 
subsequent visit for 48 months after treatment completion. 
Table 2 
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Time from Completion of 
Treatment 
Evaluation 
Team Providing Clinical Follow-
uo 
3 months 
PE, CT, scope 
MO, XRT, CRS 
6 months 
PE, scope 
MO + CRS* 
9 months 
PE 
XRT 
12 months 
PE, CT, scope 
MO + CRS 
15 months 
PE 
XRT 
18 months 
PE, CT (CT not needed if <T3 or 
<N2) 
MO 
21 months 
PE 
XRT 
24 months 
PE, CT, scope 
MO + CRS 
30 months 
PE 
XRT 
36 months 
PE, CT, scope 
MO 
42 months 
PE 
XRT 
48 months 
PE, CT 
MO 
>48 months 
 
Survivorship or discharge to PCP 
for routine care 
*initial visits with CRS for proctoscopy until complete response or disease persistence is established.  
PE = physical exam, CT = computed tomography, MO = medical oncology, XRT = radiation oncology, 
CRS = colorectal surgery, PCP = primary care physician. 
6.4 
Administrative/Other Procedures 
6.4.1 
Subject Withdrawal/Discontinuation Criteria: Subjects may withdraw consent at any time for 
any reason or be dropped from the trial at the discretion of the investigator should any 
untoward effect occur. In addition, a subject may be withdrawn by the investigator if enrollment 
onto the trial is inappropriate, if the trial plan is violated, or for administrative and/or other 
safety reasons.  
 
A subject must be discontinued from the trial for any of the following reasons: 
• 
The subject or legal withdraws consent. 
• 
Inter-current illness that prevents further monitoring. 
• 
Investigator’s decision to withdraw the subject. 
• 
The subject has a confirmed positive serum pregnancy test. 
• 
Noncompliance with trial treatment or procedure requirements. 
• 
The subject is lost to follow-up. 
 
Additional subjects may be enrolled on an as-needed basis to substitute for patient’s removed prior to 
the first follow up visit after chemoradiation.  
 
6.4.2 
Adverse Event (AE) Monitoring: The investigator or qualified designee will assess each subject 
to evaluate for potential new or worsening AEs as specified in the Trial Flow Chart and more 
frequently if clinically indicated.  Adverse experiences will be graded and recorded throughout 
the study and during the follow-up period.  Toxicities will be characterized regarding 
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seriousness, causality, grading, and action taken with regard to trial treatment. Grading will be 
determined utilizing CTCAE v. 4.0.   
6.4.3 
Trial Database: All data on trial including toxicities, demographics, medical history, and 
treatment response will be entered into a trial-specific REDCap database. 
6.5 
Correlative Analyses 
 
6.5.1 
Both traditionally-optimized IMPT and LET-optimized IMPT plans will be generated for 
each patient enrolled on study.  The goal of LET-optimized IMPT is to maximize the LET within 
the target and minimize it in normal tissues while maintaining the coverage requirements for 
target volumes and dose volume constraints for OARs expressed in terms of (RBE=1.1) weighted 
doses.  This requirement is imposed to assure safety and for consistency with the current 
practice.  The difference in dose distribution between IMPT and LET-optimized IMPT plans is 
expected to be minimal to moderate.  Even though constraints are fully met, due to possible 
redistribution of high LET values from normal tissues into target volumes in LET-optimized IMPT 
plans, for some cases mean dose to surrounding critical organs may be increased. Our goal is to 
evaluate the safety of such differences in dose distributions.  
 
6.5.2 
Blood will be drawn at baseline, weekly during chemoradiation and at the 12-week post-
treatment follow up visit as per standard of care (Table 1). WBC, ANC and ALC values will be 
recorded from the standard of care CBC drawn and their nadirs will be correlated with radiation 
dose to the pelvic bone marrow.  
 
 
 
 
7.0 STASTICAL PLAN:  
 
7.1 
Data Collection, Management and Statistical Summary 
 
Study data will be collected and managed using REDCap (Research Electronic Data Capture) electronic 
data capture tools hosted at MD Anderson 27. REDCap (http://www.project-redcap.org) is a secure, web-
based application with controlled access designed to support data capture for research studies, 
providing: 1) an intuitive interface for validated data entry; 2) audit trails for tracking data manipulation 
and export procedures; 3) automated export procedures for seamless downloads to common statistical 
packages; and 4) procedures for importing data from external sources. In the case of multi-center 
studies REDCap uses Data Access Groups (DAGs) to ensure that personnel at each institution are blinded 
to the data from other institutions. REDCap (https://redcap.mdanderson.org) is hosted on a secure 
server by MD Anderson Cancer Center's Department of Research Information Systems & Technology 
Services. REDCap has undergone a Governance Risk & Compliance Assessment (05/14/14) by MD 
Anderson's Information Security Office and found to be compliant with HIPAA, Texas Administrative 
Codes 202-203, University of Texas Policy 165, federal regulations outlined in 21CFR Part 11, and 
UTMDACC Institutional Policy #ADM0335. Those having access to the data file include the study PI and 
research team personnel. All protected health information (PHI) will be removed from the data when it 
is exported from REDCap for analysis. All dates for a given patient will be shifted by a randomly 
generated number between 0 and 364, thus preserving the distance between dates. Dates for each 
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patient will be shifted by a different randomly generated number. Following publication study data will 
be archived in REDCap. 
  
General descriptive statistics will be computed to report toxicity and outcome metrics. In addition, 
descriptive statistics will describe pretreatment patient demographics including age, gender, and 
performance status as well as disease-related characteristics including disease tumor and nodal stage. 
All time to event analyses will start from the time of enrollment. 
 
7.2 
Enrollment 
 
Anticipated enrollment is 1 patient every other month. We should be able to enroll 48 evaluable 
patients over 8 years. We anticipate 8 patients may not be evaluable such that we will have a total of 40 
evaluable patients on this trial. Following enrollment of the last patient, we anticipate 6 months of 
follow up to obtain adequate toxicity data for the primary endpoint. Thus, we anticipate that this trial 
will take approximately 6-8 years to complete.  
 
7.3 
Evaluability 
To be evaluable for toxicity, patients must have at least one weekly assessments of adverse events 
(CTCAEv4).  
 
 
 
7.4 
Statistical Analysis Plan 
7.4.1 
Primary Clinical Endpoint: To assess physician-reported acute grade 3 or greater gastrointestinal, 
genitourinary and hematologic toxicies at 12 weeks post-treatment for patients treated with 
linear energy transfer (LET)-optimized, intensity-modulated proton therapy (IMPT) and compare 
to contemporary controls treated with VMAT to determine the feasibility of this outcome for a 
future randomized trial. 
o At baseline, weekly during treatment, and at the 12 week post-treatment follow up 
appointment, the treating physician will document physician-assessed acute 
hematologic, gastrointestinal, genitourinary, dermatologic and other toxicities 
according to the Common Toxicity Criteria for Adverse Events v-4 (CTCAE v4). 
o For each cumulative physician-reported toxicity (hematologic, gastrointestinal, 
genitourinary, dermatologic and other) at 12-weeks post-treatment, we will 
tabulate results by type, grade, and attribution and compare with contemporary 
controls treated with standard of care VMAT-based chemoradiation with 5FU and 
cisplatin for non-metastatic anal squamous cell carcinoma manually and individually 
matched for (in order): T-stage, radiation dose, age and gender. We will compare 
toxicity rates using a McNemar’s chi-squared test for paired proportions.  
o A separate PA protocol will be submitted to retrospectively review the data from 
these contemporary controls.  
o Subset analyses will be carried out to evaluate the effect of other variables that may 
also impact toxicity in addition to radiation modality (IMPT vs VMAT).  
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On RTOG 0529, patients treated with dose-painted IMRT-based concurrent CRT for anal cancer had 
reported worst overall G3 or greater toxicity rates of 83%. GU/GI G3 or greater toxicity rates were 21%, 
dermatologic G3 or greater toxicity rates were 23% and hematologic G3 or greater toxicity rates were 
58% 4.  
 
To ensure an LET-optimized IMPT-based CRT approach is not overly toxic, we will monitor physician-
assessed toxicity using the Bayesian optimal phase 2 (BOP2) design 28. Specifically, let 𝑛𝑛 denote the 
interim sample size and 𝑁𝑁 denote the maximum sample size. Let 𝑝𝑝𝑡𝑡𝑡𝑡𝑡𝑡 denote the probability of G4 or 
greater toxicity and define the null hypothesis 𝐻𝐻0: 𝑝𝑝𝑡𝑡𝑡𝑡𝑡𝑡> 0.5, representing that the treatment is too 
toxic. We will stop enrolling patients and inspect the safety data for possible trial termination if 
𝑃𝑃𝑃𝑃(𝑝𝑝𝑡𝑡𝑡𝑡𝑡𝑡≤0.5 ∣𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑) < 𝜆𝜆(𝑛𝑛
𝑁𝑁)𝛼𝛼, 
where 𝜆𝜆 and 𝛼𝛼 are design parameters optimized to minimize the chance of incorrectly claiming that a 
safe treatment is unacceptable under the alternative hypothesis 𝐻𝐻1: 𝑝𝑝𝑡𝑡𝑡𝑡𝑡𝑡= 0.3, while controlling the 
type I error rate at 0.1 (i.e., the chance of incorrectly claiming that an overly toxic treatment is 
acceptable is no more than 10%). Assuming a Beta (0.5,0.5) prior distribution for 𝑝𝑝𝑡𝑡𝑡𝑡𝑡𝑡, the above 
decision rule corresponds to the following stopping boundaries: 
 
 
 
 
Table 3: Optimized stopping boundaries 
 
# patients treated Stop if # toxicity >= 
10 
7 
20 
11 
30 
14 
40 
16 
 
Based on Table 3, we perform the interim analysis when the number of enrolled patients reaches 10, 20, 
30. When the total number of patients reaches the maximum sample size of 40, we reject the null 
hypothesis and conclude that the treatment is acceptable if the number of toxicities are less than 16; 
otherwise we conclude that the treatment is unacceptable. We anticipate we will have to enroll 48 
patients to have 40 evaluable patients for this analysis.  
Below in Table 4 are the operating characteristics for the safety monitoring based on 10000 simulations 
using the BOP2 web application, which is available at http://www.trialdesign.org. 
 
Table 4: Operating characteristics 
 
Toxicity rate Early stopping (%) Claim acceptable (%) Sample size 
0.5 
72.70 
7.31 
26.7 
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0.4 
30.55 
42.83 
34.9 
0.3 
4.93 
87.57 
39.1 
0.2 
0.17 
99.57 
40.0 
0.1 
0.00 
100.00 
40.0 
 
 
7.4.2 
Secondary Clinical Endpoints:   
 
• 
Secondary Endpoint #1: To assess the feasibility of enrolling patients on a prospective trial 
delivering LET-optimized IMPT for newly diagnosed, non-metastatic anal cancer. 
o We will assess accrual at 24 months after the study open to determine feasibility of enrolling 
40 patients and obtaining insurance approval for IMPT treatment over the planned  9 years.  
 
• 
Secondary Endpoint #2: To develop guidelines and workflow to create and deliver anal canal 
cancer treatments using LET-optimized IMPT. 
o We will present the results of our workflows in a descriptive manner.  
 
• 
Secondary Endpoint #3: To evaluate complete response rate at 12 weeks and 24 weeks post-
treatment. 
o Complete response will be defined as no evidence of disease by physical exam, 
endoscopy and cross-sectional imaging. 
o Complete response will be reported at 12 and 24 weeks post-treatment as determined 
clinically by physical exam, endoscopic examination and imaging.   
 
• 
Secondary Endpoint #4: To evaluate local progression-free survival, distant metastasis-free 
survival and overall survival at 24 and 48 months.  
o Patients will follow up with their treating physician at every 3-6 months per the current 
standard of care MD Anderson gastrointestinal center follow-up algorithm (Table 2).  
o Local Failure/Progression: Either recurrence of disease in the anal canal following 
clearance, progression of disease in the anal canal after completion of treatment or 
persistence of disease in the anal canal for more than 6 months after completion of 
treatment.  
o Distant Metastatic Failure: the appearance of distant metastatic disease.  
o Disease-Free Survival: measured as time to locoregional failure, appearance of distant 
metastases or death due to any cause.  
o Overall Survival: measured as time due to death due to any cause.  
 
We will estimate LPFS, DMFS, and OS from time of enrollment using the Kaplan-
Meier method and report estimates with appropriate 95% confidence intervals. 
 
For local and regional failure, the date of failure will be recorded as 6 months 
after the completion of treatment in the case of persistent, biopsy-proven 
disease after 6 months status-post completion of all therapy.  
 
• 
Secondary Endpoint #5: To evaluate rates of patient-reported acute toxicity, function, distress 
and QOL at 12 weeks post-treatment.  
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• 
PRO-CTCAE will be collected weekly during treatment and also at the 12 week post-
treatment follow up visit 
• 
EQ-5D will be collected at baseline and also at the 12 week post-treatment follow-up visit 
• 
The EORTC QLQ- C30will be collected at baseline and also at the 12 week post-treatment 
followup visit 
• 
Treatment-Related Stress Questionnaire and the Perceived Stress Scale will be collected at 
baseline and also at the 12 week post-treatment followup visit 
• 
For female patients:  
o Female Sexual Function Index (FSFI)- 19 question survey validated in cancer survivors 
will be collected at baseline and also at the 12 week post-treatment followup visit.  
• 
For male patients: 
o International Index of Erectile Function Questionnaire (IIEF) will be collected at 
baseline and also at the 12 week post-treatment followup visit 
• 
For patient-reported acute toxicity, function, distress and QOL instruments, we will graph 
and summarize the distributions of scores for each instrument over time noting how many 
patients have data at each time point. We will analyze the changes over time using mixed 
effects linear models. 
 
• 
Secondary Endpoint #6: To evaluate rates of patient-reported late toxicity, function, distress and 
QOL every 6 months for 24 months. 
• 
PRO-CTCAE, EQ-5D, EORTC QLQ-C30, treatment-related stress questionnaire, perceived 
stress scale, female sexual function index, and international index of erectile function 
questionnaire will be collected every 6 months following treatment until 24 months post-
treatment. 
• 
For patient-reported acute toxicity, function, distress and QOL instruments, we will graph 
and summarize the distributions of scores for each instrument over time noting how many 
patients have data at each time point. We will analyze the changes over time using mixed 
effects linear models. 
 
• 
Secondary Endpoint #7: To evaluate the value of proton therapy by comparing Time-Driven Activity-
Based Costing data from the date of consultation until the date of the 12-week follow up visit post-
treatment with contemporary controls treated with VMAT.  
o TDABC data will be collected for the entire acute episode of care from the date of 
consultation until the 12-week follow up post-treatment for all patients using previously 
generated departmental process maps. Costs will be tabulated as either treatment or 
toxicity-management related.  
We will then compare these TDABC data with contemporary controls treated with VMAT (as 
described above) treated during the same fiscal year. 
 
7.4.3 
Exploratory Endpoints:   
 
• 
Exploratory Endpoint #1: To compare dose to the pelvic bone marrow, bowel, bladder and 
genitalia between LET-optimized IMPT, traditionally optimized IMPT and VMAT.  
o Dosimetric studies will be performed comparing the doses from plans generated using 
the techniques described above.  
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o We will record dosimetric differences between conventionally optimized (RBE = 1.1) 
IMPT plans and LET-optimized IMPT plans for analysis using the Wilcoxon rank-sum test. 
We will also record how often the LET-optimized IMPT plan is chosen by the treating 
physician over the conventionally optimized (RBE = 1.1) IMPT plan.  
 
• 
Exploratory Endpoint #2: To assess rates of leukopenia, neutropenia and lymphopenia at 12-
weeks post-treatment for patients treated with LET-optimized IMPT and compare to 
contemporary controls treated with VMAT.  
o We will compare the on-treatment blood count nadirs for patients treated with LET-
optimized IMPT with matched historical controls treated with VMAT (as described 
above). Continuous variables will be compared using a Wilcoxon-Rank-Sum test and 
corresponding p-values will be reported.  
 
• 
Exploratory Endpoint #3: To correlate white blood cell counts (WBC), absolute neutrophil counts 
(ANC) and absolute lymphocyte counts (ALC) with dose to the pelvic bone marrow for patients 
treated with LET-optimized IMPT.  
o For each patient treated with LET-optimized IMPT, mean bone marrow dose and bone 
marrow V10 will be correlated with WBC, ANC and ALC nadir using the Spearman rank 
correlation coefficient to evaluate for correlation.  
 
• 
Exploratory Endpoint #4: To encourage optional co-enrollment on study 2014-0543 so that 
tumor DNA, rectal microbiome and MRI imaging-based biomarkers can be assessed for patients 
receiving LET-optimized IMPT and compared with other patients enrolled on 2014-0543 receiving 
VMAT-based radiation.   
o Data from tumor swabs, tumor brushings and rectal swabs will be evaluated on 2014-
0543 to identify mutations in cancer related genes enriched during the course of 
chemoradiation. Changes in tumor gene mutations are also correlated with protein 
phosphorylation status. Additionally, shifts in the microbiome occurring during the 
course of chemoradiation in the rectal flora. 
o Data from patients coenrolled on 2014-0543 receiving LET-optimized IMPT will be 
compared with patients enrolled on 2014-0543 only who receive VMAT-based 
chemoradiation.  
o We will use descriptive statistics and graphical methods illustrate genomic mutations 
and rectal flora from baseline at each assessment during chemoradiation (week 1, 3 and 
5). 
 
 
 
 
 
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9.0 
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