Research Organization Document Section 1

***Your topic must be approved by the instructors before you can begin working on this
assignment. The purpose of this document is to organize your ideas and keep in mind the key
research components as you begin working through your research. Please refer to this document
often so that you remember the key questions you are answering and to update the research
components as you research them. First, you will outline the 3 key components to selecting a
research topic: a problem that needs to be solved, evidence of gap in the literature (a summary of
different journal articles that support a similar topic or a journal article that says further research
should be conducted on the topic you are interested in researching), an active “references” page
that you update continuously to keep track of your research information. For the “problem that
needs to be solved section,” you need to decide what the problem is for your research. This
includes addressing a set of 5-7 questions that you need to refer to often in your research to make
sure that you are staying on topic. Key questions should be your active research questions. When
you have finished writing your research paper, you reader should be able to address and answer
these questions easily. Now that you have identified your problem, you need to demonstrate that
there is a gap in the literature and therefore, a need for a topic to be researched. You will use
your outside resources to demonstrate that there is a gap in the literature. Refer back to your
literature gap assignment and follow that same process here.

**It’ important to differentiate between a topic that hasn’t been researched and a topic that
shouldn’t be researched. Not all topics that haven’t been researched should be. The “references
to support your research section” should include all of the references you have used for your
research in AMA formatting. Use this as a place to keep track of your articles and update this
often as you get into your research. Finally, you will indicate the title of your official research
topic. This may change as you begin your research so it is important that you keep your topic
updated so that the instructor may track your progress through the research paper progression.
For most groups, this information was decided in the conference call with the instructor so it
should be easy to answer these questions. All data, supporting research, drafts, outlines ect., will
be kept in OneDrive. Each group will have their own OneDrive folder to house all of this data
and keep it in one place. Throughout the development of your paper, instructors will review your
folder to make sure you are on track so it’s important that all of your resources be located there.
Instructors may periodically check-in on your data collection process, so it is ESSENTIAL that
all documents are labeled accurately and appropriately in OneDrive.

Problem that needs to be solved

Head and neck patients are frequently replanned in intensity modulated proton therapy (IMPT)
due to setup variation, particularly with shoulder positioning. However, replans are time
consuming and unsettling for patients. How can we generate robust plans to minimize the impact
of range uncertainties, thereby reducing the need for replanning?

Key questions that need to be answered

1. What is the relationship between replans (yes or no) and number of beams?
2. What is the relationship between replans and beam arrangement?
3. What is the relationship between replans and initial approved CTV coverage (%)
4. What is the relationship between replans and initial plan CTV high robustness %?
5. What is the relationship between replans and presence of dental fillings?
6. What is the relationship between replans and verification CTV coverage that prompt
replans? Does this coverage align with worst robustness accepted initially or does it fall
below?
Evidence of gap in literature

Liang et al¹ established dosimetric advantage of proton pencil beam scanning (PBS) over
photon volumated arc therapy (VMAT) for bilateral oropharyngeal cancer with increased sparing
of critical structures. However, little is known about optimal field arrangement for PBS.
Contributors note the need for further research examining 3 field proton pencil beam scanning
plans in clinical application.

Malyapa et al² found a clear link between number of beams and plan robustness. Data
comparing 1-field, 2-field, and 4-field treatment plans demonstrate the advantage of multi-field
treatments as more robust than single field. While the study establishes the benefit of a multiple
field planning approach compared to a single field approach specifically, a gap remains as to
what number of beams is optimal and how avoidance of anatomical boundaries, such as
shoulders, impacts plan robustness.
 Evans et al³ assessed 50 head and neck intensity modulated proton therapy (IMPT)
weekly verification CT plans to identify the reasons for replan as well as ideal timing for replan.
Main factors which influenced the decision to replan included decreased target coverage and
increased dose to organs at risk (OAR). As patients moved through a 5 week treatment course,
the likelihood of replan increased each week. Thirty-six percent of the patients studied received a
re-plan during this time period. Trends in the research showed 4-field beam arrangements
resulted in increased replans compared to 3-field arrangements. However, there has not been
further investigation to compare updated planning techniques and beam arrangement impact on
plan robustness.

Yeh et al⁴ discussed the need for adaptive replanning for head and neck cancer patients
treated with intensity modulated proton therapy (IMPT). The sensitive nature of protons to tissue
depth creates the need for constant CT verification of anatomical changes. Data showed 90% of
head and neck plans failed to maintain initial dose constraints over treatment course and required
replanning. However, no further investigation has been done on cases that did manage to
maintain initial dose constraints without replan. Here is where our topic of interest lies; what
planning techniques enabled this plan to “hold up” through anatomical variation throughout the
course of the treatment when others could not? How can we reproduce these plans to decrease or
eliminate the need for replanning altogether?

References to support research

1. Fakhry C, Cohen E. The rise of HPV-positive oropharyngeal cancers in the United States.
Cancer Prev Res. 2014;8(1):9-11. http://dx.doi.org/10.1158/1940-6207.capr-14-0425
2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7-
34. http://dx.doi.org/10.3322/caac.21551
3. Sharma S, Zhou O, Thompson R, et al. Quality of life of postoperative photon versus
proton radiation therapy for oropharynx cancer. Int J Part Ther. 2018;5(2):11-17.
http://dx.doi.org/10.14338/ijpt-18-00032.1
4. Wu RY, Liu AY, Sio TT, et al. Intensity-modulated proton therapy adaptive planning for
patients with oropharyngeal cancer. Int J Part Ther. 2017;4(2):26-34.
http://dx.doi.org/10.14338/ijpt-17-00010.1
5. Leeman JE, Romesser PB, Zhou Y, et al. Proton therapy for head and neck cancer:
expanding the therapeutic window. Lancet Oncol.
2017;18(5).http://dx.doi.org/10.1016/s1470-2045(17)30179-1
6. Frank SJ, Blanchard P, Lee JJ, et al. Comparing intensity-modulated proton therapy with
intensity-modulated photon therapy for oropharyngeal cancer: The journey from clinical
trial concept to activation. Semin Radiat Oncol. 2018;28(2):108-113.
http://dx.doi.org/10.1016/j.semradonc.2017.12.002
7. Moreno AC, Frank SJ, Garden AS, et al. Intensity modulated proton therapy (IMPT) –
The future of IMRT for head and neck cancer. Oral Oncol. 2019;88:66-74.
http://dx.doi.org/10.1016/j.oraloncology.2018.11.015
8. Lupu-Plesu M, Claren A, Martial S et al. Effects of proton versus photon irradiation on
(lymph)angiogenic, inflammatory, proliferative and anti-tumor immune responses in head
and neck squamous cell carcinoma. Oncogenesis. 2017;6(7):354.
http://dx.doi.org/10.1038/oncsis.2017.56
9. Zhang J, Nguyen D, Woods K, et al. SU-F-T-186: A treatment planning study of normal
tissue sparing with robustness optimized IMPT, 4Pi IMRT, and VMAT for head and neck
cases. Med Phys. 2016;43(6Part15):3504-3504. http://dx.doi.org/10.1118/1.4956323
10. Yeh B, Georges R, Zhu X, et al. Adaptive replanning is required during intensity
modulated proton therapy for head-and-neck cancers. Int J Radiat Oncol Biol Phys.
2012;84(3):S56-S57. http://dx.doi.org/10.1016/j.ijrobp.2012.07.354
11. Evans J, Mundy D, Anand A, et al. Optimal timing of computed tomography verification
treated in spot scanning intensity-modulated proton therapy for head and neck cancers.
Int J Radiat Oncol Biol Phys. 2017;99(2):E336-E337.
http://dx.doi.org/10.1016/j.ijrobp.2017.06.1404
12. Langen K, Zhu M. Concepts of PTV and robustness in passively scattered and pencil
beam scanning proton therapy. Semin Radiat Oncol. 2018;28(3):248-255.
http://dx.doi.org/10.1016/j.semradonc.2018.02.009
13. Van Dijk L, Steenbakkers R, Ten Haken B, et al. Robust intensity modulated proton
therapy (IMPT) increases estimated clinical benefit in head and neck cancer patients.
PloS One. 2016;11(3): e0152477. http://dx.doi.org/10.1371/journal.pone.0152477.
 14. Blakey M, Price S, Robison B, et al. SU-E-J-78: Adaptive planning workflow in a pencil
beam scanning proton therapy center. Med Phys. 2015;42(6Part8):3282-3282.
http://dx.doi.org/10.1118/1.4924165
15. Wei L, Frank S, Xiaoqiang L, et al. Effectiveness of robust optimization in intensity-
modulated proton therapy planning for head and neck cancers. Med Phys. 2013;40(5):
051711. http://dx.doi.org/10.1118/1.4801899
16. Stützer K, Lin A, Kirk M, Lin L. Superiority in robustness of multifield optimization over
single-field optimization for pencil-beam proton therapy for oropharynx carcinoma: an
enhanced robustness analysis. Int J Radiat Oncol Biol Phys. 2017;99(3):738-749.
http://dx.doi.org/10.1016/j.ijrobp.2017.06.017
17. Malyapa R, Lowe M, Bolsi A, Lomax AJ, Weber DC, Albertini F. Evaluation of
robustness to setup and range uncertainties for head and neck patients treated with pencil
beam scanning proton therapy. Int J Radiat Oncol Biol Phys. 2016;95(1):154-162.
http://dx.doi.org/10.1016/j.ijrobp.2016.02.016

Finalized Research Topic

What dosimetric factors contribute to proton oropharyngeal replanning? How can we limit the
need to replan?

Research approach Section 2: The next section of your research organization document
contains your research template to follow as you begin your data collection. This section will
change often but it will help you to follow your goals closely as you progress.

Basic Study Components

1. Do any group members need to obtain IRB approval? (To determine if you need IRB
approval from your clinical site to conduct research, ask your clinical preceptor. The
preceptor should be aware of the protocol for your site or will be able to direct you to the
correct resource. If you DO need IRB approval you will most likely need to prepare a
formal research proposal and submit to the IRB.) No

2. Will your study by prospective or retrospective? retrospective

3. Number of patients for data collection - 27

4. Type of study (Ex: Comparison of planning techniques, comparison of OAR ect) -
Planning comparison of beam number, arrangement, accepted CTV coverage, presence of dental
work, and robustness curve values with replan frequency

5. Roles of each group member (members may have multiple roles)

Group Leader (someone who will keep the group on track, make sure group members are
adhering to deadlines, be the direct point of contact for the instructor with overall
questions, update the research organization document throughout the course of research) -
Felicia

Data Collector(s) (someone who will be doing the data collection and data reporting in
excel; maintaining journal entries) - Noelle

Data Analysis (someone who will be responsible for analyzing the raw data, running any
statistical tests and providing conclusive data for the writer) - Noelle

Writer (someone who is responsible for writing the outline (later in the course) and the
paper; usually the best writer of the group takes this role) - Felicia

Editor (someone who is responsible for checking each draft for errors and providing
feedback and corrections to writer) - Noelle

**The roles must be assigned in such a way that all of the work is divided equally. For example,
if 2 of 3 group members are data collectors, the 3rd group member should be the writer. Only 1
group member can write the paper so that the tone of paper is consistent. Because the writing is
such a large part of the research paper, the writer should have a smaller part in the other aspects
of the research paper.

Data Collection Details

1. How many clinical sites will you be collecting data from? Single site

Data will be collected from a single proton center site.

2. What information are you interested in (if a planning study, list structures for
evaluation; if a study survey, list your study questions)?
  Relationship between replans (yes or no) and number of beams
 Relationship between replans and beam arrangement
 Relationship between replans and initial approved CTV coverage (%)
 Relationship between replans and initial plan CTV high robustness %
 Relationship between replans and presence of dental fillings?
 Relationship between replans and verification CTV coverage that prompt replans?
 Does this coverage align with worst robustness accepted initially or does it fall below?

What are your inclusion criteria?

The study includes bilateral head and neck oropharynx plans including base of tongue and
tonsilar cancers. The plans were treated between 5/01/2018 and 5/01/2019. Planning techniques
include the proton facility’s traditional 3 or 4 beam arrangement. The patients in the study must
have also received weekly verification CT scans for the duration of treatment. The CTV volumes
include a high and low risk volume.

Exclusion criteria? The study excludes unilateral head and neck treatments, nasopharynx
cancers, and bolus helmet plans. It also excludes non-traditional beam arrangements and plans
with less than 3 fields or more than 5 fields.

4. How will you limit the number of variables in your study? (For example, if you are doing
a planning study, only 1 person should be doing the planning to eliminate the variables.)

 Gathering data from one single institution will eliminate major variables in planning and
atypical beam arrangements for bilateral oropharynx head and neck patients. Collecting
data from the past year will include the most up-to-date planning techniques at the proton
center
 Exclusion of variable CTV volumes and locations
 Exclusion criteria such as untraditional beam arrangements as well as the number and
location of high risk/low risk volumes

5. Read through Chapter 20 in your textbook. Are you interested in completing a statistical
analysis on this data? If so, what parameters will you be analyzing? (p-value, mean, t-test
ect.). (Keep in mind that anything beyond the test listed might be required for your paper.
The UWL stats center is an excellent resource for students need a more complex statistical
analysis. If you don’t know if you should do a more in-depth analysis, reach out to the stats
center and they will be able to provide you with insight. It is also important to note that
statistical analysis of any kind will add robustness and validity to your research study!)
Why do you think that those metrics will be best for your topic? A correlation analysis is
necessary because we want to determine if the two variables in beam arrangement have a
connection. Inferential statistical analysis, including a t-test will allow us to distinguish a
clear difference in results between beam number groups. These differences enable us to
isolate which group is advantageous in robustness. The greater the calculated size of
difference (t-value), the greater the evidence that there is a significant difference.

 Fisher’s exact tests were used to determine if number of re-plans (0, 1, or 2) is associated
with beam, CTV coverage, or the presence of dental fillings or implants for patients
under treatment with proton radiation therapy for head and neck cancer
 Logistic regression modeling was used to verify if the occurrence of a re-plan (Yes or
No) was related to the initial approved high CTV coverage (95% of vol. receives this
dose or more) or the initial plan CTV high robustness curve (D95%). A 5% level of
significance was used for each test
 Statistical analysis was performed using R (R Core Team, 2019).

6. Where will you house your data? (Excel ect., this will all be housed in OneDrive).

 One Drive, excel

7. How will you anonymize your patients? (It is often necessary to transfer data sets or
patient information between group members. It is VERY IMPORTANT that you respect
HIPPA protocols! If you need to transfer data sets between facilities, we can assist you
through ProKnow. If you simply need to transfer data using a spreadsheet, you must
anonymize the patient information. It is up to you to decide how to do this).

 Anonymous spreadsheet
 Anonymize scans through MIM software, export structure set, plan, and CT scan to One
Drive

8. What resources (in addition to the literature search) are available for you to use?
  Proton dosimetrist
 Physicist
 UW-L statistics
 Research advisor and instructor

9. Previous research study that will be used for data analysis (ex: RTOG study
constraints): No prior study

10. List a loose weekly deadline for your data collection. (If you want to add writing
deadlines as well, feel free. However, paper due dates will be assigned in Research II and
Research III). It is very easy to be overwhelmed with this project, therefore, it is
ESSENTIAL that you set yourselves up for success and set deadlines within your group to
stay on track. We cannot set the deadlines for you because every project develops at a
different rate and with differing complexities. Based on your deadlines, we will setup
conference calls with each group to check-in. Remember that this project will continue
from now until graduation. You will get busy with other courses and clinicals therefore, it’s
essential to lay the foundation for success with this project. May 29 - June 2: Work on
research organization, talk with site about collection, statistics, and image sharing methods.
Make a spreadsheet.

 June 3- 9: Enter patient data into spreadsheet and upload into one drive, work on outline I
June 10 – 16
 Finalize outline 1
o 1. Have subsections divided with generalized information June 17 –23
o Finalize outline 2
 Group feedback on outline 2
 June 24 - 30: Finalize outline 3
 July 1 - July 7: Finalize outline 4
 August: finalize research
 September: dive further into discussion of results