Shelby Wingold, Shahad Al-Ward, Trevor Moe

Research Proposal
Working Title:
Evaluation of normal tissue complication probability to organs-at-risk when treating rectal
cancer patients with 3DCRT versus VMAT.

Problem Statement:
The problem is the paucity of literature of NTCP OAR values for rectal cancer radiotherapy

Purpose Statement:

The purpose of the study is to compare VMAT to 3DCRT and evaluate the radiobiological
outcome for rectal cancer patients.

Hypotheses Statements:
H1A: The first research hypothesis (H 1) is that treating rectal patients with VMAT will have an
average difference greater than 0 in NTCP values in the bowel bag (µ d<0), when compared to
3DCRT.
H10: The first null hypothesis (H1 0) is that treating rectal patients with VMAT will not have an
average difference greater than 0 in NTCP values in the bowel bag (µd=0) when compared to
3DCRT.
H2A: The second research hypothesis (H1) is that treating rectal patients with VMAT will have an
average difference greater than 0 in NTCP values in the bladder (µ d<0), when compared to
3DCRT.
H20: The second null hypothesis (H10) is that treating rectal patients with VMAT will not have an
average difference greater than 0 in NTCP values in the bladder (µd=0) when compared to
3DCRT.
H3A: The third research hypothesis (H1) is that treating rectal patients with VMAT will have an
average difference greater than 0 in NTCP values in the femoral heads (µ d<0), when compared to
3DCRT.
H30: The third null hypothesis (H1 0) is that treating rectal patients with VMAT will not have an
average difference greater than 0 in NTCP values in the femoral heads (µd=0) when compared to
3DCRT.
H4A: The fourth research hypothesis (H1) is that treating rectal patients with VMAT will have an
average difference greater than 0 in NTCP values in the cauda (µ d<0), when compared to
3DCRT.
H40: The fourth null hypothesis (H10) is that treating rectal patients with VMAT will not have an
average difference greater than 0 in NTCP values in the cauda (µd=0) when compared to
3DCRT.
Shelby Wingold, Shahad Al-Ward, Trevor Moe

H5A: The fifth research hypothesis (H 1) is that treating rectal patients with VMAT will have an
average difference greater than 0 in NTCP values in the spinal canal (µ d<0), when compared to
3DCRT.
H50: The fifth null hypothesis (H10) is that treating rectal patients with VMAT will not have an
average difference greater than 0 in NTCP values in the spinal canal (µd=0) when compared to
3DCRT.

Summary:

Colorectal cancer ranks as the third most frequently diagnosed cancer among both men
and women in the United States. According to the American Cancer society, it is predicted that
in 2024, there will be approximately 46,220 new cases of rectal cancer (27,330 in males and
18,890 in females).1 Given the prevalence of colorectal cancer, it is imperative when deliberating
radiotherapy treatment options that limiting radiation dose to normal tissue is considered. As
radiation therapy is a treatment option for colorectal cancer patients, different techniques can be
employed for external beam photon treatment. Techniques used for radiotherapy treatment of
colorectal cancer include Three-Dimensional Conformal Radiation Therapy (3DCRT), Intensity
modulated radiation therapy (IMRT), and Volumetric Modulated Arc Therapy (VMAT). VMAT
allows for simultaneous motion of MLCs and gantry to help modulate the beam; which results in
increased conformality and decreased dose to Organs-At-Risk (OARS) when compared to
3DCRT.2 When performing treatment planning, dose constraints to OARs can be evaluated from
dose volume histograms (DVHs). OARs involved with treating rectal cancer patients with
radiation therapy include bowels, sigmoid colon, bladder, femoral heads, cauda and spinal cord.
Dose constraints for treating patients with radiation therapy are provided by QUANTEC. 3
Evaluating the probability of these toxicity end points allows us to understand the consequences
of exceeding dose limits to OARs and provides a baseline to keep dose to OARs as low as
reasonably achievable.
Marks at al have highlighted how DVHs notoriously ignore the overall 3D dose
distribution of the treatment plan. Moreover, taking single points on the DVH graph (e.g: V20,
V30) to evaluate the acceptability of a certain plan ignores the 3D dose distribution.4 Given this,
Marks et al have emphasized the significance of using Normal Tissue Complication Probability
(NTCP) values in the clinic along with values from QUANTEC. A recent study by Barbara et al
has evaluated the toxicities related with cervical cancer, but this study did not evaluate NTCP
values.5 Use of NTCP allows us to evaluate the radiobiological impact when using 3DCRT vs
VMAT plans for colorectal radiotherapy treatments. However, a recent review article by Yorke
et al has emphasized the need to refine NTCP models and gather detailed data for patients treated
with radiation therapy.6 A prospective study by Urban et al has reported gastrointestinal (GI)
toxicities to cervical cancer patients receiving VMAT, IMRT, and 3DCRT. The study concluded
that patients receiving 3DCRT reported significantly worse GI outcomes than those who
received VMAT or IMRT.7 Our group anticipates similar outcomes with colorectal patients.
Shelby Wingold, Shahad Al-Ward, Trevor Moe

To our knowledge, no group has performed a computational radiobiological comparison

for rectal cancer radiotherapy patients receiving VMAT versus patients receiving 3DCRT. Tai et
al have compared NTCP values between IMRT and 3DCRT for head and neck patients. The
study has found that IMRT was superior to 3DCRT when it comes to reducing NTCP to head
and neck OARs. The study, however, has not investigated GI or pelvic patients. 8 In addition, a
study by Pedersen et al has evaluated NTCP values for rectal and urinary morbidity for prostate
cancer patients. However, this study was performed for proton therapy which has different
radiobiological properties than photon therapy.9
The problem is the paucity of literature for NTCP OAR values for rectal cancer
radiotherapy using 3DCRT versus VMAT. Evaluating these NTCP values can demonstrate the
theoretical radiobiological effects on OARs for colorectal radiotherapy treatments. The purpose
of the study is to compare VMAT to 3DCRT and evaluate the calculated (or predicted)
radiobiological outcome for rectal cancer patients. Currently, there is no defined metric for a
clinically relevant reduction in NTCP values. However, Tai et al, 8 Pederson et al9 and Mazonakis
et al12 have provided p-values to test the significance of NTCP reductions. Our group has
followed a similar pathway for quantifying the reduction in NTCP values for rectal cancer OARs
by using the average difference in NTCP values between planning methods. Researchers tested
hypotheses that using VMAT planning over 3DCRT planning will have an average difference
greater than 0 in NTCP values to OARs of rectal cancer radiotherapy. These OARs include the
bowels (H1A), sigmoid colon (H2A), bladder (H3A), femoral heads(H4A), cauda (H5A), and spinal
canal (H6A). Researchers used the Layman-Kutcher-Burman model (LKB) to calculate NTCP
values for rectal RT OARs.10 Parameters for the model calculations were taken from Luxton et
al.11

References

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http://doi.org/10.1259/bjr.20201289.
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1552. http://doi.org/10.1007/s11547-023-01705-7
Shelby Wingold, Shahad Al-Ward, Trevor Moe

6. Yorke E. Modeling clinical outcomes in radiotherapy: NTCP, TCP and the "TECs". Med
Phys. 2023;50 Suppl 1:122-124. http://doi.org/10.1002/mp.16274.
7. Urban R, Wong J, Lim P, et al. Cervical cancer patient reported gastrointestinal
outcomes: intensity/volumetric modulated vs. 3D conformal radiation therapy. J Gynecol
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complication probability models for prospectively scored late rectal and urinary
morbidity after proton therapy of prostate cancer. Phys Imaging Radiat Oncol.
2021;20:62-68. Published 2021 Nov 8. http://doi.org/10.1016/j.phro.2021.10.004
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(NTCP) as a function of equivalent uniform dose (EUD). Phys Med Biol. 2008;53(1):23-
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12. Mazonakis M, Kachris S, Tolia M, Damilakis J. NTCP Calculations of Five Different
Irradiation Techniques for the Treatment of Thymoma. Curr Oncol. 2023;30(8):7740-7752.
Published 2023 Aug 19. doi:10.3390/curroncol30080561