Half-Field Volumetric Modulated Arc Therapy for Multileaf Collimator Leakage Reduction and Dosimetric Impact in Large Irradiated Field

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Doctoral Thesis in

Medical Sciences

Half-Field

Volumetric Modulated Arc

Therapy

for

Multileaf Collimator

Leakage

Reduction and Dosimetric Impact

in Large Irradiated Field

Graduate School of Ajou University

Department of Medical Sciences

Half-Field

Volumetric Modulated Arc

Therapy

for

Multileaf Collimator

Leakage

Reduction and Dosimetric Impact

in Large Irradiated Field

Young-Taek Oh, M.D., Ph.D., Advisor

I submit this thesis as the

Doctoral thesis in Medical Sciences.

February 2020

Graduate School of Ajou University

Department of Medical Sciences

The Doctoral thesis of Hyunsoo Jang in Medical Sciences

is hereby approved.

Thesis Defense Committee Chair

Mison Chun Seal

Member O Kyu Noh Seal

Member Hae-Jin Park Seal

Member Sunyoung Lee Seal

Member Young-Taek Oh Seal

Graduate School of Ajou University

-ABSTRACT-

Half-Field

Volumetric Modulated Arc Therapy

for

Multileaf

Collimator

Leakage Reduction and Dosimetric Impact

in Large Irradiated Field

Background:

Although there are some controversies regarding whole pelvic radiation

therapy (WPRT) due to its gastrointestinal toxicities, it is combined with other systemic

treatment to find an effective strategy for patients with gynecological, rectal, and prostate

cancer. To effectively spare organ at risk (OAR), doses using multileaf collimator’s optimal

segments and volumetric modulated arc therapy (VMAT) using a half-beam technique (HF)

were implemented for WPRT.

Methods and Materials:

Dosimetric benefits of HF-VMAT were presented with dose

conformity and dose volume parameters in terms of modulation complex score, as

compared to VMAT optimized using a fully opened field (FF).

The size of the FF was

decided to entirely include a planning target volume plus a 3-mm margin in all beam’s eye

view at arc angles. Half of the FF from the isocenter was opened for dose optimization in

HF-VMAT. Consequent normal tissue complication probabilities (NTCPs) by reduction of

the irradiated volumes and delivered doses for OAR were evaluated

Results: Compared to FF-VMAT, HF-VMAT showed superior conformal dose distribution

where the 75% isodose line compactly surrounded the separated regional lymph nodes.

Dose conformity was comparable between VMAT and FF-VMAT, however,

HF-VMAT used 60%-70% less intensity modulation than that used by FF-HF-VMAT. The small

intestine and colon showed noticeable reduction in the irradiated volumes of up to 35%

and 15%, respectively, at an intermediate dose of 20-45 Gy. The small intestine showed

statistically significant dose sparing at the volumes that received a dose every 5 Gy from

15 to 45 Gy. Such a dose reduction for the small intestine and colon in HF-VMAT

presented significant NTCP reduction than that in FF-VMAT.

of multileaf collimator segments to deliver conformal doses without excessive intensity

modulation. It achieved distinguishable dose sparing for gastrointestinal OAR in WPRT

without sacrificing the target dose conformity. HF-VMAT can be useful in reducing OAR

toxicities associated with WPRT.

Keyword: whole pelvic radiotherapy, volumetric modulated radiation therapy, half-beam

TABLE OF CONTENTS

ABSTRACT ···i

TABLE OF CONTENTS ···iii

LIST OF TABLES ···iv

LIST OF FIGURES ···v

I. INTRODUCTION ···1

II. MATERIALS AND METHODS ···3

A. Patient selection and simulation

···3

B. Target delineation

···

5

C. Volumetric modulated arc therapy planning

···5

D. Analysis of dosimetric factors

···7

E. Beam complexity of volumetric modulated arc therapy plans

···9

F. Dose homogeneity evaluation

···10

G. Statistical analysis

···10

III.RESULTS ···11

A. Normal organ dosimetry ···11

1. Small bowel

···12

2. Bladder

···14

3. Colon

···16

4. Rectum

···18

B.

Normal tissue complication probability

···20

C. Target coverage ···22

D. Modulation index ···24

IV. Discussion

···25

REFERENCES

···28

LIST OF TABLES

Table 1. Characteristics of patients, tumors, and treatment regimen selected for whole

pelvic radiation therapy. ···4

Table 2. Radiobiological parameters to calculate equivalent uniform dose and normal tissue

complicatin probabilities for organs at risk in whole pelvic radiation therapy···8

Table 3. Comparison of dose-volume parameters for small bowel in VMAT plans using

three different techniques. ···13

Table 4. Comparison of dose-volume parameters for bladder in VMAT plans using three

different techniques. ···15

Table 5. Comparison of dose-volume parameters for colon in VMAT plans using three

different techniques. ···17

Table 6. Comparison of dose-volume parameters for rectum in VMAT plans using three

different techniques. ···19

Table 7. Evaluation of normal tissue complication probabilities and equivalent-uniform

dose (EUD) with statistical significance. ···21

Table 8. Mean conformity number (CN) and homogeneity index (HI) according to three

plans. ···22

LIST OF FIGURES

Figure 1. Beam's eye views of three plans. (a) FF-VMAT (b) MFF-VMAT (c) HF-VMAT.

···6

Figure 2. Comparison of irradiated isodose distributions according to three plans. (a)

FF-VMAT (b) MFF-FF-VMAT (c) HF-FF-VMAT.

···11

Figure 3. The mean dose-volume histogram of small bowel.···12

Figure 4. The mean dose-volume histogram of bladder. ···14

I. Introduction

Radiation therapy (RT) is an important part of cancer treatment and is applied to various

organs and cancers (1-3). However, during RT, normal organs are exposed to radiation,

which causes various radiation induced toxicity (4). Because the side effects of RT can

cause not only the toxicity but also the total dose reduction, a delicate RT plan is needed.

Especially, more careful attention is required in the abdominal RT planning due there are

many sensitive organs in abdomen. Of abdominal organs, the radiation tolerance of small

bowel is lower than the other organs and the toxicity is fatal (5, 6). So, the dosimetry of

small bowel is important part in abdominal RT planning.

Colon and bladder have higher

radiation tolerance than small bowel. However, due to the individual difference of

radiosensitivity, toxicity can be induced at lower radiation doses (7, 8).

The whole pelvic radiotherapy (WPRT) including pelvic lymph node irradiation is

regarded as a standard treatment regimen for locally advanced gastrointestinal and

gynecological cancers (9, 10). Although WPRT can bring out clinical merits (11-15), acute

and late intestinal and urinary complications have been significant concerns (16-18).

Recently, the trend of RT is rapidly changing due to the advancement of radiation delivery

and patient fixation techniques. In particular, the utilization of

intensity modulated

radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT) is greatly increasing,

and these techniques are actively used in wide field irradiation such as WPRT (19, 20).

The important point of IMRT and VMAT techniques are dynamic movements of multileaf

collimator (MLC). And, It makes optimal dose distribution depending on gantry movement

and dose rate change. To achieve the improved organ at risk (OAR) in large and

complicated anatomical geometries, the VMAT is the useful radiation delivery method to

provide conformal dose distribution (21-23). Optimal fluence, which is created by MLC

segments at individual numerous beam angles going through the arc trajectories in VMAT,

can effectively reduce the normal organ doses.

However, when the irradiation range is widened, the MLC movement is restricted. This

leads to MLC leakage and non-blocking phenomenon, and degrades the efficiency of

IMRT and VMAT plan. The MLC leaves move in a horizontal direction when a collimator

angle is 0° in a beam’s eye view. If the OAR are placed between the separated target

volumes including lymph nodes in the same direction with the MLC movement,

suboptimal MLC segments can be created to meet the mechanical restrictions such as

gantry and MLC speed with varying dose rate (24-26). For example, one side of the MLC

can reach the target volume, however the other side cannot properly shield OAR exposure

or opens outside of the planning target volume (PTV) to deliver the prescribed dose to the

both of the two separated targets. Half field technique is possible to supplement these

problems. The use of half field in VMAT plan has attempted in RT of breast cancer, and the

dosimetric benefit was proved (27). The half field technique has also been applied to

improve lower neck coverage in head and neck cancer (28). However, there are rare studies

about the half field technique, and no study has yet been conducted in abdominal

irradiation. In present study, a VMAT planning method using a half-beam technique was

devised to provide superior normal tissue dose sparing, as well as to achieve dose

conformity for target volumes in WPRT.

II. Materials and methods

A. Patient selection and simulation

To evaluate the large and complicated irradiated field, patients with inguinal lymph node

in the irradiation field were enrolled in present study. A total of ten patients with a

diagnosis of cervical, anal, and vaginal cancer was selected.

Cervical, anal, and vaginal

cancer were 4, 4, and 2, respectively. The four patients with cervical cancer were involved

to lower 1/3 vagina. Treatment decision and radiotherapy protocol reflected

National

Comprehensive Cancer Network guidelines (29, 30). The patient and tumor characteristics

were summarized in Table 1. For cervical and vaginal cancer patients, WPRT was followed

by high-dose rate brachytherapy.

All patients underwent a computed tomography simulation in a supine position with

arms on the chest. This retrospective dosimetric study was approved by the Institutional

Review Board of the Dongguk University Medical Center (110757-201711-HR-02-01),

and informed consent in writing was obtained from individual patient. All information was

anonymous prior to analysis.

Table 1. Characteristics of patients, tumors, and treatment regimen selected for

whole pelvic radiation therapy.

No Sex/Age Origin Stage Pathology Treatment aim WPRT Prescribed Dose (Gy) Chemotherapy 1 M/59 Anus T2N0 SCC Adjuvant 50 -

2 F/75 Anus Recurrent SCC Adjuvant 50 -

3 F/78 Anus T2N1 SCC Definitive 50 FMC

4 M/88 Anus T2N0 SCC Definitive 41.4 FMC

5 F/51 Vagina T2N0 AC Definitive 45 -

6 F/61 Vagina T1N0 SCC Definitive 45 -

7 F/67 Cervix T3aN0 SCC Definitive 45 WC

8 F/71 Cervix T3bN0 SCC Definitive 45 WC

9 F/89 Cervix T3aN0 AC Definitive 45 -

10 F/86 Cervix T3aN1 SCC Definitive 45 -

WPRT, whole pelvis radiotherapy; SCC, squamous cell carcinoma; FMC, 5-fluorouracil,

mitomycin C; AC, adenocarcinoma; WC,

weekly cisplatin.

B. Target delineation

Clinical target volume (CTV) and pelvic lymph nodes were delineated according to the

consensus guidelines (31-33). Treatment volume for gynecological cancer patients includes

the tumor involving the lower third of the vagina as well as tumor bed, parametria,

uterosacral ligaments, and pelvic lymph nodes. Obturator, presacral, and internal iliac node

chains come under the pelvic lymph nodes in all cases. External and perirectal nodes are

added for gynecological and anal cancer patients, respectively. The PTV was created by

adding a 5 mm margin to the CTV. Small bowel, bladder, rectum, and femur heads, were

contoured as OAR. Each PTV received a prescribed dose of 50 Gy in 25 fractions. Dose

constraints were applied for OAR as per Radiation Therapy Oncology Group (RTOG)

protocols for each treatment site (9, 10, 32).

C. Volumetric modulated arc therapy

planning

All VMAT plans consisted of four full arcs alternately rotating clockwise and

counterclockwise in Eclipse (ver. 10.0, Varian Medical Systems, Palo Alto, CA) and the

normal tissue optimization. The collimator angles less than ± 40° were used for each arc to

improve dose conformity as well as to minimize the interleaf leakage and the

tongue-and-groove effect in VMAT. Meanwhile, dose distributions of the VMAT plans were optimized

by using different field sizes. As shown in figure 1, an optimized VMAT plan (FF-VMAT)

is created with a field size (FF) which is enough to fully cover an entire PTV, but less than

15 cm with X-jaws in consideration of the maximum leaf span of the Millenium MLC. The

opening of the FF in a superior-inferior direction was adjusted to sufficiently include the

PTV plus a margin less than 1cm. The field size was reviewed using beam’s eye views at

all different gantry angles of the arcs. A new VMAT plan (HF-VMAT) is optimized with

half size of the FF. The optimized dose was delivered by opening the half and the other

half of the FF for two arcs rotating clockwise and counter clockwise, respectively, as in

Fig.1(c). In addition, a modified field size (MFF) 2 cm reduced from the each X-jaw of the

FF is employed for a VMAT plan (MFF-VMAT) to evaluate dose conformity depending on

MLC segments and sequences. Dosimetric benefits among three VMAT plans were

analyzed, when a 95% of the PTV was covered by the prescribed dose with the same dose

constraints applied for OAR. The dose distributions for each treatment site were calculated

by Analytical Anisotropic Algorithm (ver. 10.0, Varian Medical Systems) and progressive

resolution optimizer (ver. 10.0, Varian Medical Systems).

Figure 1. Beam's eye views of three plans. (a) FF-VMAT

, an optimized VMAT plan

using a beam fully open to cover the planning target volume

(b) MFF-VMAT

, an

optimized VMAT plan using a 2-cm reduced field from each side of Jaw rather than the

fully open field used for FF-VMAT

(c) HF-VMAT,

an optimized VMAT plan using a half

beam.

D. Analysis of dosimetric factors

As the dose conformity for the PTV are comparable among the VMAT plans optimized

with different field sizes, dose sparing for OAR was evaluated with dose-volume

histogram (DVH) as well as relevant dose-volume parameters associated with estimating

complications for individual OAR.

The normal organ dosimetric parameters for small

bowel, bladder, rectum and femur head were compared according to radiotherapy planning

technique. The DVH of all plans obtained, and dosimetric parameters, such as, V

and

mean dose, were calculated from DVH. The V

was defined as the percentage volume

that received at least the dose.

Maximum (D

) and mean (D

) doses, and the dose (D

)

delivered to the most irradiated 2cc volume were analyzed for OAR. For small bowel and

colon, each volume receiving the doses from 45 Gy to 5 Gy at a dose interval of 10 Gy was

evaluated, especially including the V

regarded as an important parameter to predict

gastrointestinal toxicities (34).

Because rectum is included in the treatment volume of anal

cancer, rectal dose was analyzed in 6 patients except anal cancer.

In addition, to evaluate

the potential radiobiological impacts on OAR depending on dose distributions in WPRT,

equivalent uniform dose (EUD) and

normal tissue complication probability (NTCP) were

calculated using Emami-Burman parameters. To present the sensitivities and variability of

NTCP in terms of analytic models, Lyman-Kutcher-Burman (LKB) and EUD-based

log-logistic models were adopted (35). The effect of varying alpha-beta ratios for acute and late

complications on EUD and NTCP were discussed accordingly for individual OAR. The

alpha-beta ratios and required biological parameters to calculated NTCP were summarized

in Table 2 (35-40).

Table 2. Radiobiological parameters to calculate the equivalent uniform dose and

normal tissue complication probabilities for organs at risk in whole pelvic radiation

therapy

OAR

α/β

Endpoint

Parameters for

LKB model

Parameter for

log-logistic

model

TD

n

m

γ

Bladder

5

Late reaction

0.5

0.11

3.63

80

7.5

Shrinkage/

Ulceration

10

Acute cystitis

Small bowel

4

Ulcer/

Obstruction

0.15

0.16

2.49

55

8

Acute-

malabsorption

Colon

10

Early

reactions

0.17

0.11

3.63

55

Rectum

2.5

Late reactions

0.09

0.13

3.07

76.9

5.4

Chronic

inflammation/

Ulcer

E. Beam complexity of volumetric modulated arc therapy plans

The traveling distances between control points and segment shapes of the VMAT arcs

can affect complexity of the beam intensity modulation. The modulation complexity score

(MCS) using variabilities of leaf sequences (LSV) and segment area (AAV) was adopted to

comprehensively present the plan complexity across all segments (34). It is formulated

using equation [1] by reflecting each segment weight to the corresponding relative arc

weight,

𝑴𝑪𝑺

=

∑

∑

[(

) × (

) × (

)]

eq. [1]

The parameters of n and N mean the total number of control points per each arc and the

total number of arcs used in each VMAT plan. The LSV

and the AAV

for each control

point are calculated using Eq. [2] and [3], respectively, where m is the number of MLC

leaves which move underneath the unblocking portion of the field defined by X and Y jaws

for each control point.

𝐿𝑆𝑉

=

∑

(𝑝𝑜𝑠

− |(𝑝𝑜𝑠

_{− 𝑝𝑜𝑠}

)|)

(𝑚 − 1) × 𝑝𝑜𝑠

×

∑

(𝑝𝑜𝑠

− |(𝑝𝑜𝑠

_{− 𝑝𝑜𝑠}

)|)

(𝑚 − 1) × 𝑝𝑜𝑠

eq. [2]

𝐴𝐴𝑉

=

∑

(𝑝𝑜𝑠

_{− 𝑝𝑜𝑠}

)

𝑚 × (𝑝𝑜𝑠

_{− 𝑝𝑜𝑠}

)

eq. [3]

The

𝑝𝑜𝑠

presents the i-th leaf position of the MLC at the left bank. The

𝑝𝑜𝑠

and

𝑝𝑜𝑠

_{mean the furthest position of the MLC leaf from the isocenter among the all MLC}

leaves constituting a shape of the individual segment and across the all the control points

of an individual arc. The R denotes the MLC leaves on the right bank. Thus, while the LSV

presents variability of traveling distances of the MLC leaf sweeping the each set of control

points relative to the maximum lateral separation from the isocenter for the each side, the

AAV presents the complexity of the separation of each pair of the MLC leaves relative to

the maximum separation created among all of MLC leaves across all segments consisting

of the arc.

F. Dose homogeneity evaluation

The conformity number (CN), and homogeneity index (HI) were evaluated to know the

dose homogeneity.

The CN was defined as: CN = (V

/V

)/(V

/V

). V

is the target volume covered

by the reference isodose. V

is the total target volume, and V

is the corresponding volume

to the reference isodose (41).

The HI was defined as:

HI = √∑ (𝐷

− 𝐷

)

×

𝑇

𝑖

D

is the delivered dose to the i-th

voxel, and D

is the prescribed dose. V

is the total target volume, and v

is the

corresponding volume of i-th voxel (42).

G. Statistical analysis

To distinguish statistically significant dosimetric effects by the different planning

techniques for WPRT using VMAT,

Wilcoxon signed rank test was performed using

statistical analysis software (SPSS, version 20, SPSS Inc., Chicago, IL). The p-value less

than 0.05 were considered statistically significant.

III. Results

A. Normal organ dosimetry

When the PTV has met the same goal for the dose coverage in VMAT plans using three

different techniques, dose sparing for the bladder and the small bowel was noticeable in an

axial and a coronal view (figure 2).

Figure 2. Comparison of irradiated isodose distributions according to three plans. (a)

FF-VMAT (b) MFF-VMAT (c) HF-VMAT.

1. Small bowel

Mean small bowel dose of HF-VMAT plan was significantly lower than FF-VMAT plan

(29.57 vs 32.89, p<0.05). V30 and V40 to small bowel were also significantly lower (V30:

46.43 vs 62.38, V40: 21.44 vs 28.72, p<0.05). Although it was no statistically significant

between HF-VMAT and MFF-VMAT plan, HF-VMAT plan showed the improved

dosimetric values of small bowel. V10 to small bowel was 91.74, 91.61, and 91.76 in

FF-VMAT, MFF-FF-VMAT, and HF-VMAT plan, respectively. The small bowel presented a

13-14% reduced volume at V35 and V25

Even if the volume difference was little at V15

HF-VMAT plan brought about smaller volumes as compared to the other HF-VMAT plans. The

mean value of 10 patients according to three VMAT plans is shown in figure 3. And, more

detailed DVH values are shown in table 3.

Table 3. Comparison of dose-volume parameters for small bowel in VMAT plans

using three different techniques. The mean dose (D

), maximum dose (D

), dose

delivered to 2cc of the most irradiated organ volume (D

) were evaluated for small bowel.

Dmean (Gy) 32.89±3.69 30.68±3.57 29.57±2.28 0.005 0.005 0.074 Dmax (Gy) 55.29±0.56 55.12±34.44 55.39±4.52 0.508 0.114 0.074 D2cc (Gy) 53.91±0.84 53.89±0.29 53.74±17.01 0.169 0.760 0.445 V5 (%) 97.39±30.86 96.56±2.56 96.59±2.41 0.066 0.008 0.953 V10 (%) 91.74±5.09 91.61±5.24 91.76±5.07 0.646 0.173 0.683 V15 (%) 89.16±6.10 89.03±6.29 88.37±5.56 0.017 0.074 0.074 V20 (%) 85.50±8.44 83.35±8.90 79.95±5.62 0.005 0.013 0.037 V25 (%) 78.10±12.60 70.28±12.48 65.01±7.13 0.005 0.005 0.173 V30 (%) 62.38±14.16 50.77±13.88 46.43±9.17 0.009 0.005 0.285 V35 (%) 45.29±11.50 34.36±10.17 31.10±6.65 0.005 0.005 0.074 V40 (%) 28.72±7.51 24.27±8.68 21.44±4.94 0.005 0.047 0.059 V45 (%) 18.72±5.89 15.70±5.18 14.18±3.44 0.009 0.005 0.047

Values are presented as mean ± standard deviation,

Comparison of FF-VMAT and

HF-VMAT,

Comparison of FF-VMAT and MFF-VMAT,

Comparison of MFF-VMAT and

HF-VMAT

2. Bladder

Mean bladder dose of HF-VMAT plan was significantly lower than FF-VMAT and

MFF-VMAT plan (33.64 vs 38.63 vs 37.21, p<0.05). V30 and V40 to bladder were also

significantly lower (V30: 62.57 vs 89.15 vs 86.20, p<0.05, V40: 25.69 vs 37.74 vs 31.27).

V10 to bladder was 100 in all plans. The bladder showed highest volume reduction of 12%

at V40 and 27% at V30. Although

MVMAT plan showed better results than the

FF-VMAT plan at > 35Gy, it was not as good as HF-FF-VMAT plan.

The mean value of 10

patients according to three VMAT plans is shown in figure 4. More detailed DVH values

are shown in table 4.

Table 4. Comparison of dose-volume parameters for bladder in VMAT plans using

three different techniques. The mean dose (D

), maximum dose (D

), dose delivered

to 2cc of the most irradiated organ volume (D

) were evaluated for bladder.

Variable FF-VMAT MFF-VMAT HF-VMAT p-valuea) p-valueb) p-valuec) Dmean (Gy) 38.63±2.25 37.21±2.21 33.64±3.86 0.005 0.017 0.005 Dmax (Gy) 53.85±1.18 53.41±1.42 53.53±1.52 0.721 0.203 0.646 D2cc (Gy) 51.35±1.87 50.88±1.87 50.15±2.14 0.005 0.019 0.013 V5 (%) _{100 100 100 - - -} V10 (%) _{100 100 99.44±1.76 0.317 - 0.317} V15 (%) _{100 100 97.86±5.12 0.068 - 0.068} V20 (%) _{100 100 91.69±9.99 0.018 - 0.018} V25 (%) _{99.87±0.35 99.53±0.97 82.54±17.25 0.018 0.273 0.018} V30 (%) _{89.15±12.24 86.20±9.29 62.57±23.62 0.011 0.260 0.017} V35 (%) _{66.61±16.61 55.98±14.48 42.13±13.20 0.005 0.022 0.005} V40 (%) _{37.74±12.40 31.27±11.10 25.69±10.68 0.005 0.013 0.005} V45 (%) _{20.11±10.04 17.41±8.86 14.28±7.81 0.005 0.013 0.005}

Values are presented as mean ± standard deviation,

Comparison of FF-VMAT and

HF-VMAT,

Comparison of FF-VMAT and MFF-VMAT,

Comparison of MFF-VMAT and

HF-VMAT

3. Colon

Mean colon dose of HF-VMAT plan was significantly lower than FF-VMAT plan (23.45

vs 25.27, p<0.05). V30 and V40 to small bowel were also significantly lower (V30: 34.85

vs 40.01, V40: 20.22 vs 26.34, p<0.05). Colon showed highest volume reduction at V35

up

to 8%

The HF-VMAT plan achieved a 4-5% volume decrease for colon at V45

V35.

Dose sparing for the volumes at the same percentage led to 2 Gy less D

for colon.

MFF-VMAT plan showed better results than the FF-VMAT plan at > 25Gy and it was

statistically significant. However the MFF-VMAT plan was not as good as HF-VMAT plan.

Table 5. Comparison of dose-volume parameters for colon in VMAT plans using three

different techniques. The mean dose (D

), maximum dose (D

), dose delivered to 2cc

of the most irradiated organ volume (D

) were evaluated for colon.

Variable FF-VMAT MFF-VMAT HF-VMAT p-valuea) p-valueb) p-valuec)

Dmean (Gy) 25.27±6.81 23.98±6.34 23.45±6.29 0.005 0.005 0.037 Dmax (Gy) 55.11±0.97 55.12±0.34 54.95±0.46 0.959 0.508 0.959 D2cc (Gy) 52.85±16.73 53.89±0.29 52.31±1.21 0.285 0.114 0.799 V5 (%) 85.98±15.11 85.87±15.18 84.95±15.17 0.074 0.799 0.074 V10 (%) 74.20±15.81 72.49±16.40 71.51±16.10 0.047 0.721 0.074 V15 (%) 65.37±16.89 64.71±17.19 63.12±18.32 0.114 0.333 0.059 V20 (%) 57.91±18.21 55.71±18.56 53.90±2011 0.028 0.093 0.285 V25 (%) 48.45±19.39 44.35±19.99 43.74±18.81 0.005 0.005 0.386 V30 (%) 40.01±19.54 36.60±17.87 34.85±16.17 0.005 0.013 0.093 V35 (%) 35.32±19.65 34.36±10.17 27.68±12.48 0.005 0.005 0.037 V40 (%) 26.34±12.33 20.89±9.27 20.22±8.79 0.005 0.005 0.093 V45 (%) 16.80±8.83 15.70±5.18 13.16±5.98 0.005 0.005 0.333

Values are presented as mean ± standard deviation,

Comparison of FF-VMAT and

HF-VMAT,

Comparison of FF-VMAT and MFF-VMAT,

Comparison of MFF-VMAT and

HF-VMAT

4. Rectum

Because rectum is included in the treatment volume of anal cancer, six patients except

anal cancer were analyzed.

Mean rectal dose of HF-VMAT plan was significantly lower

than FF-VMAT plan (38.84 vs 40.02, p<0.05). V30 and V40 to small bowel were also

significantly lower (V30: 82.84 vs 88.04, V40: 43.82 vs 49.69, p<0.05). HF-VMAT and

MFF-VMAT plans showed improved OAR compared to FF-VMAT plan, and it was

statistically significant differences at > 30Gy. However the difference was small. More

detailed DVH values are shown in table 6.

Table 6. Comparison of dose-volume parameters for rectum in VMAT plans using

three different techniques. The mean dose (D

), maximum dose (D

), dose delivered

to 2cc of the most irradiated organ volume (D

) were evaluated for rectum.

Variable FF-VMAT MFF-VMAT HF-VMAT p-valuea) p-valueb) p-valuec) Anal cancer (n=4) Dmean (Gy) _{54.40±1.03 53.86±0.42 54.17±0.69 1.000 0.068 0.144} Dmax (Gy) _{56.61±1.83 55.51±0.35 56.37±0.94 0.715 0.068 0.144} D2cc (Gy) 55.83±1.61 54.93±38.28 55.42±73.99 0.715 0.068 0.144 Non-anal cancer (n=6) Dmean (Gy) 40.02±2.65 39.00±1.93 38.84±2.05 0.028 0.028 0.345 Dmax (Gy) 55.10±0.45 55.01±0.37 55.14±0.94 0.753 0.345 0.833 D2cc (Gy) 52.57±0.74 52.44±0.72 52.90±1.10 0.116 0.116 0.075 V5 (%) _{100 100 100 - - -} V10 (%) _{99.99±0.04 99.95±0.13 99.84±0.38 0.317 0.655 0.655} V15 (%) _{99.65±0.68 99.57±0.84 99.53±0.82 0.068 0.180 0.461} V20 (%) _{99.21±1.27 99.12±1.36 98.92±1.08 0.225 0.141 0.686} V25 (%) _{97.32±2.20 97.74±1.68 97.13±2.36 0.753 0.249 0.917} V30 (%) _{88.04±10.73 83.76±8.51 82.84±11.06 0.028 0.028 0.463} V35 (%) _{69.43±16.18 61.64±10.21 61.15±11.03 0.027 0.028 0.600} V40 (%) _{49.69±12.80 44.84±9.71 43.82±9.22 0.028 0.028 0.138} V45 (%) _{32.82±9.23 30.43±8.00 29.87±7.46 0.028 0.028 0.345}

Values are presented as mean ± standard deviation,

Comparison of FF-VMAT and

HF-VMAT,

Comparison of FF-VMAT and MFF-VMAT,

Comparison of MFF-VMAT and

HF-VMAT

B.

Normal tissue complication probability

The NTCP values of small bowel, colon, bladder and rectum were compared according

to three VMAT plans. In small bowel and colon, HF-VMAT and MFF-VMAT plans

showed improved NTCP compared to FF-VMAT plan, and it was statistically significant.

HF-VMAT plan reduced the NTCP for small bowel toxicity from 12 - 13% to 8 - 9% than

FF-VMAT plan. And, colon toxicity was reduced from 3.2% to 1.8%. Although HF-VMAT

plan showed improved NTCP compared to MFF-VMAT plan, the difference was small.

More detailed NTCP values are shown in table 7.

Table 7. Evaluation of normal tissue complication probabilities and

equivalent-uniform dose (EUD) with statistical significance. The NTCP was evaluated using two

analytic models including Lyman-Kutcher-Burman (LKB) and log-logistic model.

Variable Variable FF-VMAT MFF-VMAT HF-VMAT p-valuea) p-valueb) p-valuec)

Small bowel LKB (%) 12.81±4.24 10.25±3.69 8.98±2.42 0.007 0.005 0.047 Logistic(%) 11.99±4.27 9.41±3.65 8.12±2.38 0.007 0.005 0.047 EUD (Gy) 40.68±1.96 39.57±1.88 39.06±1.32 0.007 0.005 0.093 Colon LKB (%) 3.14±2.63 1.93±1.82 1.75±1.70 0.005 0.005 0.153 Logistic (%) 3.20±2.58 2.02±1.79 1.84±1.68 0.005 0.005 0.139 EUD (Gy) 38.37±3.20 37.07±3.08 36.87±3.02 0.005 0.005 0.203 Bladder LKB (%) 0.00 0.00 0.00 - - - Logistic(%) 0.00 0.00 0.00 - - - EUD (Gy) 39.15±2.20 37.81±2.24 34.77±3.49 0.005 0.013 0.005 Rectum LKB (%) 1.67±0.45 1.43±0.14 1.56±0.24 0.715 0.068 0.144 (anal cancer, n=4) Logistic(%) 2.52±0.55 2.24±0.18 2.40±0.31 0.715 0.068 0.144 EUD (Gy) 54.48±1.06 53.91±0.41 54.25±0.69 0.715 0.068 0.144 Rectum LKB (%) 0.16±0.06 0.15±0.04 0.15±0.05 0.116 0.028 0.345 (non-anal cancer, n=6) Logistic(%) 0.39±0.11 0.36±0.08 0.37±0.10 0.116 0.028 0.345 EUD (Gy) 45.55±1.29 45.20±1.12 45.55±1.29 0.116 0.028 0.345

Values are presented as mean ± standard deviation,

Comparison of FF-VMAT and

HF-VMAT,

Comparison of FF-VMAT and MFF-VMAT,

Comparison of MFF-VMAT and

HF-VMAT

C. Target coverage

HF-VMAT plan showed superiority compared with FF-VMAT plan in CN (0.90 vs 0.86,

p<0.05). The CN of MFF-VMAT plan was also increased than FF-VMAT (0.89 vs 0.86,

p<0.05). And, it was similar between HF-VMAT and MFF-VMAT (0.90 vs 0.89). There

was no statistically significant in the HI. The mean values and comparison are provided in

Table 8. And, the DVH of PTV to three VMAT plans is shown in figure 5.

Table 8. Mean conformity number (CN) and homogeneity index (HI) according to

three plans.

Variable FF-VMAT MFF-VMAT HF-VMAT p-valuea) p-valueb) p-valuec) CN 0.86±0.01 0.89±0.02 0.90±0.03 0.007 0.160 0.005 HI 35.90±2.20 34.87±2.64 36.07±4.31 0.575 0.052 0.139

Values are presented as mean ± standard deviation,

Comparison of FF-VMAT and

HF-VMAT,

Comparison of FF-VMAT and MFF-VMAT,

Comparison of MFF-VMAT and

HF-VMAT

D. Modulation index

HF-VMAT and MFF-VMAT plans showed improved MI compared to FF-VMAT plan, it

showed a statistically significant differences. The MI values of FF-VMAT and HF-VMAT

plans were respectively 366.95 and 306.31, which was about 20% lower. The MI value of

MFF-VMAT plan was similar with HF-VMAT plan. The mean values and comparison are

provided in Table 9.

Table 9. Mean modulation index (MI) according to three plans.

Variable FF-VMAT MFF-VMAT HF-VMAT p-valuea) _p-valueb) _p-valuec)

MI (MCS) 366.95±92.28 307.88±74.11 306.31±62.95 0.017 0.005 0.959

Values are presented as mean ± standard deviation,

Comparison of FF-VMAT and

HF-VMAT,

Comparison of FF-VMAT and MFF-VMAT,

Comparison of MFF-VMAT and

HF-VMAT

IV. Discussion

The elective WPRT including pelvic lymph node irradiation is regarded as a standard

treatment regimen for intermediate or high-risk rectal and gynecological cancers. Although

the benefits of WPRT has been controversial for the locally advanced prostate cancer

patients (43), its role and gain have been reexamined with consideration of interaction

between RT and adjuvant androgen deprivation therapy (ADT) according to the duration

and timing of the hormone therapy and the field sizes of RT. Long-term outcomes were

suggested in terms of improved free from progression and biochemical failure in ADT plus

RT. In addition, recent results as per a new protocol were reported treatment gains in

short-term ADT plus pelvic lymph node irradiation using IMRT (44, 45).

WPRT can bring out clinical merits with other treatment modalities, or clever radiation

dose delivery techniques such as simultaneously integrated boost using a different dose

scheme can be useful (46-48). However, acute and late radiation-induced complications

have been significant concerns due to the use of a large size of the field (16-18). When

large and irregular irradiated field is required to cover target volumes and regional lymph

nodes, the radiation exposure of normal organ is inevitable. To achieve the target dose

coverage with normal organ sparing in large and irregular anatomical geometries, VMAT is

one of the useful dose delivery methods (21-23). Optimal fluence, which is created by

MLC segments at individual numerous beam angles going through the arc trajectories in

VMAT, can effectively reduce the radiation doses of normal organs.

The present study was conducted to overcome the limitation of MLC motion in wide

field VMAT plan. In order to compensate for MLC leakage and non-blocking phenomena,

HF-VMAT and MVMAT plans were designed and compared with conventional

FF-VMAT. Anal cancer and vaginal cancer patients were enrolled due the benefit of

HF-VMAT plan was expected to be more pronounced in WPRT patients with inguinal field.

Studies about HF-VMAT plan were already published, however they were very rare. Lai et

al. reported that HF-VMAT plan was more effective for normal organ saving and dose

distribution than FF-VMAT plan in breast cancer irradiation. HF-VMAT plan showed

improved dosimetry in ipsilateral lung and heart than FF-VMAT plan (27). There is also a

study that the HF-VMAT plan showed an improved dose distribution in radiotherapy of

scalp and lower neck node (49, 50). Previous studies have shown that RT field is large and

irregular, like breast cancer or head and neck cancer. In present study, we analyzed the

effect of VMAT plan in patients undergoing WPRT with inguinal node, and the

HF-VMAT plan showed some dosimetric benefit compared to FF-HF-VMAT plan. We also

compared MFF-VMAT plan with HF-VMAT and FF-VMAT plan in present study. The

MFF-VMAT plan is a plan that X field size is fixed at the maximum equipment size (14

cm), in order to optimize the MLC modulation. Most of the parameters were not as good as

HF-VMAT plan, but showed better results than FF-VMAT plan. This means that the

adjustment of irradiation field size is possible to improve the dose distribution by the

increasing of MLC modulation.

The small bowel requires careful treatment planning, because it is an organ that can

cause fatal side effects, such as perforation, even at low radiation dose (51, 52). Especially,

for gynecologic malignancies, the possibility of side effects may be increased because the

small bowel can come down to the empty space after hysterectomy. Even in older patients,

there is a high possibility that the small bowel may become deformed due to the elasticity

of the abdominal wall or muscle weakness. Ahamad et al. analyzed the effect of IMRT in

cervical cancer patient undergoing postoperative radiotherapy, and

significantly

less small bowel was irradiated by IMRT than conformal radiotherapy for doses greater

than 25 Gy (53).

For this reason, we focused on small bowel and compared various

dosimetric factors according to various plans. As a result, we were able to confirm the

advantages of HF-VMAT plan in several parameters. The bladder and colon also showed

improved dosimetry and was statistically significant. The dosimetry of rectum did not

show any difference. It is probably due to the inclusion of anal cancer patients in enrolled

patients. Rectum is included in PTV of anal cancer. Except anal cancer patients, the

analysis showed improved dosimetry in HF-VMAT plan.

HF-VMAT plan is effective in reducing the radiation dose of normal organ. However it

is possible to impair the dose homogeneity of PTV. We evaluated this through CN and HI,

and there was no difference between the three plans. On the contrary, CN showed

improved PTV homogeneity in HF-VMAT plan than FF-VMAT plan and it was

statistically significant. Finally, HF-VMAT plan successfully reduced the normal organ

dose without compromising the PTV dose homogeneity compared to FF-VMAT plan. We

anticipated that the optimization of MLC movement enabled it, and MI was analyzed to

access it. The concept of MI has already been applied to evaluate mechanical uncertainty

in several previous studies on the VMAT plan (54, 55). In present study, we tried to

analyze the values of MI using MCS model, which reflects MLC motion and PTV shape.

HF-VMAT plan showed improved MI than FF-VMAT plan, and MFF-VMAT plan also

showed about 20% improved MI value than FF-VMAT plan. This implies that the

optimization of MLC modulation affects the dose distribution of VMAT plan.

This study was conducted to improve the dose distribution when the irradiated field is

large. However, not only the size of the irradiated field but also the shape is important

factors. We conducted a preliminary study on WPRT without inguinal lymph node chain

and obtained unsatisfactory results. In the WPRT without the inguinal lymph node, there

was no effect of HF-VMAT plan. Like the WPRT containing the inguinal lymph node

chain, the more irregular the irradiated field, the more effective HF-VMAT plan is.

Although there are rare studies about HF-VMAT plan, the studies were conducted on head

and neck cancer and breast cancer with supraclavicular lymph node (27, 28). This implies

that the shape of the irradiated field is an important factor.

HF-VMAT plan showed the improved dosimetric impact of normal organ, and the

homogeneity of target volume was comparable with FF-VMAT plan.

HF-VMAT plan can

be more useful option than conventional FF-VMAT plan in patient with large and irregular

irradiation field, such as WPRT with inguinal lymph node chains.

The shape of irradiated

field as well as size is considered as an important factor, therefore the further study about

suitable cases for HF-VMAT plan are required.

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-국문요약-

반 영역

체적조절호형 방사선치료의 선량학적 효과 분석

아주대학교 대학원 의학과

장현수

(지도교수: 오 영 택)

연구목적: 오늘날 전 골반 방사선치료와 같은 넓은 방사선치료 타겟에 대해 체

적조절호형 방사선치료 (VMAT)가 적극적으로 시도되고 있다. 하지만 방사선

조사 범위가 크고 불규칙한 모양이라면 multileaf collimator (MLC) 움직임의

제한이 발생하게 되고, 이는 만족스럽지 못한 선량 분포의 원인이 된다. 본 연

구진은 넓고 불규칙한 모양의 방사선치료 타겟을 대상으로 half-field 기법의

효용성을 검증하고자 하였고, 이를 MLC 움직임의 최적화 측면에서 분석해 보

았다.

대상 및 방법: 전 골반 방사선치료를 받은 10명의 환자를 대상으로 half-field

VMAT (HF-VMAT), full-field VMAT (FF-VMAT), modified full-field

VMAT (MFF-VMAT) 기법을 비교 분석 하였다. 서혜부 임파선을 치료 범위

로 포함하는 자궁경부암, 항문암, 질암 환자들을 대상으로 하였고 처방선량은

50Gy (25 x 2Gy) 이었다. 치료 기법에 따라 직장, 방광, 소장과 같은 정상 장

기의 선량 분포를 획득하였다. 또한

Normal tissue complication probability

(NTCP), conformity number (CN), homogeneity index (HI), modulation

index (MI)

를 계산하여 기법에 따른 차이를 분석하였다.

결과: HF-VMAT 기법의 평균 소장 선량은 MFF-VMAT와 FF-VMAT 기법

에 비해 낮았고 (29.57 vs 30.68 vs 29.57, p<0.05), V15부터 V45까지의 값

역시 유의하게 감소되었다. HF-VMAT 기법의 방광 평균 선량은

MFF-VMAT와 FF-VMAT 기법에 비해 낮았고 (33.64 vs 37.21 vs 38.63,

p<0.05), V35부터 V45까지의 값도 유의하게 감소되었다. 대장과 직장에서도

HF-VMAT 기법에 따른 향상된 DVH를 관찰할 수 있었다. 기법에 따른

NTCP값을 분석한 결과, HF-VMAT 기법의 소장 독성은 8 – 9%로 12 – 13%

의 FF-VMAT 기법에 비해 유의하게 향상된 값을 보여주었다. MLC 움직임의

불확실성을 반영하는 MI을 비교한 결과, HF-VMAT과 MFF-VMAT 기법에

서 FF-VMAT 기법에 비해 향상된 값을 보여주었다 (306.31 vs 307.88 vs

366.95, p<0.05).

결론: 넓고 불규칙한 모양의 방사선치료 타겟에서 HF-VMAT 기법은

FF-VMAT 기법에 비해 향상된 MLC 움직임을 보여주었고, 이는 정상 장기의 선

량 분포의 향상으로 연결되었다. 넓고 불규칙한 모양의 방사선치료 타겟을 가

진 환자들에게 HF-VMAT 기법은 도움이 될 것으로 기대된다.

핵심어: 전 골반 방사선치료, 체적조절호형 방사선치료, half-beam 기법,

modulation index