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A Dosimetric Comparison of the Field in Field Method versus Irregular Surface


Compensator in the Treatment of Left Sided, Early Stage Breast Cancer: A Case Study
Authors: Ryan Salem, BS, RT(T); Christina Ong, BS; Sean Ferguson, BS, RT(T);
Rodger Williams, BS, CMD, RT(R)(T); Ashley Hunzeker, MS, CMD; Nishele Lenards, PhD,
CMD, RT(R)(T), FAAMD; Matt Tobler, RT(T), CMD
Medical Dosimetry Program at the University of Wisconsin – La Crosse, WI
Abstract
Introduction: The objective of this case study was to perform a dosimetric comparison between
the 3D conformal field in field (FIF) and irregular surface compensator (ISC) techniques in
whole breast radiation therapy for left sided, early stage breast cancer. The metrics of target
coverage, healthy tissue constraints, and maximum dose regions were analyzed to determine the
more effective treatment method.
Case Description: A retrospective case study of 10 patients diagnosed with left sided, early
stage breast cancer ranging from ductal carcinoma in situ (DCIS) to Stage II T2N0M0 from a
single cancer center was completed. All patients received a lumpectomy procedure prior to
radiation therapy. The planning target volume (PTV) and gross tumor volume (GTV) for all 10
patient datasets were contoured by 1 physician according to the Radiation Therapy Oncology
Group (RTOG) 1005 guidelines. A PTV_EVAL structure was created for PTV evaluation and
excluded the PTV outside the ipsilateral breast and the posterior portion of the breast tissue,
including a 5 mm retraction from the skin as per protocol guidelines. Treatment plans were
developed for both treatment methods on the same 10 patients with 1 medical dosimetrist using
the FIF technique and 1 medical dosimetrist using the ISC technique in accordance with RTOG
1005. Dosimetric comparisons were performed based on the statistical results from the 2
treatment techniques.
Conclusion: Field in field and ISC treatment methods for left sided, early stage breast cancer
resulted in dosimetric differences. Field in field was found to be advantageous when compared to
ISC in increasing dose conformity while lowering dose to critical structures.
Key Words: Field in field, irregular surface compensator, early stage breast cancer
Introduction
According to the Center for Disease Control, breast cancer has the highest incidence of
all cancers for women in the United States at 125 cases per 100,000 women and is the deadliest
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cancer in women second to lung cancer.1 Whole breast radiotherapy is a common way to treat
early stage breast cancer. Radiotherapy is the use of high energy x-ray beams to kill cancer cells
while sparing the healthy tissue surrounding the tumor. Toxicity in healthy tissue is a
consequence of radiotherapy when excess dose is delivered to healthy tissue and organs. Both
FIF and ISC techniques used in radiotherapy utilize advanced technology to improve dose
homogeneity while reducing dose to healthy tissue during treatment in order to minimize post-
treatment complications.2 To decrease the risk of post-treatment complications from breast
radiotherapy, such as tumor recurrence, chest wall recurrence, contralateral breast tumors, heart
toxicity, and radiation pneumonitis, the FIF and ISC techniques can be used.3
The FIF technique is a common method in whole breast radiation therapy that utilizes
tangential beams. Tangential fields are created to deliver the dose with multileaf collimator
(MLC) shaping to conform the fields to the desired treatment area. To limit regions where dose
exceeds the prescription dose, the FIF technique incorporates subfields by use of additional MLC
shaping to block high dose regions. Dose conformity is increased and maximum dose is lowered
as a result.4
Irregular surface compensation is a forward planning technique utilizing MLC movement
to create fluence. By use of dynamic MLC leaf motion to compensate for the curvature of breast
tissue, ISC creates a more homogeneous dose distribution within the tissue. A fluence editor is
employed to further adjust dose distribution within the target volume until an optimum result is
obtained. The ISC technique reduces high dose regions, acute toxicity, and changes in breast
cosmesis.5
Previous comparative studies demonstrate differences in common whole breast
radiotherapy treatment techniques, including FIF and ISC. Studies from Al-Rahbi et al6 and
Hideki et al7 have shown mixed results as to the best treatment planning method for early stage
breast cancer. Limitations of previous research include the use of CT datasets from different CT
scanners, planning software and treatment equipment differences, inconsistently drawn target
volumes, and the variable stages of the treatment disease. Differences in treatment machines,
manufacturers, MLC sizes, and treatment energies have been reported to pose variability in
treatment planning results.2 Vicini et al8 discovered treatment differences when the PTV was
created by a GTV expansion but not with a physician-contoured PTV, representative of the
whole breast on the affected side. Treatment differences were found in a study by Koivumaki et
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al2 while comparing treatment methods with site specific target volumes rather than protocol
specific. Different treatment planning systems (TPSs) can calculate the same plan but yield
different results in terms of dose homogeneity and the dose to contoured structures. By
controlling the variables in treatment planning, results may yield significant statistical
differences in the comparison of 2 treatment methods.
The objective of this case study was to perform a comparison between the FIF and ISC
techniques in whole breast radiotherapy. This case study avoided the use of multiple TPSs and
treatment machines to allow consistent dose calculations and homogeneity corrections through
both methods of treatment planning. The variables within treatment planning involving patient
selection and setup, target delineation, and plan normalization were controlled, ensuring the
accuracy of the results. Both treatment planning techniques were compared for target coverage,
maximum dose regions, dose homogeneity, and organs at risk (OAR) to determine whether one
technique was advantageous over the other. For the variables reported, population means were
compared using confidence intervals and paired-data t-tests. A 5% level of significance was used
for all hypothesis tests and a 95% level of confidence was used in developing interval estimates.
No correction was applied for multiple testing and the small sample sizes of the case study.
Case Description
Patient Selection & Setup
Ten patients from a single cancer center diagnosed with left sided, early stage breast
cancer ranging from DCIS to Stage II T2N0M0 were retrospectively selected for this case study.
Only patients with a lumpectomy procedure were chosen so that the physician could delineate
the lumpectomy cavity or GTV. The patient population was limited to left sided breast patients
for specific analysis and comparison of dose to the breast target volume, contralateral breast,
lungs, and heart. The separation, or distance between the medial and lateral borders of the
treatment area, was taken into consideration to avoid cases of patients with a separation larger
than 30 cm as research has shown immobilization and treatment method differences across
various clinical sites for these patients.9 The separation distances in this case study ranged from
19.3 cm to 26.9 cm with an average distance of 23.0 cm.
The selected patients underwent a free breathing CT simulation that was performed on a
Phillips Brilliance large bore CT scanner with 3 mm slices at a single cancer center. All patients
in this case study were simulated in the same or similar treatment position. Patient positioning
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was head first, supine with both arms up holding a T-grip. A breast board was table-indexed with
a vacuum bag under the arms and head area. The head was tilted away from the affected side. A
knee cushion was used with a ring placed around the feet to limit leg movement during treatment
(Figures 1&2). Free breathing was used to emphasize the importance of target coverage and
OAR avoidance as well as to limit variability between the locations of target volumes and lungs
in this case study.
Target Delineation
To allow for a quantitative analysis of treatment plan quality, the GTV and PTV_EVAL
were contoured according to RTOG 1005 by a single physician on the Varian Eclipse TPS
version 13.6.8 The GTV was defined as the excision cavity volume, lumpectomy scar, seroma,
and/or extension of surgical clips. All patients in the study had a clearly identifiable lumpectomy
bed and breast tissue (Figure 3). The GTV sizes ranged from 4.2 cc to 51.6 cc with an average
size of 24.8 cc. The PTV_EVAL was drawn to include the palpable breast tissue, apparent
glandular breast tissue, and the GTV. The PTV_EVAL contour was limited to 5 mm from the
skin and extended no deeper than the anterior surface of the ribs and beyond the posterior extent
of the chest wall, pectoralis muscles, and lungs as per RTOG 1005 (Figure 3).8 The PTV_EVAL
sizes ranged from 211.7 cc to 1460.8 cc with an average size of 788.9 cc.
The contoured OAR included the contralateral breast, ipsilateral lung, contralateral lung,
and heart in accordance with RTOG 1005. The contralateral breast included visible glandular
tissue delineated from the CT dataset while following the RTOG Breast Atlas. All lung volumes
were contoured with auto-segmentation and manual editing and verification. The heart was
contoured from the pulmonary trunk bifurcation into the left and right pulmonary arteries and
extended to its most inferior region in the diaphragm or lower.8
Treatment Planning
Field in field and ISC treatment techniques were used to plan the same 10 patients
selected in this case study. The plans were created on anonymized datasets using the same
structure set including the contours delineated by 1 physician. The prescription and fractionation
schedules were consistent with Arm 1 of RTOG 1005, Standard Whole Breast Irradiation with
Sequential Boost, delivering 50 Gy in 25 fractions of 2 Gy, 5 days a week for the primary plan to
the whole breast. Only the primary plans of 50 Gy were analyzed for this study to compare FIF
and ISC treatment techniques due to the variability in boost treatment modalities at different
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treatment centers. Dose conformity, PTV_EVAL coverage, and OAR doses were to be
compared.
Both FIF and ISC techniques were planned for treatment on a Varian TrueBeam linear
accelerator with the same MLC configuration. Both treatment machines had an equal number of
0.5 cm and 1.0 cm MLC leaves used in collimation. Treatment planning was completed by 2
different medical dosimetrists: 1 for FIF and 1 for ISC. Both medical dosimetrists created plans
using the Varian Eclipse TPS version 13.6, utilizing the Anisotropic Analytical Algorithm
(AAA) for photon energies in this case study. The conditions allowed for accurate and similar
dose calculations independent of the treatment technique utilized in planning. The medical
dosimetrist planning with the FIF technique had access to 6 MV, 10 MV, and 15 MV beam
energies for treatment planning. The medical dosimetrist planning with the ISC technique had 6
MV and 15 MV beam energies available. In this case study, 6 MV beams were required in both
planning techniques and higher energies were used to achieve planning objectives. Tangential
beams consisting of a right anterior oblique (RAO) field and a left posterior oblique (LPO) field
were utilized in both FIF and ISC techniques. Collimator angles were kept at 0 degrees, ensuring
consistent radiation fields between both treatment techniques.
To accurately compare both treatment methods, all plans were normalized to achieve 3
goals for coverage to the PTV_EVAL and GTV: (1) the maximum permissible hot spot for any
plan was to be lower than 115%; (2) 95% of the PTV_EVAL was to be covered by 95% of the
prescription dose; (3) and 100% of the GTV was to be covered by 99% of the prescription dose.
The medical dosimetrists chose a normalization value that achieved all 3 of these coverage
requirements at a minimum. Under-dosing of target volumes was not allowed in this case study
to accommodate OAR limitations to help distinguish the capabilities of each treatment modality
regarding target coverage and OAR avoidance.
Constraints for OAR from RTOG 1005 were followed in this case study. The
contralateral breast was not to exceed 310 cGy and no more than 5% of the contralateral breast
volume was to exceed 186 cGy. For the ipsilateral lung, the volume receiving 20 Gy was to be
less than 15% (V20 < 15%), the volume receiving 10 Gy was to be less than 35% (V10 < 35%),
and the volume receiving 5 Gy was to be less than 50% (V5 < 50%). For the contralateral lung, 5
Gy was not to exceed 10% of the contralateral lung volume (V5 < 10%). The heart mean dose
was limited to 400 cGy, no more than 5% of the volume could exceed 20 Gy (V20 < 5%) and no
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more than 30% of the volume was to exceed 10 Gy (V10 < 30%).8 Dose homogeneity was
analyzed based on guidelines from International Commission of Radiation Units and
Measurements (ICRU) and RTOG 1005.10
Plan Analysis and Evaluation
Both techniques were compared to the following criteria: PTV_EVAL coverage, dose
homogeneity and OAR toxicities. Following plan normalization, the FIF plans had 106.35% as a
mean maximum dose and the ISC plans had a mean maximum dose of 105.73%. Of 95% of the
PTV_EVAL volume, the FIF method averaged 97.4% prescription coverage with ISC averaging
97.2% prescription coverage. Both target coverages (p = 0.785) and maximum doses (p = 0.334)
were only marginally different in this sample, indicating that neither technique posed a
significant advantage to the other in terms of mean maximum dose, PTV_EVAL coverage, and
GTV coverage for a primary breast radiation plan in general (Table 1).
Overall dose homogeneity was evaluated using a conformity index (CI). The CI was
implemented into the case study to evaluate PTV_EVAL coverage based on the 95% isodose
line. The conformity index is defined by ICRU and RTOG 1005 guidelines as a ratio between the
volume covered by the reference isodose line and the target volume, was presented by the
equation:
CI = VRI / TV
where VRI = reference isodose volume and TV = target volume.10 A CI value equal to 1
corresponds to the ideal dose coverage. The greater the CI is from 1, poorer dose conformity is
apparent as the irradiated volume further exceeds the target volume and is being deposited in
healthy tissue.10 In this case study; all CI values were greater than 1. The FIF technique produced
plans with an average CI of 1.522, whereas ISC produced plans with a CI of 1.721 on average.
The study indicated that the FIF technique was able to achieve similar coverage of target
volumes with significantly better dose conformity or homogeneity (p = 0.003) (Table 1).
Contralateral breast and contralateral lung maximum doses were evaluated based on the
cumulative dose volume histogram (DVH) in the Eclipse TPS. Since doses to the contralateral
breast and contralateral lung were relatively low, maximum doses were evaluated instead of
mean doses. With the FIF technique, the average maximum dose to the contralateral breast was
165 cGy, with the highest at 299 cGy. The average maximum dose to the contralateral breast
with the ISC technique was 327.4 cGy and the highest dose at 664 cGy. Therefore, the FIF
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technique had a 162.4 cGy lower dose to the contralateral breast (p = 0.001). Following plan
normalization, the ISC technique did not meet the maximum dose constraint of 310 cGy in 6
patients, whereas the FIF technique had 0 patients fail the same constraint (Table 2). The average
maximum dose to the contralateral lung for the FIF and ISC techniques was 98.4 cGy and 196.6
cGy respectively, resulting in a 98.2 cGy difference in favor of FIF (p = 0.018). In both treatment
methods, all patients passed the V5 < 10% constraint for the contralateral lung (Table 2). The
research suggests that the FIF technique may be advantageous when compared to the ISC
technique regarding contralateral OAR constraints.
All treatment plans passed the 3 ipsilateral lung constraints. The V20, V10, and V5 for the
FIF technique on average were 5.6%, 9.4%, and 15.7%, respectively. The ISC technique yielded
11.3%, 16.6%, and 26% for the same ipsilateral lung constraints. The FIF technique was 5.7%
lower, 7.2% lower, and 10.3% lower compared to the ISC technique when evaluating the V20,
V10, and V5 of the ipsilateral lung (Table 3). The results suggest that the FIF method may yield
lower ipsilateral lung doses than treatments using the ISC technique (p < 0.005).
All treatment plans passed the 3 heart constraints as well. The average V20 of the heart for
the FIF technique was 0.7% and for the ISC technique was 0.9% (p = 0.263). The average V10 of
the heart for the FIF technique was 1.38% and for the ISC technique was 1.73% (p = 0.211).
There was less than a 0.5% difference which is not significantly different between the two
treatment methods for both constraints. The average mean dose of the heart in the sample was
148.9 cGy for FIF and 192 cGy for ISC, resulting in a difference 43 cGy on average in favor of
the FIF technique (p = 0.001). These results suggest that the heart dose may be kept marginally
lower with the FIF technique without making a tangible clinical difference as all plans passed the
constraints by a large margin in both techniques (Table 4).
Overall, both treatment methods were effective in meeting all the coverage requirements
and most of the OAR dose constraints as only the contralateral breast maximum dose was not
met by the ISC method in 6 cases. The significant outcomes from the results in this case study
include the differences in dose conformity, contralateral OAR doses, and ipsilateral lung doses.
The FIF method consistently provided plans with a better CI without sacrificing maximum dose
and target volume coverage. A CI between 1 and 2 is considered in accordance with RTOG
standards for breast cancer radiotherapy, so in only 1 case dose conformity deviated from
protocol standards.10 The FIF also produced plans with less dose to both the contralateral breast
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and contralateral lung when compared with ISC. Both planning methods were consistently able
to produce acceptable plans based on RTOG guidelines, so the research suggests that already
acceptable treatment plans could possibly be improved by using the FIF method with 6 MV, 10
MV, and 15 MV treatment beams.
Conclusion
Breast cancer radiotherapy techniques have been widely studied. The benefits of both FIF
and ISC are well documented.4,5,7 This case study was designed to compare FIF and ISC
techniques with limited variability to determine if 1 technique yielded superior results. The
patient selection was intended to represent a sample population of patients with left sided, early
stage breast cancer ranged from DCIS to Stage II T2N0M0, utilizing retrospective CT datasets
with different breast volumes, body sizes, and lumpectomy cavity locations. The case study
followed RTOG 1005 recommendations and a single physician delineated the PTV, GTV, and
OAR according to the protocol guidelines. The same TPS and treatment machine used in the
treatment planning process increased the accuracy of the research data.
Results from this case study with consistent target volumes, treatment machine, and TPS
suggest that the FIF method is advantageous to the ISC method in free-breathing treatment
planning for left sided, early stage breast cancer. Of the metrics used for comparison in this case
study, FIF showed statistically significant improvements. The FIF technique produced a
significantly better CI than ISC in this case study. Contralateral lung and breast doses were found
significantly lower in the FIF technique when compared with ISC. Ipsilateral lung V20, V10, and
V5 doses as well as mean heart doses showed improvement with FIF over ISC. Treatment
planning with deep inspiration breath hold (DIBH) datasets may yield different results as patient
respiration can lead to increased doses to the heart and ipsilateral lung and cause variation in
location of structures in comparison with free-breathing treatment planning.2 A further study
with a larger patient population would be needed to confirm that the FIF technique is beneficial
when compared to ISC.

Acknowledgement
The authors would like to thank Dr. David Reineke, Thomas Theisen, and Carsten
Hiltgen of the University of Wisconsin-La Crosse Statistical Consulting Center for their
contributions to the statistical analysis and interpretation of statistical results.
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References
1. Breast Cancer Statistics. Centers for Disease Control and Prevention Web site.
https://www.cdc.gov/cancer/breast/statistics/index.htm. Updated June 12, 2018. Accessed
July 23, 2018
2. Koivumaki T, Fogliata A, Zeverino M, et al. Dosimetric evaluation of modern radiation
therapy techniques for left breast in deep-inspiration breath-
hold. Physica Medica. 2018;45:82-87. https://dx.doi.org/10.1016/j.ejmp.2017.12.009
3. Fragkandrea I, Kouloulias V, Mavridis P, et al. Radiation induced pneumonitis following
whole breast radiotherapy treatment in early breast cancer patients treated with breast
conserving surgery: A single institution study. Hippokratia. 2013;17(3):233-238.
4. Tanaka H, Hayashi S, Hoshi H. Determination of the optimal method for the field-in-field
technique in breast tangential radiotherapy. JRadiat Res. 2014;55(4):769-773.
https://dx.doi.org/10.1093/jrr/rrt233
5. Emmens DJ, James HV. Irregular surface compensation for radiotherapy of the breast:
Correlating depth of the compensation surface with breast size and resultant dose
distribution. Br J Radiol. 2010;83(986):159-165. http://dx.doi.org/10.1259/bjr/65264916
6. Al-Rahbi ZS, Ravichandran R, Binukumar JP, Davis CA, Satyapal N, Al-Mandhari Z.
A dosimetric comparison of radiotherapy techniques in the treatment of carcinoma of
breast. J Cancer Ther. 2013;4:10-17. http://dx.doi.org/10.4236/jct.2013.411A002
7. Hideki F, Nao K, Hiroyuki H, Hiroshi K, Haruyuki F. Improvement of dose distribution
with irregular surface compensator in whole breast radiotherapy. J Med Phys.
2013;38(3):115-119. http://dx.doi.org/10.4103/0971-6203.116361
8. Vicini FA, Freedman GM, White JR, et al. A phase III trial of accelerated whole breast
irradiation with hypofractionation plus concurrent boost versus standard whole breast
irradiation plus sequential boost for early-stage breast cancer. Radiation Therapy
Oncology Group (RTOG).
http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?action=openFile&Fi
leID=9366. Updated 2014. Accessed July 23, 2018.
9. Keller LM, Cohen R, Sopka DM, et al. Effect of bra use during radiation therapy for
large-breasted women: Acute toxicity and treated heart and lung volumes. Practical Rad
Onc. 2013;3(1):9-15. https://dx.doi.org/10.1016/j.prro.2012.07.003
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10. Petrova D, Smickovska S, Lazarevska E. Conformity index and homogeneity index of the
postoperative whole breast radiotherapy. Open Access Maced J Med Sci. 2017;5(6):736-
739. https://dx.doi.org/10.3889/oamjms.2017.161
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Figures

Figure 1. Images showing how the arms and torso were positioned in CT simulation. T-grip was
to be moved for comfort.

Figure 2. Images showing the torso and legs from a lateral view in the treatment position, with
the breast board, knee sponge, and foot ring position.

Figure 3. A visual representation of GTV, PTV_EVAL, and contralateral breast contoured by


the physician.
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Tables
a
Table 1. A comparison of target coverages and dose conformity for both treatment methods.
PTV_EVAL Coverage Maximum Dose Conformity Index
(% of PTV covered by (%) (CI)
% of Prescription Dose)
Technique FIF ISC FIF ISC FIF ISC
Patient A 95% of 97% 95% of 96% 106.7 106.1 1.33 1.47
Patient B 95% of 99% 95% of 99% 104.7 107.1 1.41 1.70
Patient C 95% of 96% 95% of 98% 107.0 107.1 1.36 1.81
Patient D 95% of 98% 95% of 96% 107.0 104.8 1.34 1.55
Patient E 95% of 97% 95% of 98% 104.8 104.5 1.22 1.47
Patient F 95% of 97% 95% of 97% 106.7 105.4 1.35 1.49
Patient G 95% of 99% 95% of 95% 108.9 104.6 1.38 1.34
Patient H 95% of 99% 95% of 99% 107.5 106.6 1.45 1.77
Patient I 95% of 95% 95% of 99% 104.4 105.8 2.90 2.85
Patient J 95% of 97% 95% of 95% 105.8 105.3 1.48 1.76
Mean 97.4% 97.2% 106.4 105.7 1.522 1.721
p-value p = 0.785 p = 0.314 p = 0.003
a
All treatment plans were normalized to 100% of GTV covered by 99% of the prescription dose.

Table 2. A comparison of contralateral breast and contralateral lung dose for both treatment
methods.
Contralateral Breast Maximum Dose Contralateral Lung Maximum Dosea
(cGy) (cGy)
Technique FIF ISC FIF ISC
Patient A 248 332 176 223
Patient B 133 348 103 253
Patient C 159 375 55 56
Patient D 101 247 108 212
Patient E 80 82 24 35
Patient F 299 664 100 137
Patient G 165 420 32 51
Patient H 263 396 29 87
Patient I 88 231 243 570
Patient J 114 179 114 262
Mean 165 327.4 98.4 188.6
p-value p = 0.001 p = 0.018
a
Contralateral lung maximum dose was compared instead of the volume of contralateral lung at
500 cGy as none of the treatment plans had dose over 500 cGy for the contralateral lung.
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Table 3. A comparison ipsilateral lung dose for both treatment methods.


Ipsilateral Lung Ipsilateral Lung Ipsilateral Lung
Volume (%) at 20 Gy Volume (%) at 10 Gy Volume (%) at 5 Gy
Technique FIF ISC FIF ISC FIF ISC
Patient A 9 11 13 17 22 27
Patient B 4 12 8 19 16 30
Patient C 3 10 5 15 9 24
Patient D 9 14 12 20 19 32
Patient E 2 6 3 9 6 14
Patient F 7 13 11 19 19 28
Patient G 3 8 7 13 16 23
Patient H 6 13 9 17 16 25
Patient I 7 13 10 17 16 24
Patient J 6 13 16 20 18 33
Mean 5.6 11.3 9.4 16.6 15.7 26
p -value p < 0.005 p < 0.005 p < 0.005

Table 4. A comparison of heart dose for both treatment methods.


Heart Volume (%) at Heart Volume (%) at Heart Mean Dose (cGy)
20 Gy 10 Gy
Technique FIF ISC FIF ISC FIF ISC
Patient A 0.5 0.02 1 0.3 137 135
Patient B 0 0 0 0.1 88 127
Patient C 1 0.7 2 2 163 177
Patient D 0.4 0.6 0.8 1.4 129 197
Patient E 0.9 1.4 2 2.5 171 223
Patient F 0.3 0.6 0.8 1.4 153 203
Patient G 0.04 0.6 0.2 1.5 122 162
Patient H 2 2.5 3 3.6 210 288
Patient I 1 2.4 2 3.6 175 253
Patient J 1 0.5 2 0.9 141 155
Mean 0.7 0.9 1.38 1.73 149 192
p-value p = 0.263 p = 0.211 p = 0.001

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