Keywords breast cancer - adjuvant radiotherapy - deep inspiration breath hold - radiation -
toxicities
Introduction
Carcinoma of the breast is the commonest cancer in women worldwide and its incidence
in India is steadily increasing.[1 ] Adjuvant radiotherapy (RT) is a standard treatment for breast cancer and significantly
improves local control up to 8% in postmastectomy for locally advanced breast cancers
and up to 25% in women undergoing breast conservation surgery (BCS).[2 ]
[3 ]
[4 ] The incidence of breast cancer is on the rise in younger women. Patients with breast
cancers are long-term survivors and as a result, live with various treatment-related
toxicities such as radiation pneumonitis due to lung fibrosis and radiation-induced
cardiac disease.[5 ]
[6 ]
[7 ]
[8 ]
[9 ]
[10 ]
Cardiac toxicity, particularly those receiving radiation for left-sided breast cancer,
is associated with risks of cardiac mortality and coronary events.[11 ]
[12 ] The toxicity is strongly correlated with the mean heart dose. It is estimated that
for every 1 Gy increase in mean heart dose, the risk of ischemic heart disease increased
by 4 to 7%.[13 ] Hence, reducing the mean heart dose during radiation planning is essential. Various
methods include intensity-modulated RT, prone position, protons, and deep inspiration
breath-hold (DIBH) technique.[14 ]
DIBH is a recent technique that helps reduce the dose received by the underlying heart
and ipsilateral lung during RT treatment delivery. During the inspiratory effort,
the heart is displaced downward and backward, distancing itself from the chest wall
and thereby helps reduce the volume of heart receiving radiation without compromising
the dose distribution to the breast or chest wall.[15 ]
[16 ]
[17 ]
[18 ] Several studies have shown beneficial cardiac sparing with DIBH, and the UK consensus
statement on postoperative RT for breast cancer recommends using the breath-hold technique
for maximal cardiac sparing.[19 ]
[20 ]
[21 ]
[22 ]
The routine implementation of DIBH is resource intensive and is not uniformly adapted
across all institutions.[23 ]
[24 ] In the present study, we report on our initial experience of implementing DIBH for
breast cancer in terms of dosimetry comparing free-breathing (FB) and DIBH techniques,
reproducibility, compliance, ease of execution, and acute toxicities.
Materials and Methods
This is a prospective study conducted at a tertiary cancer hospital and approved by
the institutional ethics committee (IEC no.: 632/2018). Patients who presented to
the RT OPD following either BCS or mastectomy requiring adjuvant RT, able to comprehend
and follow the instructions that are required to execute a DIBH treatment, and willing
to provide informed consent were included in the study. Patients with preexisting
lung or heart pathology that prevents the patient from adequately holding her breath
in inspiration for the reasonable time required (around 20 seconds) to execute DIBH,
metastatic disease at presentation, and prior RT for breast cancers or other cancers
of the thoracic region were excluded from the study.
Patients satisfying the inclusion criteria underwent trial runs where they were assessed
for their ability to hold breath in inspiration, at least 20 seconds at a stretch.
The patients then underwent a planning computed tomography (CT) scan where two sets
of CT images were acquired for all patients, one during FB and the other one in DIBH
([Fig. 1 ]). The planning CT images were transferred to the Monaco planning system. The clinical
target volume (CTV) and organs at risk (OAR), heart, lungs, and spinal cord were delineated
on the CT images. CTV delineation was done using Radiation Therapy Oncology Group
(RTOG) guidelines, and the left anterior descending (LAD) artery was contoured with
the help of cardiac contouring guidelines for RT by Duane et al and heart atlas by
Feng et al.[25 ]
[26 ] The treatment planning was done using either the three-dimensional conformal RT
(3DCRT) technique or volumetric modulated arc therapy (VMAT) technique on the treatment
planning system. Patients were planned for the total RT dose of 42.5 Gy/16 Fr for
postmastectomy and 42.5 Gy/16 Fr followed by 10 Gy/5 Fr boost in breast conservation
cases. The planning target volume (PTV) for the FB technique was taken as 1 cm (as
per institutional protocol), and the PTV margin for DIBH was taken as 0.5 cm. In the
event of any breathing difficulty, the patient is equipped with a safety button which
on activation can terminate the treatment cycle. As a safety measure, the treating
physician also monitors that patient's breathing from the console.
Fig. 1 An overlay to compare lung and heart volume between free-breathing and deep inspiration
breath-hold techniques.
Demographic data and clinical details were collected from the outpatient records of
the patients. RT treatment details, including volumes of lung and heart irradiated,
adequacy of tumor volume coverage, OAR parameters such as lung mean dose, lung V20
Gy, heart mean dose and V25 of heart, and LAD artery mean dose and maximum dose were
recorded. The patients were monitored for acute toxicities (typically, radiation dermatitis,
acute dysphagia, and hematological toxicities) during treatment as per routine practice.
On follow-up, they were assessed for any evidence of recurrence, treatment toxicities,
specifically radiation pneumonitis, and other toxicities that might have potentially
occurred due to RT.
Data collected were entered in MS Excel, analyzed using the trial version of Statistical
Package for Social Sciences (SPSS) software and a p -value <0.05 was considered statistically significant. All quantitative variables
were expressed as mean and standard deviation (SD) and qualitative variables as percentages.
The distribution of dose–volume parameters was tested for normality. If normally distributed,
parametric test such as paired t -test was applied, and if not normally distributed, a nonparametric test was used.
Pearson's correlation was done to test the association between the categorical variables.
The sample size was calculated using formula,
With 5% alpha error, 80% power of the study, and a clinically significant difference
of 1.5 Gy in the dose received by heart with the use of DIBH, the sample size calculated
was 32.
Results
The study was conducted from September 2018 to August 2020, and 32 patients were included.
The demographic variables are shown in [Table 1 ]. The mean age of patients was 49.5 years (SD ± 11.3). Three percent of our patients
had a history of bronchial asthma which was mild and did not require any treatment;
81% of patients had left-sided breast cancer. The most common stage at presentation
was stage II (65%) followed by stage III (26%). While majority of the patients underwent
upfront surgery (72%), 28% patients received neoadjuvant chemotherapy prior to surgery,
and 31% underwent BCS.
Table 1
Demographic variables of patients
Characteristics
Categories (%)
Categories (%)
Age
< 40 y
> 40 y
8 (25%)
24 (75%)
Education
< Metric
≥ Secondary education
4 (12.5%)
28 (87.5%)
Occupation
Homemaker
Employed
27 (84.4%)
5 (6.3%)
Comorbidities
Nil
Diabetes mellitus/hypertension/hypothyroidism
24 (75%)
8 (25%)
Cardio/respiratory illness
None
Bronchial asthma
31 (97%)
1 (3%)
Personal habits
None
Pan chewers
30 (94%)
2 (6%)
Tumor laterality
Right sided
Left sided
6 (19%)
26 (81%)
Quadrants
Outer
Inner and central
22 (68.75%)
10 (31.25%)
Histopathological grade
Grade I—1 (3%)
Grade II—23 (72%)
Grade III—8 (25%)
Histopathological type
Infiltrating ductal carcinoma
Metaplastic carcinoma
31 (97%)
1 (3%)
Hormone status
Luminal A—4 (12.5%)
Luminal B Her2 −ve—10 (31.3%), Her2 +ve—8 (25%)
TNBC/basal like—4 (12.5%)
Her2 enriched—6 (18.8%)
Clinical stage
I—3 (9.37%)
≥ III—8 (25%)
II—21 (65.6%)
Pathological stage
0—4 (12.5%)
I—8 (25%)
II—14 (43.75%)
≥ III—6 (18.75%)
NACT
Upfront surgery
NACT
23 (71.875%)
9 (28.125%)
Lymph nodes dissected
Adequate
< 10 nodes
24 (75%)
8 (25%)
Nodal status
N0—13 (41%)
N1—6 (18.8%)
N2—4 (12.5%)
N3—2 (6.3%)
pNx—3 (9.3%)
pN0(i + )—4 (12.5%)
Extracapsular extension
No
Yes
30 (94%)
2 (6%)
Margin status
Positive
Negative
1 (3%)
31 (97%)
Treatment details
Surgery
BCS
MRM
22 (69%)
10 (31%)
Chemotherapy
4AC→4 Taxol 9 (28%)
4AC→12 paclitaxel + trastuzumab →maintenance trastuzumab 13 (40.8%)
4AC→12 paclitaxel 7 (22%)
No chemo/stopped chemo—3 (9.3%)
Radiotherapy
42.15 Gy/16 Fr—10 (31.3%)
40 Gy/15 Fr f/b boost—1 (3%)
42.5 Gy/16 Fr f/b 10 Gy/5 Fr boost—21 (65.6%)
Treated areas
Breast only—11 (34%)
Chest wall only—3 (9.4%)
Breast + SCF—11 (34%)
Chest wall + SCF—6 (18.8%)
Chest wall + SCF + IMN—1 (3.1%)
RT technique
3DCRT
VMAT
25 (78%)
7 (22%)
Abbreviations: 3DCRT, three-dimensional conformal radiotherapy; AC, adriamycin + cyclophosphamide;
BCS, breast conservation surgery; f/b, followed by; IMN, internal mammary node; MRM,
modified radical mastectomy; NACT, neoadjuvant chemotherapy; RT, radiotherapy; SCF,
supraclavicular fossa; TNBC, triple-negative breast cancer; VMAT, volumetric modulated
arc therapy.
Patient Compliance
The compliance rate was high with 93.5% patients completing the entire radiation course
with the DIBH plan. About 6.5% could not continue DIBH plan, and had to be changed
to treatment in FB. Of the 6.5% (two patients), one patient had difficulty in comprehending
the technique and usage of the spirometer. In contrast, the second patient understood
the technique but could not achieve the breathing threshold during treatment. An interesting
observation was that both the noncompliant patients were older than 65 years. The
average breath-holding time for all patients was 27 seconds (range 20–36). The breath-hold
parameters are summarized in [Table 2 ].
Table 2
Breath-hold parameters
Breath-hold parameters
Mean ± SD
Range
Breathing threshold (L)
1.08 ± 0.11
0.8–1.2
Breath-hold seconds (s)
27.42 ± 3.71
20–36
Breath-hold cycles to complete treatment
5.78 ± 1.17
4–8
Minimum time taken (min)
15.5 ± 6.21
10–45
Maximum time taken (min)
29.6 ± 10.2
20–60
Mean time taken (min)
18.91 ± 6.58
14.2–51.4
Abbreviation: SD, standard deviation.
As treatment progressed, there was an overall improvement in total time taken for
completion of the cycle by 25% (7–40%), that is, patients required 25% less time toward
the completion of treatment as compared with the first week. On assessing the mean
time during the first and the last weeks of treatment, the mean time and the number
of breath-hold cycles required for each treatment decreased toward the completion,
indicating better compliance after the initial few fractions of RT. The mean time
taken for delivery of 3DCRT was 18.46 seconds and 23.7 seconds for VMAT.
The mean ipsilateral lung volume in DIBH was significantly higher than FB (1,312.74 ± 239.24
vs. 954.28 ± 150.74 mL). Lung expansion had a positive correlation to breathing threshold
with patients with good lung expansion having good breathing threshold and breath-hold
time in seconds. There was a moderately positive correlation between age and mean
time taken (p = 0.09).
Dosimetry
Target Volume
The mean values of V95 of the CTV in FB (88.26 ± 4.56%) and DIBH (89.53 ± 4.65%) were
comparable (p = 0.196). The mean values of D95, D2, and D98 were comparable, with no significant
difference between the two techniques.
Organs at Risk
The ipsilateral lung V20 and mean lung dose were significantly higher in FB (p < 0.001). The contralateral lung V20 and mean dose in FB were not significantly different.
The V5, V25, and mean heart dose were significantly higher in FB compared with DIBH
(p < 0.001). The mean dose received by LAD was significantly higher in FB compared with
DIBH, with an average difference of 12.276 Gy (p < 0.001). LAD D
max in FB was higher with a difference of 11.95 Gy (p < 0.001), and the LAD planning organ at risk volume (PRV) D
max dose was higher in FB. The dosimetric parameters for OARs in FB and DIBH are tabulated
and compared in [Table 3 ]. For patients undergoing VMAT, mean heart dose was 10.9 Gy in FB plans versus 6.2 Gy
with DIBH.
Table 3
Dosimetric parameters of organs at risk with free breathing and DIBH
Organ/parameter
Free breathing
DIBH
Mean difference (SD)
p -Value
Ipsilateral lung
V20 (%)
25.96 ± 8.03
17.44 ± 5.03
8.50 ± 7.57
<0.001
Mean dose (Gy)
12.06 ± 3.14
8.9 ± 2.29
3.14 ± 2.76
<0.001
Contralateral lung
V20 (%)
0.09 ± 0.23
0.06 ± 0.26
0.03 ± 0.35
0.615
Mean dose (Gy)
1.41 ± 1.88
1.28 ± 1.94
0.13 ± 1.94
0.326
Heart (for left-sided tumors only)
Mean dose (Gy)
7.01 ± 3.76
3.34 ± 3.16
3.68 ± 2.33
<0.001
V25 (%)
9.24 ± 5.62
1.88 ± 2.66
7.36 ± 4.72
<0.001
V5 (%)
31.25 ± 27.17
15.98 ± 24.55
15.26 ± 15.32
<0.001
Left anterior descending artery
Mean dose (Gy)
23.96 ± 7.27
11.68 ± 6.85
12.28 ± 7.36
<0.001
D
max (Gy)
42.2 ± 4.82
30.24 ± 10.51
11.96 ± 9.27
<0.001
PRV D
max (Gy)
43.67 ± 2.69
36.88 ± 7.13
6.79 ± 5.97
<0.001
Abbreviations: DIBH, deep inspiration breath hold; PRV, planning risk volume; SD,
standard deviation.
With increased lung expansion, there was a decrease in ipsilateral lung mean and LAD
mean doses ([Fig. 2 ]). For every percentage increase in lung expansion, the ipsilateral lung mean dose
reduces by 12%, and the LAD mean dose reduces by 15%. The acute toxicities consisted
of dermatitis and dysphagia; 86.7% developed grade 1 dermatitis, while 13.3% developed
grade II. Grade I dysphagia was seen in only 30%, while rest were asymptomatic. Of
these nine patients, seven received RT to supraclavicular fossa. The average mean
dose to esophagus was 8.7 ± 1.4 Gy and mean D
max dose was 26.76 ± 14.28 Gy. However, the esophageal mean (p = 0.045) and D
max (p = 0.249) doses did not correlate significantly with dysphagia.
Fig. 2 Correlation of lung expansion with left anterior descending (LAD) artery mean dose.
Discussion
The present study aimed to assess the dosimetric benefit of DIBH compared with FB,
compliance, and toxicities. We found that DIBH showed a significant decrease in ipsilateral
lung and heart mean dose and volume parameters. DIBH was well tolerated, with a compliance
rate of 93.5%, and patients completed treatment faster in the last week of treatment.
The acute toxicities were minimal.
In the present study, we found that DIBH contributed to a significant dose reduction
in the heart. There was reduction in V5, V25, and mean heart dose. This was in agreement
with studies done by Bruzzaniti et al, where the mean dose to the heart was significantly
lower in DIBH, and another conducted by Darapu et al, where 46% reduction in V25 for
heart was seen as compared with the FB plan.[27 ]
[28 ] Mean dose to the heart in DIBH in their study was much higher (4.78 Gy), whereas
we achieved a mean heart dose of 3.3 Gy similar to the study by Swamy et al.[29 ]
The LAD artery is in the anterior most part of the heart and is at direct risk of
developing radiation-induced ischemic heart diseases as it is maximum exposed to radiation
while using the tangential fields. Bruzzaniti et al reported reduction in heart and
LAD dose by 78% with DIBH and normal tissue complication probability (NTCP) values
for pericarditis were zero. In our study, we found that LAD mean dose, D
max , LAD PRV D
max all to be statistically significantly lower in DIBH compared with FB. These studies
also report significantly lower lung mean doses, 16% in the study by Bruzzaniti et
al, 15.7% lower in the study by Darapu et al and Swamy et al. The present study also
showed a statistically significant difference in lung mean dose and V20 doses. Many
similar studies have shown dosimetric benefit of DIBH; however, they lack information
on compliance and breath-hold parameters.[30 ]
[31 ] A systematic review and meta-analysis by Lu et al analyzed 41 studies with 3,599
left-sided breast cancer patients comparing DIBH with FB. They found that DIBH significantly
reduced heart dose (D
mean , D
max , V30, V10, V5), LAD dose (D
mean , D
max ), ipsilateral lung dose (D
mean , V20, V10, V5), and heart volume.[32 ]
Although there is significant dosimetric benefit of DIBH in breast cancer, its implementation
in routine practice varies. A survey among European Organization for Research and
Treatment of Cancer–affiliated institutions in 2010 showed only 19% implemented DIBH.[24 ] However, a recent survey conducted in the United States by Desai et al showed that
73% used a cardiac-sparing technique with DIBH accounting for 43%.[33 ] They also found patient tolerance to be the most important determinant for DIBH
in left-sided breast cancer. Our study found majority of the patients to be compliant
with the DIBH technique. The patients who were unable to continue the DIBH-based treatment
were aged more than 65 years. This was in agreement with the study conducted by Latty
et al and Nissen and Appelt.[34 ]
[35 ] Desai et al also found 23% of physicians using DIBH for right-sided breast cancer
patient with lung and heart sparing. Demiral et al showed DIBH for right-sided breast
cancer patients resulted in decrease in mean lung, heart, and liver dose.[36 ] In the present study as well, six right-sided patients were treated wherein DIBH
resulted in lung sparing.
We analyzed the correlation between various breath-hold parameters such as breathing
threshold and breath-hold seconds with lung expansion and found that lung expansion
had a good correlation concerning breathing threshold and breath-hold seconds. With
lung expansion, there was decrease in lung and LAD mean dose. This is consistent with
the results published by Cao et al.[37 ] Vuong et al reported inverse correlation with increase in DIBH left lung volume
and inspiratory volume with maximum heart dose and lung V20.[38 ]
This study explores routine implementation of DIBH in clinical practice for left-
and right-sided breast cancer patients with good compliance. Our study was limited
by sample size, lack of long-term toxicities, and clinical impact of reduced normal
tissue doses. We did not report the setup reproducibility of DIBH compared with FB.
Conclusion
The use of DIBH for delivering adjuvant RT can significantly reduce dose exposure
to critical OARs such as heart, lung, LAD especially in left-sided breast cancers
and should be implemented in all patients who are compliant with the technique.
