Key words
breast cancer - breast irradiation - cardiotoxicity - DIBH - SGRT
Schlüsselwörter
Brustkrebs - Brustbestrahlung - Kardiotoxizität - DIBH - SGRT
Background
Worldwide breast cancer is the most common cancer affecting women. Adjuvant radiotherapy
plays a central role after breast conserving surgery in early-stage breast cancer.
A considerable number of trials [12]
[13]
[18]
[19]
[23]
[24]
[29]
[34] has shown on the one hand a reduction in recurrence and death rates from breast
cancer and on the other hand an improvement in overall survival with adjuvant radiotherapy.
A large meta-analysis by the Early Breast Cancer Trialist’s Group [23] found that patients treated with radiation therapy after breast-conserving surgery
(BCS) had a 7 % chance of local recurrence after 5 years compared with 26 % in patients
who did not undergo radiotherapy. Additionally they had an absolute risk reduction
of 5.4 % in breast related mortality with radiation therapy after BCS compared with
BCS alone.
Despite its improvements, radiotherapy to the breast can cause side effects. A long-term
complication of left breast irradiation is the risk of cardiac mortality and morbidity
as well as pulmonary complications as multiple epidemiological studies have shown
[18]
[24]. Darby et al. [16] found after retrospectively analyzing 2168 patients from the Nordic cancer registry
that the relative risk for ischemic heart disease increased by 7.4 % for every 1 Gray
(Gy) in mean heart dose. However especially the Ramus interventricularis anterior
(RIVA; left anterior descending coronary artery- LADCA) has a high risk of obtaining
significant higher doses and is responsible for the development of pathologic blood
vessel disorder and myocardial or coronary artery disease [1]
[20]
[21]
[22].
Modern radiation treatment techniques may reduce the dose to the heart. For this purpose
the deep inspiration breath-hold technique has made considerable efforts to reach
this goal in minimizing the dose to the heart [3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
[14]. The technique is based upon the observation that during inspiration, the flattening
of the diaphragm and the expansion of the lungs pull the heart away from the chest
wall. Deep inspiration breath hold (DIBH) is a radiation therapy technique where patients
take a deep breath during treatment to a specific threshold and hold this level of
inspiration during every radiation therapy field delivered. By taking a deep breath
in, the lungs fill with air and thus the heart will move away from the chest.
SGRT (Surface Guided Radiation Therapy) is a system to position and monitor the patient’s
external surface during their radiation treatments to ensure they are in the correct
position. It matches surface data in real-time and tracks the patient in all six degrees
of freedom to a reference model captured either during the planning process or using
the internal imaging in the treatment room. SGRT can be used both in setup and therapy
for breast cancer patients, DIBH, SRS, SBRT, thoracic lesions and many more. With
SGRT, the radiation treatment can be delivered much more accurately to the intended
target for every patient than with other techniques.
The DIBH technique with SGRT (Catalyst System) was adopted and clinically implemented
at the institute of radiation oncology at the KFJ/SMZ-South Vienna in October 2013
for all patients with left-sided breast-cancer. The aim of this report is to provide
our experiences regarding the implementation, utilization, patient compliance, planning
methods, treatment verification, dosage and limits of the DIBH-technique with SGRT.
The primary goal was to evaluate if there would be a relative reduction in Dmean heart
and left lung dose between the two cohorts (DIBH vs. NB).
Patients and methods
Patients
Between Oct 2013 -and December 2018 548 consecutive patients with histologically confirmed
breast cancer were enrolled. The patients were referred to radiotherapy following
conservative surgery of left-sided invasive breast cancer. All eligible patients were
informed about the potential benefit of an additional deep inspiration breath hold.
Part of our daily clinical routine is that all patients are offered the oppurtunity
to try the training session for the DIBH-technique independent of age or breathing
activity or respiratory disorders. Patients who turned out to be unfit for DIBH were
enrolled for NB.
Data was collected by analysing patients records. All treatments described in the
present report were carried out in accordance with national law. Before starting the
entire treatment procedures, all patients had to give their informed consent for the
treatment in DIBH (deep inspiration breath hold) and also for the NB (normal breathing)-method.
Treatment prescriptions
Postoperative RT is strongly recommended after BCS [31]
[32]
[34]. A whole breast radiation therapy (WBRT) alone reduces the 10-year risk of any first
recurrence (including locoregional and distant) by 15 % and the 15-year risk of breast
cancer-related mortality by 4 % [34]. Boost irradiation gives a further 50 % RR reduction. It is indicated for patients
who have unfavourable risk factors for local control such as: age < 50 years, grade
3 tumours, extensive DCIS, vascular invasion or non-radical tumour excision [31]
[32]
[34]. Doses used for local and/or regional adjuvant irradiation have traditionally been
45–50 Gy in 25–28 fractions of 1.8–2.0 Gy with a typical boost dose of 10–16 Gy in
2 Gy single doses. Shorter fractionation schemes (e. g. 15–16 fractions with 2.5–2.67 Gy)
were also used according to the Start B protocol [17]
[29]
[35]
[36] or the Whelan regimen [19]. An irradiation of the axillary lymph nodes with 50 Gy in 25 fractions as specified
by guidelines [12] was performed when indicated. Nevertheless at our institute it is extremely seldom
that an irradiation of the internal mammary nodes [13] is carried out according to the AGO-and/or S3-guidelines [31]
[32] – however, in this cohort no treatment of the lymph nodes of the A. mammaria interna
was performed.
Workflow and system
Primarily all patients underwent the same workflow:
-
Training session for DIBH: upper and lower thresholds of breathing can be fixed, positioning
of respiratory marker block (with integrated infrared reflectors), audio- and video
feedback
-
CT-Scan in DIBH and or additionally in NB; for immobilization we used breast boards
with both arms positioned above the head in a spine position
-
Planning and verification (either in DIBH or if not possible in NB)
-
Daily treatment
-
Daily imaging with an adaptive planning approach
-
Psychological support and information once a week in order to enable a return to normal
life after breast cancer
At our institute the Varian Real-time Position Management™ (RPM) system and the Catalyst™
software and system from C-Rad are used. RPM is a non-invasive, video-based system
that allows for clean imaging and treatment of lung, breast, and upper abdominal sites.
The RPM system accommodates both breath hold and free breathing protocols. The Catalyst
system for real time patient tracking captures the complete body surface of the patient
continuously, compares the current patient posture and position to the previously
recorded reference setup in real-time, detects intra-fraction motion and is also used
for respiratory gating as shown in [Fig. 1]. The unit is mounted on the ceiling where it has an unobstructed view of the patient
independent of any motion of the gantry or its on-board imagers. The Catalyst™ software
has a tight connection and integration with the Varian RPM system. The specially designed
filter monitors can predict the patient’s breathing pattern and can account for the
patient’s coughing or changes from the predicted breathing pattern. The tumour position
can be correlated in relation to the patient’s respiratory cycle. Using an infrared
tracking camera and a reflective marker, the system measures the patient’s respiratory
pattern and range of motion and displays them as a waveform.
Fig. 1 SGRT using a phantom for real time patient tracking at KFJ Vienna; the tumour position
can be correlated in relation to the patient’s respiratory cycle.
The gating thresholds are set when the tumor is in the desired position of the respiratory
cycle. These thresholds determine when the gating system turns the treatment beam
on and off [25]
[26]
[27] as illustrated in [Fig. 2].
Fig. 2 Respiratory pattern in DIBH (deep-inspiration-breath-hold)-technique – deep inspiration
within upper and lower thresholds; “beam” on is illustrated by yellow bar.
In this way the dose to the heart can be minimized in our breast treatments, the maximum
heart distance of the heart irradiated is less than 1 cm ([Fig. 3]).
Fig. 3 Radiotherapy of left-sided breast cancer in DIBH – maximum heart distance of heart
irradiated is less than 1 cm.
Furthermore the patients are treated with two identical Varian Truebeam linear accelerators
with an integrated “Perfect Pitch” (6-DoF-couch), a computer-controlled robotic treatment
couchtop with remote positioning correction and 6 degrees of freedom [28]. The modern planning techniques included IMRT (intensity modulated radiotherapy)-,
FIF (field in field) – and standard techniques. The targets (whole breast or chest
wall +/– axillary lymph nodes), organs at risk (ipsilateral lung, contralateral lung,
heart and contralateral breast) and other organs of interest were delineated as per
the RTOG (Radiation Therapy Oncology Group) contouring recommendations [33].
Follow up schedule and statistical analysis
Our routine care programme lasts on average ten years; follow up was routinely scheduled
every 3 months in the first year following radiotherapy, every 6 months in the second
year and at 12-month intervals thereafter. If possible, acute radiation induced side
effects were classified according to the Radiation Therapy Oncology Group/The European
Organisation for Research (RTOG) [37]; late toxicity rates according to the Common Terminology Criteria for Adverse Events
(CTCAE Version 4.03) [38]. Toxicity was considered early if it occurred within the first 90 days from the
start of radiotherapy. Other assessments include: the complete new personal medical
history, a physical examination, imaging, a full blood count, liver and renal function
tests, alkaline phosphatase and calcium levels, an assessment of the menopausal status
of the patient, a bone densitometry every two years and an evaluation of the cardiac
function with a cardiac ultrasound or a multigated acquisition scan.
The outcomes evaluated in this retrospective analysis were primarily the feasibility
and the workflow of DIBH with SGRT and secondarily, demographics as treatment-regimens
and dosimetric outcomes like Dmean of the lungs and the heart. The statistical analysis
was performed with the SPSS (Version 20) and Excel Office 2017; the primary goal of
this analysis was an inter-cohort comparison.
The project has been displayed to the ethics committee and meets the requirements
of the local guideline.
Results
Demographics
From Oct 2013 – Mai 2018 548 patients were enrolled, 517 of them could receive the
DIBH-technique, 31 were treated in NB. We also treated 8 patients with right-sided
breast cancer [2], 15 patients had both-sided breast cancer. Two male patients were included (0.4 %).
The median age of the DIBH-patients was 58 years (27–90), of the NB-patients 65 (30–80)
years.
The majority of the patients were postmenopausal. No difference between the two groups
was found regarding tumor site, TNMstaging, grading and hormonal receptor status.
100 patients received neoadjuvant systemic treatment (NACHT-regimen), 27 adjuvant
chemotherapy, 453 antihormonal treatment and 50 patients had to undergo a Trastuzumab-regimen.
Almost all patients (94.3 %) had a breast-conserving surgery, 4.6 % of the patients
had oncoplastic techniques such as glandular adaptation, local or distant flaps or
mammoplasty permitting breast remodeling. Extremely radical and radical surgical treatment
of breast cancer were not investigated in this cohort. Nevertheless 30 patients (5.5 %)
had an Ablatio mammae. Sentinel Node Biopsy as a standard procedure was performed
in 98 % of the cases, 18 patients received an additional Level I and/or Level II axilla
dissection (23 % N+ of the patients).
The majority of the treated patients had the staging T1 (373) and N0 (416) as shown
in [Table 1]. There was an equal distribution between grading G1, G2 and G3. 40 patients suffered
from heart diseases, especially coronary heart disease; 24 patients had preliminary
lung problems including bronchial asthma and severe COPD. A detailed comparison of
the patient-related factors of both treatment groups may be found in [Table 1].
Table 1
Patient, disease and treatment characteristics.
|
|
NB (n = 31)
|
DIBH (n = 517)
|
|
Age
|
Mean
|
65
|
58
|
|
Min
|
30
|
27
|
|
Max
|
80
|
90
|
|
Sex
|
Male
|
0
|
2
|
|
Female
|
31
|
515
|
|
OP
|
AD
|
7
|
11
|
|
Ablatio
|
3
|
27
|
|
Sentinel
|
31
|
506
|
|
BET
|
28
|
490
|
|
Remodeling
|
2
|
|
|
Both sided
|
|
3
|
12
|
|
T
|
T1 (pT1 / pT1mi/ypT1)
|
24
|
349
|
|
T2 (pT2 / ypT2)
|
1
|
76
|
|
T3 (pT3 / ypT3)
|
2
|
8
|
|
T4 (pT4 / ypT4)
|
0
|
3
|
|
Tis (pTis/ypTis)
|
1
|
47
|
|
ypT0
|
2
|
30
|
|
ypTx
|
1
|
4
|
|
N
|
pN0 / ypN0
|
18
|
398
|
|
N1 (N1 / N1a/N1mi)
|
9
|
79
|
|
N2 (N2a)
|
1
|
2
|
|
N3 (N3a)
|
1
|
4
|
|
Nx
|
1
|
4
|
|
No data
|
1
|
30
|
|
Grading
|
G1
|
4
|
77
|
|
G2
|
20
|
271
|
|
G3
|
4
|
123
|
|
No data
|
3
|
46
|
|
Herceptin
|
Yes
|
3
|
47
|
|
No
|
22
|
458
|
|
No data
|
6
|
12
|
|
HRT
|
Yes
|
26
|
5
|
|
No
|
5
|
458
|
|
No data
|
0
|
17
|
|
CHT
|
Yes
|
5
|
99
|
|
No
|
26
|
402
|
|
No data
|
0
|
16
|
|
RTOG
|
RTOG1
|
22
|
331
|
|
RTOG2
|
6
|
150
|
|
RTOG3
|
2
|
29
|
|
No reaction
|
1
|
7
|
|
CTCAE
|
CTCAE1
|
16
|
65
|
|
CTCAE2
|
1
|
38
|
|
G3–5
|
0
|
0
|
|
No reaction
|
14
|
414
|
HRT = Hormontherapie; CHT = Chemotherapie; RTOG = Radiation Therapy Oncology Group/The
European Organisation for Research; CTCAE = Common Terminology Criteria for Adverse
Events.
Dose and fractionation prescribed in this analysis represent standard treatment prescriptions
at our institution and the radiotherapy treatment characteristics are shown in [Fig. 4].
Fig. 4 Coverage of dose using 3 different RT-schemes.
51 % of all 548 enrolled patients received a total dose of 50 Gy in 25 fractions +/–
boost irradiation (Standard protocol), 47 % of 40.05 Gy in 15 fractions (Start B protocol
– 17, 29, 35, 36) and 2 % of 42.5 Gy in 16 fractions (Whelan protocol – 19). In 12
cases we irradiated the axillary lymph nodes with 50 Gy in 25 fractions as specified
by guidelines [12]. Nevertheless it is interesting to note that 82 % of the NB – patients underwent
a hypofractionation protocol ([Fig. 4]).
Dosimetric outcomes
The comparison of average dose parameters to the heart and left lung using DIBH vs.
NB is summarized in [Fig. 5]. Actually great efforts were taken to optimize the treatment planning on the computed
tomography data sets of the patients; in order to be able to pick the best plan we
decided to create at least six plans per patient (Range 4–12 plans), some of them
in free-breathing (NB). The average coverage of Dmean left lung was 6.91 Gy (Range
1.44 Gy–12.4 Gy) in the DIBH cohort. 75 % of all patients were able to meet a Dmean
under 8.41 Gy. We also evaluated the NB plans. In this evaluation the Dmean left lung
was 8.92 Gy (Range 5.23–16.9 Gy). This shows that the DIBH-technique reduced the Dmean
at the ipsilateral lung around 2 Gray.
Fig. 5 Dmean for heart and left lung (Comparison NB vs. DIBH) – Dmean reduction heart by
45.4 %, ipsilateral lung by 22.5 %.
The high maximum in the DIBH group had one patient suffering from left heart failure
with an enormous breast (V 2032.91 cc) and positive lymph nodes (5/12) receiving RT
to the whole breast plus nodal RT. For this patient 12 different treatment plans were
generated, three of them were normal breathing plans (NB) in order to be able to make
a comparison it with the DIBH-plans. The Dmean left lung was much higher in the NB
plans (the best NB-plan had a Dmean left lung of 16.9 Gy), thus we could reduce the
dose to the left lung to around 4.5 Gy even in this special case. The treatment was
well tolerated. Afterwards a close follow-up care quarterly was performed in the first
24 months. In this periode the patient developed neither radiation pneumonitis nor
lung fibrosis.
Additionally, the DIBH technique reduced the Dmean of the heart compared to NB. The
average coverage of Dmean heart was 1.17 Gy (Range 0.12 Gy – 3.19 Gy) in the DIBH
cohort. 75 % of all patients were able to reach a Dmean under 1.55 Gy. The NB plans
had a Dmean heart of 2.31 Gy (Range 0.71–4.21 Gy), which means that the DIBH-technique
could halve the Dmean heart according to literature [16]
[39]
[54]
[55]
[56]
[57]
[58]. The maximum heart distance (maximal thickness of heart irradiated) was mostly less
than 1 cm (Range 0.8–1.2 cm) during irradiation of our DIBH breast cancer cases, mostly
less than 2 cm (Range 1.1–3.2 cm) in the NB plans.
In summary the Dmean heart could be reduced by 45.4 % compared with the NB-technique
and the Dmean left lung by 22.5 % ([Fig. 5]).
Technical problems
In our series this innovative technique had to deal with different problems concerning
breathing conditions (e. g. abdominal breathing, nervous breathing, respiratory problems),
the cognitive situation of the patient (e. g. memory performance, memory loss, dementia
and many more) and the barrier of language. Even the marker block sometimes caused
trouble (e. g. lack of signal, block lies in the treatment field). In daily routine
this technique was associated with a higher amount of work, the assumption of additional
responsibility for the special working group, a high expenditure of time and probably
additional costs. We determined that the additional time we needed was up to 40 minutes
according to our time schedule (Range 32–52 min) when performing the virtual simulation.
Apart from this it needed up to 10 extra-minutes in daily routine per patient for
treatment delivery due to the breathing commands and the complex set up. Although
this technique was time consuming, needed patient cooperation and technical expertise
it clearly reduced the doses to the heart and left lung. Similar findings have been
reported in literature [20]
[42]
[47].
Follow up
Follow-up was carried out until June 2019, at that time all patients were still alive.
Median follow-up for all patients was 52 months (range 7–73 m). No relevant differences
were found between both treatment groups. Side effects were classified according to
the Radiation Therapy Oncology Group/The European Organisation for Research [37], there was a slight difference between both arms, the NB arm had less RTOG 2 skin
reactions (NB: DIBH = 19.4 %:29 %). Apart from this the amount of the side effects
was comparable (RTOG 1: 70.8 % vs. 64 %, RTOG 3 6.6 % vs. 5.6 %, no reaction 3.2 %
vs. 1.4 %). Late toxicity rates according to the Common Terminology Criteria for Adverse
Events Version 4.03 (including teleangiectasia, skin and subcutaneous tissue disorders,
skin atrophia, skin hyperpigmentation, pruritus, skin induration, skin ulceration)
were distributed similarly, however we noted a higher teleangiectasia rate in patients
who received a systemic therapy with chemotherapy and trastuzumab. Additionally there
were 4 times more CTCAE 1 events in the NB-arm (51.6 % vs. 12.67 %). One reason for
this could be that the hypofractionation regimen was used in 82 % of the NB-patients.
Grade 3–5 late side effects did not occur in both arms. A detailed comparison of the
group-specific toxicity results is depicted in [Table 1], [Fig. 6].
Fig. 6 Comparison DIBH and NB patients: acute side effects RTOG-classification, late side
effects CTCAE-criteria.
Discussion
Cardiac toxicity after breast cancer [16]
[34]
[48]
[52], lung cancer [53]
[54] and mediastinal lymphoma [49]
[50]
[59] is the most reported radiation-induced complication [51]. The common clinical complications are asymptomatic pericarditis, congestive heart
failure, and heart infarction. Even though clinicians have to give particular attention
to these complications, anthracycline treatment [60]
[61]
[62]) is an additional major risk factor for additional cardiotoxicity during radiotherapy
with a synergistic effect. However, the use of anthracycline, other cardiotoxic chemotherapies,
immunotherapy [63]
[64]
[65] and targeted therapies [66]
[67] should only be used with great caution and only after carrying out a careful treatment
plan and optimization [1]
[30]
[40].
There is a wealth of evidence from retrospective and planning studies demonstrating
reduction in dose to the heart and coronary arteries with DIBH treatment of left-sided
breast cancers [10]
[14]
[15]. Additionally the total dose delivered to the planning target volume (PTV), the
dose per fraction and the irradiated volume are correlated to the risk of cardiotoxicity.
Remarkably, the volume of the heart receiving 35 Gy must be less than 30 % and dose
per fraction should not exceed 2 Gy when dose of prescription exceeds 30 Gy as previous
studies confirmed [30]. On the one hand Darby et al. [16] showed a dose/effect-relationship with an increase in the relative risk of acute
major coronary events of 7.4 % per Gy (95 % confidence interval, CI: 2.9–14.5; p < 0.001)
mean heart dose within 20 years, on the other hand Van den Bogaard et al. [58] found a relative increase in the cumulative incidence of acute coronary events (ACE)
of 16.5 % per Gray(hazard ratio, HR: 1.165; 95 % CI for HR: 1.006 to 1.350; p = 0.042)
of mean heart dose within 9 years of RT.
Modern irradiation techniques seem to be associated with a limited risk of heart complication.
Taylor et al. [21]
[56]
[57] comparatively analyzed mean heart doses from left tangential RT to cardiac structures
over several decades, and described reductions in mean heart dose from 13.3 Gy in
the 1970 s, to 4.7 Gy in the 1990 s, and 2.3 Gy in 2006 due to major advances in RT
techniques. Deep inspiration breath hold (DIBH) reduces heart and left anterior descending
artery (LAD) dose during left-sided breast radiation therapy (RT); however there is
limited information about which patients derive the most benefit from DIBH. Our study
results are similar to published retrospective and planning studies demonstrating
that DIBH lowered Dmean Heart and LAD doses [2]
[4]
[8]
[10]
[14]
[15]
[41]. Based on available findings, the DEGRO breast cancer expert panel recommends a
Dmean heart dose < 2.5 Gy [55]. Additionally, the study of Yeung et al. [39] showed that all patients receiving WBRT (whole breast irradiation) with DIBH met
a Dmean heart < 4 Gy and had less heart problems. Remarkably, in our series all patients
with DIBH could reach a Dmean heart < 1.2 Gy and almost all patients with NB a Dmean
heart < 2.3 Gy which means that our data could comply the DEGRO-recommendations.
However, proton therapy is another breast cancer radiation modality used to spare
heart radiation exposure, taking advantage of the dosimetric properties of protons
to reduce cardiac doses. Recent series have shown remarkably low cardiac doses with
proton therapy [43]. Comparisons of protons at free-breathing versus photons with DIBH have shown that
both techniques yield remarkably low heart doses, although proton plans appear to
deliver lower mean heart dose and lower dose to the LAD [44]
[45]. This may be answered by the PCORI RADCOMP trial [46]. This trial aims to enroll 1716 patients receiving radiotherapy to the breast or
chestwall in conjunction with the internal mammary nodes and randomizes them to radiotherapy
with either protons or photons. The primary endpoints of this trial are cardiac events
and cancer control events.
Nevertheless limits of our analysis are the retrospective design, the lack of randomization
and follow up in terms of recurrence probability. It is possible that the small sample
sizes used in this retrospective analysis did not achieve the statistical power to
show a significant effect. Further prospective studies with larger sample sizes are
required to determine if there is a statistical difference between NB and DIBH and
to determine threshold doses to cardiac structures in breast radiotherapy.
Conclusion
To sum up the Deep inspiration breath-hold (DIBH) technique with Surface Guided Radiation
Therapy (SGRT) is a rather simple method with a high acceptance by patients who can
actively participate in the whole treatment process. With appropriate patient selection
and adequate training the treatment delivery is acceptable and feasible. DIBH with
SGRT should be considered for all patients receiving RT for left-sided breast cancer.
In particular, patients with breast/chest wall RT plus nodal RT seem to benefit most.
In our cohort the reproducibility and stability of the combination of DIBH with SGRT
was evident.
