Single-Fraction Very Accelerated Partial Breast Irradiation (sfVAPBI) in Low-Risk Invasive or Ductal In Situ Breast Carcinoma - Phase II Multicenter Trial
Phase: NA
Conditions: Breast Neoplasms
Sponsor: National Institute of Oncology, Hungary

1 
 
GROUPE EUROPÉEN DE CURIETHÉRAPIE - EUROPEAN SOCIETY FOR 
RADIOTHERAPY & ONCOLOGY (GEC-ESTRO) 
BREAST CANCER WORKING GROUP 
 
 
SINGLE-FRACTION VERY ACCELERATED PARTIAL BREAST 
IRRADIATION (sfVAPBI) IN LOW-RISK INVASIVE OR DUCTAL IN SITU 
BREAST CARCINOMA 
 
 
PHASE II MULTICENTER TRIAL 
 
National Clinical Trial Identifier Number: NTCxxxxxxxx 
 
Study chairman:  
 
 
Co-chairmen:  
 
 
 
STUDY PROTOCOL Version 1.6 
February 19, 2025.  
 
 

2 
 
I. SYNOPSIS 
 
1. Rationale 
 
Accelerated Partial Breast Irradiation (APBI) has demonstrated the non-inferiority 
compared to external beam radiotherapy (EBRT) in the conserving-treatment of early 
breast carcinoma by using high-dose-rate (HDR) multicatheter interstitial 
brachytherapy (MIBT). The standard treatment regimen is 7-8 sessions with two 
treatments per day, for a total treatment time of 4-5 days 1. Based on 5-year results of 
the GEC-ESTRO very accelerated partial breast irradiation (VAPBI) phase I-II trial, 
in low-risk cases, 3-4 fractions delivered in 2 days reduced the overall treatment time 
with low rate of side effects and excellent oncological outcome 2.  
Retrospective and prospective studies with a single fraction HDR MIBT-based VAPBI 
suggest that by further increasing the dose delivered in one fraction, the total treatment 
time can be reduced to a single session safely 3–5.  
A phase II multicenter trial is proposed to confirm this hypothesis. 
 
2. End points 
 
Primary endpoints: 
- 
Five-year incidence of late grade ≥ 2 side effects 
 
Secondary endpoints:  
- 
Incidence (5-year actuarial rate) of ipsilateral breast recurrence (IBR) 
- 
Incidence (5-year actuarial rate) of regional relapse (RR) 
- 
Incidence (5-year actuarial rate) of contralateral breast cancer (CBC) 
- 
Incidence (5-year actuarial rate) of distant metastasis (DM) 
- 
Incidence (5-year actuarial rate) of any relapse (local, regional or distant, 
whichever came first) for disease free survival (DFS) 
- 
Incidence (5-year actuarial rate) of breast cancer death for cause specific survival 
(CSS) 
- 
Incidence (5-year actuarial rate) of death by any cause for overall survival (OS) 
- 
Incidence of acute side effects 

3 
 
- 
Cosmetic results at 5 years 
- 
Quality of Life (QoL) 
 
3. Selection criteria: 
 
Inclusion criteria 
- 
Stage 0 & I & II (< 3 cm) breast carcinoma 
- 
Lesions of < 3 cm diameter 
- 
Invasive carcinoma of any subtype and grade or DCIS 
- 
Nodal status: pN0 or pN1mi (patients with pN1mi status can be treated, but due 
to the limited clinical evidence, individual decision is needed) 
- 
M0: Absence of distant metastasis 
- 
Clear resection margins by NSABP definition (no tumor on ink) 
- 
Unifocal (multifocality limited within 2 cm) and unicentric breast cancer  
- 
Age> 40 years 
- 
Luminal A or B tumors 
- 
Time interval from surgery preferably less than 12 weeks and no longer than 20 
weeks, and from adjuvant chemotherapy less than 4 weeks 
- 
HER2+ patients receiving postoperative anti-HER2 systemic therapy 
- 
Specific signed consent form prior to treatment 
 
Exclusion criteria: 
- 
Stage II (≥ 3 cm), Stage III-IV breast cancer 
- 
Surgical margins that cannot be microscopically assessed 
- 
Extensive intraductal component (EIC+) 
- 
Extensive lymphovascular invasion (LVI+) (focal is allowed) 
- 
Triple negative breast cancer 
- 
BRCA 1-2 mutation 
- 
HER2+ patients not receiving postoperative anti-HER2 systemic therapy 
- 
Neoadjuvant systemic therapy 
- 
Paget’s disease or pathological skin involvement 
- 
Synchronous or previous breast cancer. 
- 
Pregnant or lactating women 

4 
 
4. Outline 
 
This is a prospective study, non-randomized, multicentric phase II trial.  The primary 
outcome is late grade ≥ 2 side effects. 
 
5. Projected accrual 
 
250 patients in 2 years from 22 centers.  
 
6. Treatment modality 
 
All cases will be treated with interstitial multicatheter brachytherapy. The modality is 
postoperative implant, perioperative implant is not allowed. 
A single fraction of 16 Gy in one day. 
 
7. Definition of CTV and dosimetric requirements 
 
The clinical target volume CTV will the tumor bed with a safety margin of 20mm in 
all directions (surgical margin + radiation margin), avoiding skin ≥5mm and pectoral 
muscle, as described by GEC-ESTRO recommendations 6, 7. The volume enclosed by 
the reference isodose surface depends on the tumor size and on the size of the resection 
margins, mostly about 40-150cc. 
CTV definition should be used according to the GEC-ESTRO recommendations 6, 7. 
CTV dose constraints are D90≥100%, V100>95%, V150<35%, V200<15%, 
DNR<0.35.  
Organs at risk (OARs) are skin, chest wall, lung and heart in left sided tumors. The 
dose values of OARs are registered according to the ESTRO-ACROP guidelines 8.   
Dose volume adaptation is achieved by graphical optimization.  
Dose homogeneity should be controlled keeping dose non-uniformity ratio (DNR) 
<0.35.  
If constraints are not accomplished, the patient should be excluded from the study and 
can be treated with the standard approach. 
 
 

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8. Treatment Schedule 
 
Time interval from final definitive breast surgical procedure to the brachytherapy 
implant is less than 12 weeks (84 days) and no longer than 20 weeks 8. If patients 
receive chemotherapy, brachytherapy can be done before chemotherapy or not later 
than 4 weeks after finishing it. 
 
9. Follow up 
 
- 
Minimum follow-up frequency: 1, 3, 6 and 12 months after the implant, then annually 
for the first five years 
- 
Documentation of acute side effects at 1 and 3 months 
- 
Documentation of late side effects in the next visits 
- 
Documentation of cosmetic results at baseline, at 6 months, 12 months and yearly 
thereafter until 5 years with digital photograph yearly 
- 
Mammography annually for both breasts  
- 
Documentation of QoL at baseline, at 3 months, 6 months, 1 year, 3 years and 5 years 
of follow-up 
 
 

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II. LISTING OF ABBREVIATIONS 
 
APBI: accelerated partial breast irradiation 
BCS: breast-conserving surgery 
BCT: breast-conserving therapy 
BT: brachytherapy 
CI: coverage index 
COIN: conformality index 
CT: computer tomography 
CTV: clinical target volume 
CVS: cavity visualization score 
DCIS: ductal carcinoma in situ 
DHI: dose homogeneity index 
DNR: dose non-uniformity ratio 
EBI: external beam irradiation 
EIC: extensive intraductal carcinoma 
EORTC: European Organization for Research and Treatment of Cancer 
ER: estrogen receptor 
ETB: estimated tumour bed 
FUP: follow-up period 
GEC-ESTRO: Groupe Européen de Curiethérapie - European Society for Therapeutic 
Radiology and Oncology 
Gy: Gray 
HDR: high-dose-rate 
HG: histological grade 
HI: homogeneity index 
IDC: infiltrating ductal carcinoma 
ILC: infiltrating lobular carcinoma 
ImTV: Imaging related Target Volume  
Ir: Iridium 
LDR: low-dose-rate 
LF: local-field 
LR: local recurrence 

7 
 
LTC: local tumour control 
LVI: lympho-vascular invasion 
MAST: mastectomy 
MM: marginal miss 
NR: not reported 
NS: not significant 
OARs: Organs at risk 
PBI: partial breast irradiation 
PR: progesterone receptor 
PTV: planning target volume 
QA: quality assurance 
RR: relative risk 
RT: radiotherapy 
RTOG: Radiation Therapy Oncology Group 
SMS: surgical margin status 
TR: tumor bed recurrence 
VAPBI: very accelerated partial breast irradiation 
WBRT: whole breast radiotherapy 
WS: whole surgical scar 
3D: three-dimensional 
 
 
 
 

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III. BACKGROUND 
 
1. APBI is a standard treatment 
 
Some decades ago, breast-conserving surgery (BCS) overtook and replaced modified 
mastectomy by adding radiation therapy to the whole breast (WBI). As a result, removing 
the entire breast was no longer necessary because the radiation could eliminate residual 
tumor cells and prevent relapse. This change represented a new paradigm that was further 
consolidated as results on long-term effectiveness were reported 9, 10 . In the XXI century, 
we are witnessing another paradigm shift. For years accelerated partial breast irradiation 
(APBI) has been used in phase II studies, considering that, in early low-risk tumors, is 
not necessary to irradiate the entire breast, as the highest percentage of relapses occur in 
the area near the tumor or tumor bed. First a small phase III study with multicatheter 
technique showed that APBI is probably equivalent to WBI, but with a limited number of 
cases 11. Several randomized trials were underway also with other methods of APBI, 
intraoperative radiotherapy (ELIOT 12 and TARGIT 13), intracavitary 14 and external 
beam radiotherapy (EBRT) 15 techniques with variable results. 
In October 2015, 5-year results of the European phase III study with APBI were 
published, using sole interstitial multicatheter brachytherapy versus WBI for low-risk 
invasive and in-situ carcinoma, in 1184 patients 16. This study confirms definitively that 
partial breast irradiation is as effective as WBI for carefully selected patients with early 
breast cancer. This outcome was also confirmed by the 10-year results 1. The cumulative 
incidence of local recurrence was 1.44% at five years and 3.51% at ten years with APBI 
in women over 40 years old, with unicentric small tumors under 3cm of diameter, with 
clear margins of at least 2mm, without involved lymph nodes, lymph or blood-vessel 
invasion, or extensive intraductal component. As consequence nowadays, adjuvant whole 
breast irradiation is no longer the only standard radiation treatment technique in early 
low-risk breast carcinomas. Worldwide the radiation oncologist can offer to patients with 
early breast cancer the option of APBI that allows finishing the adjuvant treatment in five 
days instead of 3-6 weeks and receiving at least fourfold lower doses of radiation to the 
heart and lung compared with WBI.  
At this moment, we can confirm these good results particularly with the multicatheter 
brachytherapy technique, which allows to insert as many catheters as needed to cover a 

9 
 
wide clinical target volume (CTV) around the tumor bed. In summary, the partial breast 
irradiation is the reasonable excellent adjuvant treatment modality in selected patients 
with early-stage breast cancer.  
 
2. Rationale for very accelerated partial breast irradiation 
 
The primary rationale for APBI is the convenience for patients, the APBI makes possible 
to finish the whole radiation treatment in 4-5 days instead of 3-6 weeks. The lower dose 
to the organs at risk (OARs) is another important issue for use of APBI. In the U.S., the 
more frequent fractionation is 3.4 Gy x 10 sessions in five days. In Europe, a fractionation 
scheme of 7-8 fractions is usually employed.  
Importantly, we know that the α / β ratio for breast cancer is low, about 4, therefore the 
fraction sensitivity of breast cancer can be exploited with higher fraction sizes, resulting 
in even more compressed treatment times 17. This option would be advantageous for 
further reduction the total treatment time to finish the whole breast conserving procedure. 
But we must be careful for not to exceed the tolerance of normal tissues. The therapeutic 
window is narrow and the tumor control needs years to be confirmed. A too high dose per 
fraction can result in increase of complications, and a too low dose per fraction can yield 
high rates of recurrences. 
In 2017, the GEC-ESTRO Breast Cancer Working Group started a Phase I-II trial to study 
if very accelerated partial breast irradiation (VAPBI) using 3–4 fractions could be 
equivalent to the standard 7-10 fractions. Eighty-one patients with low-risk invasive 
carcinomas underwent HDR MIBT. Thirty-three women received 4 fractions of 6.25 Gy 
in 2–3 days, and 48 subsequent patients 3 fractions of 7.45 Gy in 2 days. With a median 
follow-up of 62 months, the 5-year actuarial breast recurrence was 3.4% (two cases of 
local relapse). Gr.I. skin toxicity was 12.3%, gr.I. and gr.II. fibrosis was 22.2% and 9.9%, 
respectively. Cosmetic outcome was good or excellent in 95% 2.  
In the TRIUMPH-T trial 185 low-risk breast cancer patients treated with brachytherapy 
applicators. Total dose was 22.5 Gy in 3 fractions of 7.5 Gy. With a median follow-up of 
3.63 years there were 2 (1.1%) ipsilateral local recurrences, Grade 3 fibrosis at the 
treatment site was present in 1.7%, and the cosmesis were excellent or good in 94% of 
patients 18. 
 

10 
 
Workflow optimization of sfVAPBI: 
Based on a description published in 2023, the sfVAPBI procedure optimization makes it 
possible to provide adjuvant breast irradiation for low-risk breast cancer patients during 
a single session (one round trip), including pre- and postirradiation consultations, as well 
as a 5-hour VAPBI procedure in 7 different steps 19. 
 
Feasibility of sfVAPBI: 
In Nice, 26 elderly patients with early breast cancer were enrolled in a prospective phase 
II trial. After lumpectomy a single fraction 16 Gy APBI was performed. After a median 
follow-up of 63 months, 5-year local recurrence-free survival, metastasis-free survival, 
cancer-specific survival, and overall survival rates were 100%, 95.5%, 100%, and 88.5%, 
respectively. There was no grade 3 side effect. Cosmetic evaluation was excellent or good 
in 100% 3. 
 
Preliminary results for efficacy and toxicity of sfVAPBI: 
In the study of Hannoun-Levi et al., two cohorts of 157 older patients with low-risk breast 
cancer treated with APBI were analyzed retrospectively. A total dose of 34 Gy in 10 
fractions (109 pts.) or 16 Gy in 1 fraction (48 pts.) was delivered. After a median follow-
up of 97 and 72 months, no significant difference was observed between the two groups 
for local recurrence, regional recurrence, distant metastases, disease-free survival, cause-
specific survival and overall survival, further in terms of late toxicity and cosmetic results 
5. 
In a retrospective multicenter study 516 patients with low-risk breast cancer underwent 
lumpectomy + VAPBI, which was performed with 4 (4x6.2 Gy/2d, 144 pts.), 3 
(3x7.45 Gy/2d, 167 pts.) or 1 fraction (1x16Gy or 1x18Gy/1d, 205 pts.). After a median 
follow-up of 44 months, the four-year cumulative incidence rate of local recurrence was 
2%. Grade 2 and 3 late toxicities were observed in 7.2 and 0.6% respectively (no Gr.4) 
with no difference between 1 and ≥ 2 treatment days 4. 
 
Quality of life after sfVAPBI: 
Based on an auxiliary studies of the previously mentioned Nice investigation, APBI based 
on a single fraction of MIBT in older adults with low-risk breast cancer, appears to be 
feasible with a minimal loss of autonomy regarding Instrumental Activities of Daily 

11 
 
Living, no loss of autonomy in Activities of Daily Living, an acceptable decrease in other 
Comprehensive Geriatric Assessment Domains, and with no impact on global quality of 
life 20. 
 
These investigations suggest that VAPBI in one-to-three days is feasible to decrease the 
total time of treatment. 
 
3. Selecting the right dose per fraction 
 
The way to choose the right dose and fraction is based on BED calculations. A 
comparison of APBI protocols is done by Rosenstein et al 21. Depending on the α / β ratio 
the BED changes a lot. When we calculating with the generally accepted α / β = 4 value 
of breast tumor, the standard 10 x 3.4 Gy, 8 x 4 Gy and 7 x 3.4 Gy have a BED4 of 63-64 
Gy. If we use only 4 fractions, the right dose per fraction should be 6.25 Gy, and with 
three fractions should be 7.45 Gy.  
By the same reasoning, 16 Gy applied in one fraction shows higher BED and EQD2 
values than previously mentioned more fractionated treatments (Table 1.). 
However, these higher values are necessary. This is because the specific radiobiological 
effects of the possible reduction in re-oxygenation and re-arrangement must be taken into 
account when using a high dose delivered in a single fraction 22. 
Furthermore, in the case of a single fraction, cells are unable to re-arrange through the 
cell cycle. Cells in more radio-resistant phases of the cell cycle, such as the S phase, tend 
to exhibit a greater level of survival compared with cells in more radiosensitive phases, 
such as G2 or mitosis 23. 
From another point of view, the use of the linear quadratic model remains questionable 
for dose per fraction higher than 8 Gy.  
On the whole,  taking all this into account, the dose used for single-fraction treatment was 
determined on the basis of the local tumor control and acute/late side-effect results of the 
above-mentioned studies 3–5. 
 
 
 

12 
 
 
Treatment 
days 
Total dose 
(Gy) 
BED 
Gy4 
BED 
Gy10 
BED 
Gy2 
EQD2 
Gy4 
10 x 3.4 Gy 
5 - 7 
34 
63 
46 
92 
42 
8 x 4 Gy 
4 - 5 
32 
64 
45 
96 
42.7 
7 x 4.3 Gy 
4 
30.1 
63 
43 
96 
41.6 
4 x 6.25 Gy 
2 - 3 
25 
64 
40.6 
103 
42.7 
3 x 7.45 Gy 
2 
22.35 
64 
39 
105.6 
42.65 
1 x 16 Gy 
1 
16 
80 
41.6 
144 
53.33 
Table 1. Biological effective dose with different fractionation schemes 
 
IV. OBJECTIVES-END POINTS 
Primary endpoints: 
- 
Five-year incidence of late grade ≥ 2 side effects 
 
Secondary endpoints:  
- 
Incidence (5-year actuarial rate) of ipsilateral breast recurrence (IBR) 
- 
Incidence (5-year actuarial rate) of regional relapse (RR) 
- 
Incidence (5-year actuarial rate) of contralateral breast cancer (CBC) 
- 
Incidence (5-year actuarial rate) of distant metastasis (DM) 
- 
Incidence (5-year actuarial rate) of any relapse (local, regional or distant, 
whichever came first) for disease free survival (DFS) 
- 
Incidence (5-year actuarial rate) of breast cancer death for cause specific survival 
(CSS) 
- 
Incidence (5-year actuarial rate) of death by any cause for overall survival (OS) 
- 
Incidence of acute side effects 
- 
Cosmetic results at 5 years 
- 
Quality of Life (QoL) 

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V. STUDY SUMMARY 
 
1. Design  
 
This is a prospective study, non-randomized, multicentric phase I-II trial developed in 
different countries.  The primary outcome is incidence and severity of grade ≥ 2 late side 
effects. 
 
2. Study duration 
 
Start of the study: March 2025 
Duration of patient recruiting: 2 years 
Duration of therapy: 1 days 
Follow-up: max. 5 years 
End of study: 2032 
 
3. Participating centers 
 
This is a multicenter study. Each investigator (study center) must be registered (See 
appendix). 
Each investigator or group of investigators must obtain local ethic committee approval 
for this protocol before they can enroll patients. 
Further it must be guaranteed, that the participating center can recruit at least 3 patients 
per year, can ensure appropriate quality assurance and also make possible for members 
of the study group to control it, if necessary. 
 
VI. PATIENTS 
 
1. Number 
 
The sample size must be 250 patients in 2 years. 
 
 

14 
 
2. Inclusion criteria: 
 
- 
Stage 0 & I & II (< 3 cm) breast carcinoma 
- 
Lesions of < 3 cm diameter  
- 
Invasive carcinoma of any subtype and grade or DCIS 
- 
Nodal status: pN0 or pN1mi (pts. with pN1mi status can be treated, but due to the 
limited clinical evidence, individual decision is needed) 
- 
M0: Absence of distant metastasis 
- 
Clear resection margins by NSABP definition (no tumor on ink) 
- 
Unifocal (multifocality limited within 2 cm) and unicentric breast cancer  
- 
Age> 40 years 
- 
Luminal A or B tumors 
- 
Time interval from surgery preferably less than 12 weeks and no longer than 20 weeks, 
and from adjuvant chemotherapy less than 4 weeks 
- 
HER2+ patients receiving postoperative anti-HER2 systemic therapy 
- 
Specific signed consent form prior to randomization 
 
3. Exclusion criteria: 
 
- 
Stage III-IV breast cancer 
- 
Surgical margins that cannot be microscopically assessed 
- 
Extensive intraductal component (EIC+) 
- 
Extensive lymphovascular invasion (LVI+) (focal is allowed) 
- 
Triple negative breast cancer 
- 
BRCA 1-2 mutation 
- 
HER2+ pts. not receiving postoperative anti-HER2 systemic therapy 
- 
Neoadjuvant systemic therapy 
- 
Paget’s disease or pathological skin involvement 
- 
Synchronous or previous breast cancer. 
- 
Pregnant or lactating women 
 
 
 

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VII. THERAPY 
 
Below - taking into account the ESTRO recommendation of breast cancer clinical trials 
24 - we establish in details the quality assurance,  the guideline of target volumes and 
OARs delineation, dose/fractionation, templates, planning objectives for target volumes, 
constraints for OARs and techniques. 
 
 
1. Timing of surgery and brachytherapy 
 
Time interval from final definitive breast surgical procedure to the start of brachytherapy 
is preferably less than 12 weeks (84 days) and no longer than 20 weeks 8. If patients 
receive chemotherapy, the brachytherapy can be started before systemic treatment (within 
12 weeks). It is also possible to start radiation therapy after chemotherapy is completed 
according local protocols as soon as possible within 4 weeks after chemotherapy. 
 
2. Target definition 
  
The target volume consists of the tumor bed with an adequate safety margin in all 
directions. The "clinical target volume” (CTV) is in this case identical with the "planning 
target volume” (PTV). In some cases, restrictions have to be made in direction to the chest 
wall and skin, which is inevitable and unavoidable. For such cases, the boundaries of the 
CTV should be redefined as 5-7 mm below the skin surface, and 5 mm above the 
underlying ribs. The knowledge of the tumor-free margins is important, since the size of 
safety margins of implant volume depends on the size of these tumor-free resection 
margins. The distance of the border of the CTV (safety margin) to the tumor surface 
(tumor margin) must be at least 20 mm, because this area contains 80% of the microscopic 
tumor extensions around the primary macroscopic tumor. From these results we conclude: 
20 mm minus the minimum tumor-free resection margin (A) is the safety margin (B) 
included in the CTV. The larger the tumor-free resection margin, the smaller the safety 
margin, so CTV: B = 20 - A (mm). (e.g. if the pathologist describes a minimum resection 
margin 12 mm lateral, 2 mm medial, 5 mm cranial, and 10 mm caudal, then the minimal 

16 
 
safety margin should around the tumor cavity (surgical scar, clips) should be lateral >8 
mm, medial >18 mm, cranial >15 mm and caudal >10 mm).  
 
 
Figure 1. Definition of CTV and PTV 
 
Of course, in most cases, these margins include a large amount of tissue in the lateral 
directions and especially in the direction to the nipple. Breast skin or thoracic wall are not 
the target volume for brachytherapy alone. The overlying skin is usually surgically 
removed with the superficially located tumors, and the residual skin does not need any 
treatment. For the localization of the target volume, any information source has to be 
taken into account, because the surgical scar alone is not enough for tumor bed 
localization. 
 
The physician carries the responsibility for the planning of the implant and for the 
definition of the CTV. Before the insertion of catheters it is obligatory to know: 
mammograms and ultrasound images, surgical report and written histological findings. 
In the histological findings the description of the tumor-free resection margins in mm in 
all dimensions are important. Also, the CT or MR investigation can be helpful. It is 
optimal, if the tumor bed is marked with clips, ideally with 6 clips indicating the cranio-
caudal, medio-lateral and antero-posterior borders of the resected volume. 
 
The definition of CTV for adjuvant breast irradiation has evolved and the GEC-ESTRO 
Breast Working Group has published two recommendations for cases with closed cavity 

17 
 
and open cavity 6, 7. Some surgeons close the cavity of tumorectomy and the postoperative 
CT planning is unable to distinguish a cavity to be delineated (closed cavity technique). 
It corresponds to the Cavity Visualization Score (CVS) 1, 2 and 3. In other cases, the 
surgeon leaves the cavity opened, which is fulfilled with blood or seroma. In this situation, 
surgical cavity can be delineated and a margin added to define the CTV (open cavity 
technique). It corresponds to the CVS 3, 4 and 5 25, 26. 
 
3. Delineation of the target 
 
Delineation of the target – CTV (PTV) in closed cavity 6 
The following seven steps for target delineation after closed cavity surgery are 
recommended: 
a. Perform a CT with radiopaque marks on the skin scar and nipple. 
b. Delineation of clips, decide relevant and irrelevant clips (e.g. clips on the chest 
wall far from the tumor site, mark the surgical cavity, not the tumor bed, and are 
irrelevant). 
c. Delineation of surgical bed – whole surgical scar (WS) inside the breast, if visible, 
from the skin scar to the bottom clips. 
d. Delineation of ImTV (Imaging related Target Volume), defining the distance from 
the tumor to the skin and the chest wall in image studies.  
e. Delineation of ETB (Estimated Tumour Bed): The addition of relevant surgical 
scar, clips and ImTV. 
f. Delineation of CTV (Clinical Target Volume): Add a margin to the ETB 
according to the pathological distances to complete at least 20mm. 
g. Delineation of PTV (Planning Target Volume). In case of uncertainties on 
position of clips – typically by large-breasted patients or in case of absence of 
clips or impaired visibility of surgical scar or cavity, an adapted PTV margin (5 
to 10 mm) in the region of doubt can added.  
In the case of oncoplastic surgery no recommendations can be given, but CTV can 
be considered as the sum of the clipped area and the distance of 20 mm minus the 
smallest surgical free margin. 
 
 
 

18 
 
Delineation of the target – CTV (PTV) in open cavity 7 
At delineation of surgical cavity only the homogeneous part of the postoperative seroma 
has to be included in the contours and protrusions or sharp irregularities have to be 
excluded. When surgical clips are present, they have to be surrounded by the contour with 
close contact.  
CTV is created from the outlined surgical cavity with a non-isotropic geometrical 
extension. In each direction the safety margin is calculated by taking into account the size 
of the free resection margin. The total size of safety margin is always 20 mm, which is 
the sum of the surgical and added safety margins. CTV is limited to chest wall/pectoral 
muscles and 5 mm below the skin surface. 
 
4. Techniques  
 
Breast implants can be carried out under general or local anaesthesia. For the implantation 
are needed: 20 cm long implantation needles (guide needles), templates in different sizes 
(with channels in square or triangular arrangement and with distances of the channels 
between 12 and 18 mm) (Fig. 2.). 
The patient is placed in supine position with the ipsilateral arm in 90° abduction. Once 
the tumor centre is localized, and the three dimensions of the CTV and the PTV (length, 
width, and thickness) are defined and delineated on the patient’s skin, implantation of the 
first needle follows, the so-called "guidance needle or reference needle" without or with 
template. 
The position of this needle has to be selected in such a manner, that this needle is placed 
under the deepest place of the tumor bed and in the center of the lowest level of the 
implant. It is important to consider both the position of the clips and the tumor position 
in the preoperative mammograms (the tumor distance from the thorax wall is represented 
only in the preoperative ultrasound and mammography pictures!). 
To ensure that the following needles will be implanted parallel and equally distant from 
each other afterwards a template of suitable size is placed over the guidance needle. Then 
the needles are implanted according to the rules of the Paris System parallel and equally 
distant from each other. In most cases, preferably they are inserted in a medio-lateral or 
cranio-caudal direction. In the outer quadrants it is possible to implant with needles 
orientated in a 45° angle. Usually, two or three planes of needles are implanted. A single 
plane implant is not allowed. Number and spacing between needles (template size) is 

19 
 
chosen to adequately cover the width and the thickness of the PTV. Nine to eighteen 
needles spaced 12-18 mm are usually required. Guide needles must be replaced by plastic 
tubes immobilized by buttons at both sides of the breast.  
 
 
Figure 2. Plastic catheters and templates 
 
An implantation of needles on a quadrant of the breast can be performed under a clinical 
assessment of the tumor bed, but the risk of geographical miss exists. Hence some image 
system to define the CTV to be implanted is mandatory. Depending on whether clips are 
present or not, and whether a residual open cavity is visible or not, several techniques are 
useful. 
 
CT guided implantation with open cavity: 
Pre-implant CT-scan for planning of the implant geometry and confirm that a CTV can 
be delineated, and post-implant CT-scan for treatment planning and documentation is 
mandatory. 
CT-image based preplanning of implant geometry and PTV: A full CT-scan (with 3mm 
slice reconstruction thickness) of the breast should be done with template on the breast. 
Following contouring of the excision cavity in each slice, the 
CTV can be generated manually or automatically by adding an appropriate safety margin 
around the excision cavity. Then, the boundaries of the PTV should be modified (if 
necessary) to 5-7mm below the skin surface, and 5 mm above the underlying ribs to avoid 
skin teleangiectasia and rib fracture. Following 3-D reconstruction of the PTV, position 
of implant needles can be defined using the needle-eye-view technique (Fig. 3.). 
 

20 
 
 
 
Figure 3. CT guided implantation with open cavity 
 
 
Ultrasound guided implantation with open cavity: 
Ultrasound can be used to delineate the open cavity. The needles are inserted and the 
position is verified to cover the whole cavity with margin. The number of planes is 
decided according to the cavity size (Fig. 4.).  
 
 

21 
 
 
Figure 4. Ultrasound guided implantation with open cavity. 
 
 
X-Ray guided implantation when clip marking of the tumor bed is present: 
Under x-ray control, e.g. with the help of a conventional simulator or an Integrated 
Brachytherapy Unit (IBU) or a CT unit, the position of the clips and so the tumor bed are 
identified. Pre-implant CT scan and CT-based treatment planning is recommended. The 
optimal direction of the needles is determined and the appropriate point for insertion 
(entrance and exit points) of the needles at the skin is marked. As an alternative making 
a CT simulation on the basis of the same markings is acceptable. Post-implant CT scan is 
obligatory (Fig.5.). 

22 
 
 
Figure 5. X-Ray guided implantation with closed cavity and clips markers. 
 
Ultrasound guided implantation with closed cavity: 
With closed clavity, a preplanning CT is mandatory in order to be sure that some marks 
allow us to know how to draw a CTV. Scar inside the tissue or clips, are necessary to do 
a clinical assessment of the volume to implant and be able to draw on the skin the volume 
to be implanted. Starting the procedure, with ultrasound, the scar is visible as a grey area 
under the skin compared with normal lobular areas. The distance from skin to the chest 
wall is measured and the deepest needle is visualized and corrected to keep it at the right 
position according to the depth where the tumor was placed in the mammograms. The 
rest of the needles are inserted and the number of planes is decided according to the 
distance to the skin (Fig. 6.). 
 

23 
 
 
Figure 6. Ultrasound guided implantation with closed cavity. 
 
 
5. CT-image based treatment planning: 
 
After implantation a CT-scan (with ≤ 3 mm slice thickness) of the implanted breast should 
be performed for evaluation of the PTV coverage and planning. Following contouring of 
the excision cavity, the PTV can be generated as described previously (Fig. 7, 9.). When 
an open cavity is visible, diluted contrast can be inserted to better visualize the margins.  
The active source positions can be defined individually in each catheter. 
Dose specification and prescription should be done according to the Paris system 27. 
Geometrical dose optimization is allowed. The dose is usually prescribed to 85% of the 
MCD. 
DVH analysis should be used to confirm that 100% of the prescribed dose covering >90% 
of the PTV (i.e. CI >0.9). If adequate coverage cannot be achieved, prescription of dose 
to a lower percentage isodose is allowed, keeping the DNR below 0.35. Otherwise, the 
implant should be improved with the addition of new implant catheters. 
An alternative way of dose prescription for CT-image based treatment planning is to 
generate automatically dose points on the surface of the 3D reconstructed PTV (Fig. 8.). 

24 
 
Following the geometric optimization for volume implant, the dose can be prescribed to 
the “dose points on target”, keeping the DNR below 0.35. DVH analysis should be used 
to confirm that 100% of the prescribed dose covering >90% of the PTV (CI >0.9). If 
adequate coverage with acceptable dose homogeneity cannot be achieved, then the 
implant should be improved with the addition of new implant catheters. Reporting the 
value of MCD is mandatory. 
 
 
Figure 7. Post-implant CT-image based definition of the PTV. Excision cavity (red); PTV 
(green) 
 
 
Figure 8. Dose prescription to “dose points on target”. PTV (thick red line); dose points 
defined on the surface of the PTV (blue points); 100% isodose line (thin red line); 50% 
isodose line (green line). 
 
 

25 
 
 
 
Figure 9. Schematic representation of relation of the resection cavity to the CTV. In all 
directions the total margin around the tumor is 20 mm. Different margins in anterior 
(ANT), medial (MED) and lateral (LAT) directions around the cavity (red) which have 
been calculated by taking into account the tumor-free surgical margins. 
 
 
 
Treatment parameters for CT-image based planning: 
- DVH analysis of target coverage will confirm 100% of the prescribed dose covering 
>90% of the PTV (CI >0.9). 
- DNR (V150%/V100%) <0.35. 
- Maximum skin dose <70%. 
- For reporting values of volume of Dref, 1.5 x MCD, 1.5 x Dref, surface CI, DNR, MCD, 
DHI, COIN should be also given (see Appendix) 
 
 
6. Dose specification 
 
When treating with a single stepping source the length of the source steps has to be 
determined in that way, that the reference isodose encloses the tumor bed with an 
adequate safety margin (PTV). The reference isodose corresponds the MTD according 
ICRU 58 (in the ideal case congruently with the CTV). For this, several reference points 
according to ICRU 58 in the central implant plane must be defined. Calculating the 

26 
 
average value of doses at this individual reference points we receive the so-called "mean 
central dose” (MCD). 
The reference dose enclosing the target volume is usually defined within the range of 80-
90% of the MCD (usually 85%). A specification on isodoses smaller than 80% of the 
MCD has the consequence that the percentage of volume which is enclosed by larger 
isodoses (120 - 150%), increases. To avoid unwanted overdosing, we advise against this 
procedure. If the prescription isodose is lower than 80%, the DNR must be <0.35 
(preferably <0.30). If these dose prescription and homogeneity constraints are not 
fulfilled, it must be the consequence to implant additional needles/catheters. It is 
necessary therefore that during the implantation the target volume must be covered by a 
sufficient number of needles/catheters. 
The volume enclosed by the reference isodose surface depends on the tumor size and on 
the size of the resection margins (size of the PTV) - mostly about 40 - 200 cc. A volume 
over 200 cc should be exceeded only in justified cases. Smaller volumes mostly develop 
with a one-plane implant, which is not allowed in this study! As additional parameter for 
the quality of the implant the DNR must be calculated. The dose distribution is seen as 
sufficiently homogeneous, if the DNR is <0.35 (preferably <0.30). If these criteria are not 
fulfilled, physician and physicist should clarify the causes and look for improvements for 
the further procedure on an individual basis. 
 
Recommended dose-limits for implant and PTV (adapted from 8):  
 
 
 
 
 
 
 
 
200 cm3 

27 
 
Recommended dose-volume limits for OARs 8: 
 
 
 
 
 
7. Prescription of Dose, Fractionation 
 
We will treat the patient in one day, with the aim that the patient does not have to spend 
a single night with the implanted tubes and that the treatment can be provided on an 
outpatient basis.  
The prescribed dose is 1x16 Gy. 
 
8. Surgery 
 
Within the present trial lumpectomy, wide excision or quadrantectomy should be utilized 
for suspected or known malignancy. Lumpectomy and wide excision are defined as 
resection with a significant margin of breast tissue. Lesions that are superficial should be 
ellipsed with a segment of skin that affords gross clearance of at least 1 cm for the lesion. 
The part of the pectoralis fascia which is next to the lesion should be included, if 
indicated. The specimen should be marked with different length sutures in order to tag at 
least three of the six axes of the mass for orientation purposes for the pathologist, for 
evaluation of the margins. Clips are used to mark the tumour site for the radiotherapist. 

28 
 
The standard treatment of the axilla within this trial is sentinel lymph node biopsy alone 
or axillary dissection is admissible with at least 6 removed nodes. 
 
9. Drug therapy 
 
Adjuvant sequential chemotherapy and/or hormonal therapy is allowed according to the 
local protocol of the treating center (keeping the time schedule defined in VII.1.). 
 
 
 
VIII. DATA MANAGEMENT 
 
1. Statistical considerations 
 
Sample Size 
 
Overview: 
The primary goal of this trial is to estimate the rate of all late grade ≥ 2 toxicity 
(RTOG/EORTC skin, RTOG/EORTC subcutaneous tissue, hyperpigmentation, 
teleangiecteasia, fibrosis, fat necrosis, brachial lymphedema and breast pain) following 
treatment with a single-fraction brachytherapy. 
 
Sample size derivation:  
The sample size is calculated with type I error of 0.05, type II error of 0.2 (power of 80%) 
and a one-sided hypothesis (only excess of cases is of interest). Based on the 5-years 
results of the GEC-ESTRO vAPBI trial 2, we conservatively assuming a ‘normal’ rate of 
9.9% grade 2 or higher late toxicity. Based on the 5-years results of the SiFEBI study 3, 
the expected rate of grade ≥ 2 side effects with a single-fraction treatment is 8%. Using 
the above data, calculated with the sample size calculator of the Statistica 12.5 software 
(StatSoft, USA), a minimum sample size is 196 patients. After adjusting the number of 
cases by 10% for ineligible or unanalyzable cases, this study requires a sample of at least 
216 patients. 
 

29 
 
Analysis plan 
 
Interim reports: 
Interim reports will be prepared every six months until the last patient has been entered 
to the trial. In general, the interim reports will contain information about patient accrual 
rate with projected completion dates of the trial, status of QA review and compliance rate 
of treatment per protocol, the frequencies and severity of toxicity. 
 
The analysis of late grade 3 toxicity: 
This analysis will be carried out when each patient has had at least 18 months of follow-
up. The time to the occurrence of late Grade 3 toxicity is defined as the time interval from 
the start of protocol treatment to the date of onset of late Grade 3. If no such toxicity is 
observed until the time of the analysis, the patient will be censored at the time of the 
analysis. 
 
Estimation of secondary endpoints related to the efficacy: 
Cumulative incidence approach will be used to estimate the failure rate for biochemical, 
disease-specific, local-regional and distant metastasis-free survival. 
 
2. Data collection 
 
Data collection will be done utilizing report forms in digital form, and also as hard copy. 
The digital report from the original is sent to the study centre, the hard copy remains on 
site with the local department. 
Personal data of patients remain in the local participating centres. Only anonymized data 
will be passed on to the study centre via registered mail services. Access to the biometrical 
study centre is restricted to authorized users. In addition, within these precincts, access to 
electronic data, including the study databases mentioned, is restricted to a user group 
explicitly authorized. All these users sign a declaration that they will treat all data 
confidently.  
 
3. Confidentiality 
 

30 
 
Study protocol and patient data forms are confidential and it is not allowed to 
communicate confidential data orally or in writing to unauthorized persons. 
The information obtained as a result of this research is confidential and the investigator 
must ensure that the patient’s anonymity will be maintained. All records, evaluation 
forms, and reports will be identified by an identification code to maintain confidentiality. 
The investigator should keep a separate log of patient’s codes, names and addresses. All 
records should be kept in locked files. The chairmen may have access to this information 
in order to comply with any law or regulations, or in the interest of patient safety. 
 
 
IX. PATIENT ASSESSMENTS 
 
1. Clinical examinations 
 
The study physician in each study center is responsible for the treatment, for the 
examinations before, during and after the treatment as well as for the appropriate 
documentation of each recruited patient. 
The following examinations are obligatory: 
 
Examinations 
Before irradiation 
After irradiation 
Follow-up examinations* 
Informed consent 
x 
 
 
Patient history 
x 
x 
x 
Clinical examination 
x 
x 
x 
Karnofsky, ECOG 
x 
x 
x 
Chest X-ray or CT 
x 
 
 
Liver ultrasound 
o 
 
 
Bone-scintigraphy 
o 
 
 
Mammography and 
ultrasound of the breast 
 
 
x* 
Acute side effects 
 
x 
 
Late side effects 
 
 
x 
Cosmetic results 
x 
x 
x* 
Digital photographs 
x 
 
x* 
EORTC QLC-C30 
x 
x 
x* 
EORTC QLC-BR23 
x 
x 
x* 
Patient eligibility form 
x 
 
 
Radiotherapy report form 
 
x 
 
Follow-up form 
 
 
x 
*: for correct timing see table below, o: optional 

31 
 
Follow –up examinations 
1 
3 
6 
12 
24 
36 
48 
60 
72 
84 
96 
108 
120 
Patient history 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Karnofsky, ECOG 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Clinical examination 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Inspection and palpation 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mammography of  
both breast 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Documentation of  
acute side effects 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
Documentation of  
late side effects 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Documentation of  
cosmetic results 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Digital photographs 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Documentation of QoL 
 
x 
x 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
 
 
2. Cosmetic outcome 
 
- Documentation of bra cup size of the untreated breast (category A, B, C and D or larger). 
- Digital photographs from ventral (see example). 
 
 
 
 
-Evaluation of the cosmetic result of the breast-conserving surgery based on the Harvard 
criteria system 28: 
- 
Patient’s view (subjective): excellent, good, fair, poor. 
- 
Doctor’s view (using classification below): excellent, good, fair, poor. 
 
 
 

32 
 
______________________________________________________________________ 
 
Excellent (1):  perfect symmetry, no visible distortion or skin changes, and no visible 
catheter entry/exit sequelae 
Good (2):  
slight skin distortion, retraction or edema, any visible telangiectasia, any 
visible catheter entry/exit scar, or mild hyperpigmentation 
Fair (3): 
moderate distortion of the nipple or breast symmetry, moderate 
hyperpigmentation, or prominent skin retraction, edema, or telangiectasia 
Poor (4): 
marked distortion, edema, fibrosis, or severe hyperpigmentation 
______________________________________________________________________ 
 
 
3. Side effects 
 
Documentation of surgery-related pre-existing side effects with the Common 
Terminology Criteria for Adverse Events v3.0 (CTCAE) 29 and with the RTOG/EORTC 
Late Radiation Morbidity Scoring Schema 30. See tables below. 
 
 

33 
 
 
 
 
To assess fat necrosis, we use a classification system previously developed 31: 
Grade 
Definition 
0 
No fat necrosis 
1 
Asymptomatic fat necrosis (only radiologic and/or cytologic findings) 
2 
Symptomatic fat necrosis not requiring medication  
(palpable mass with or without mild pain) 
3 
Symptomatic fat necrosis requiring medication  
(palpable mass with significant pain) 
4 
Symptomatic fat necrosis requiring surgical intervention 
 
 
 
 
 

34 
 
4. Quality of life (QoL) 
 
Before starting radiotherapy, patients are intended to fill out an QoL-questionaire 
(EORTC QLQ-C30 including the Breast cancer module QLQ-BR23, see appendix) 32, 33. 
Latest information about development of the QLQ-C30 and its modules (also different 
languages) may be found on the EORTC Quality of Life web pages, at: 
https://qol.eortc.org/questionnaires/ 
 
 
 
 
X. Determination of therapy safety 
 
1. Collection, evaluation and reporting 
 
All adverse clinical events (AE), whether observed by the investigator or reported by the 
patient, must be recorded in the Case Report Form together with details of the duration 
and severity of each episode, the action taken with respect to the treatment and the patient 
outcome. The investigator must evaluate each adverse event as to its relationship to the 
radiation treatment and as to whether or not it was serious. 
Serious AE: An event that suggests a clinically significant hazard, contradiction, side 
effect or precaution. A serious AE includes any that is fatal or life threatening (at 
the time of occurrence), is permanently disabling or incapacitating, requires or 
prolongs inpatient hospitalization, or is a congenital anomaly, cancer or overdose. 
Toxicity should be observed and recorded using the criteria, which are attached in 
Appendix. Adverse events not included among the toxicity criteria should be evaluated 
using the scale 1 = mild, 2 = moderate, 3 = severe, 4 = life-threatening. 
 
2. Documentation of unexpected events 
 
ALL SERIOUS OR UNEXPECTED ADVERSE EVENTS, INCLUDING DEATH, 
WHICH OCCUR ON STUDY OR WITHIN 30 DAYS SUBSEQUENT TO 
WITHDRAWAL FROM STUDY, MUST BE REPORTED IMMEDIATELY TO Dr. 

35 
 
Viktor Smanykó BY TELEPHONE OR E-MAIL, REGARDLESS OF PRESUMED 
CAUSAL RELATIONSHIP: 
 
 
 
Tel Business 
 E-mail 
Chairman 
 
 
 
 
3. Serious or unexpected events 
 
Unexpected side effects are diseases, signs of disease or symptoms, that appear or 
aggravate after the patient was recruited to the trial. 
The grading of an unexpected side effect will be performed with the Common 
Terminology Criteria for Adverse Events v3.0 (CTCAE). 
If grading with these criteria is not possible, side effects will be classified with the 
following classification: 
1. slight 
2. moderate 
3. severe 
4. life threatening 
 
For every event the causality with the treatment has to be evaluated and classified with 
the following classification: 
1. no causality 
2. causality possible 
3. causality likely 
4. causality proved. 
 
Serious unexpected events are: 
- 
Every death (independent of cause of death) that appears during and within 30 
days after study-protocol-conformal treatment 
- 
Life-threatening diseases 
- 
Events that will lead to permanent disability 
- 
Events that lead to or prolong hospitalization 
- 
Secondary malignancies 
- 
Symptomatic overdosing 

36 
 
- 
Congenital abnormalities 
 
4. Patient insurance 
 
All patients participating in this clinical trial will be insured for the standard insurance 
for radiation therapy in every Department of Radiation Oncology. All patients with such 
events should immediately inform the responsible local study physician. 
 
 
 
XI. CONSENT AND WITHDRAWAL OF PATIENTS 
 
1. Patient’s consent and declaration of consent 
 
Before a patient can be recruited for the protocol, the study concept and aim as well as 
possible alternatives must be explained to her and patient’s consent must be declared by 
filling out and signing the Patient consent form (see appendix). 
 
2. Patient’s withdrawal  
 
Patients may be withdrawn from the study for any of the following 
1. Completed as per protocol (60 months follow-up) 
2. Patient’s own request 
3. Unacceptable side-effects of treatment 
4. Protocol violations, e.g. non-compliance, treatment schedule modification or 
dose modifications not specified by protocol 
5. Investigator’s considered opinion that it would be in the patient’s best interest, 
e.g. deteriorating general condition of patient. The reason must be recorded by 
the investigator. The patient will be off-protocol and further treatment will be 
at the investigator’s discretion 
6. Loss to follow-up 
 
 

37 
 
XII. FINAL REPORT/ PUBLICATIONS 
 
After completion of the study the clinical results will written by the study chairmen and 
published in a scientific journal. The sequence of the co-authors will be determined by 
the number of recruited patients. 
 
 
 

38 
 
Appendix I 
 
Declaration of participation on the study for study physician 
 
 
[Date] 
 
 
The [institution’s name] will participate as a study center in the 
 
PHASE II MULTICENTER TRIAL: 
SINGLE-FRACTION VERY ACCELERATED PARTIAL BREAST IRRADIATION 
(sfVAPBI) IN LOW-RISK INVASIVE OR DUCTAL IN SITU BREAST CARCINOMA 
 
of the 
 
GEC-ESTRO BREAST CANCER WORKING GROUP. 
 
 
As the local investigator for this study, I have received the protocol of the above-mentioned Phase 
II multicenter trial dated ........................ and agree to follow this protocol as written. 
 
I confirm my commitment to contribute to this trial and to recruit and randomise at least 3 patients 
per year. Patient data will be documented properly, follow-up data assessed regularly as lined out 
in the protocol. 
 
 
Name and signature of the local investigator: ______________________________________ 
 
 
 
Name and signature of the center's director: _______________________________________ 
 
 
 
 
 
 
(Stamp) 
 
 

39 
 
Appendix II 
 
Patient Consent Form and Declaration of Consent 
 
PHASE II MULTICENTER TRIAL: 
SINGLE-FRACTION VERY ACCELERATED PARTIAL BREAST IRRADIATION 
(sfVAPBI) IN LOW-RISK INVASIVE OR DUCTAL IN SITU BREAST CARCINOMA 
 
GEC-ESTRO BREAST CANCER WORKING GROUP. 
 
 
Dear Patient! 
 
You suffer from breast cancer. The conventional treatment consists of breast-conserving surgery 
(BCS) and an irradiation of the whole breast (WBI) following surgery. Recently, it has been 
shown that in the subgroup of women with breast cancer with a low risk of local recurrence the 
whole breast irradiation can be changed by an accelerated partial breast irradiation (APBI), 
restricted to the former tumor area. This kind of irradiation is performed by the implantation of 
small plastic tubes in general/local anaesthesia in the so called “tumor bed”, the former cancer 
carrying area. Then a very small radiation source is able to reach the tissue at risk via those tubes. 
With this so-called “interstitial brachytherapy (iBT)”, the radiation dose can be applied in only 
five-seven days, in contrast to a 3–6-week lasting whole breast irradiation, and in a smaller area 
than the external irradiation on the whole breast. 
 
Together with other European radiotherapy clinics our hospital carries out an investigation to find 
out, on the basis of the available scientific knowledge, if you can receive this treatment only in 
one day. We expect in your favourable situation that partial breast irradiation leads to sufficient 
tumor control in the ipsilateral breast. A 100-percent-security is not reachable, but we can expect 
a very low percentage of local recurrences. The advantages of partial breast irradiation are a short 
treatment duration and a lower rate of side effects at the skin surface. The advantages of a “single-
fraction very accelerated partial breast irradiation” (sfVAPBI) are a more comfortable tolerance 
of the plastic tubes and less probability of acute effects like infection or bleeding. 
This Phase II treatment trial looks to know the secondary effects and cosmesis outcome of the 
same treatment in one day (a single fraction a day), removing the tubes the same day of the 
implantation and treatment. 
 
Side effects 
Possible side effects of sfAPBI are: 
Acute effects: hematoma, radiodermatitis, oedema, implant infection, bleeding, pain. 
Late effects: fibrosis of the skin and breast tissue, oedema, lipoid necrosis, teleangiectasia, pain. 
 
Confidentiality 
Your patient and treatment data will be only used anonymously for scientific evaluation. Your 
personal data will be kept confidential and never be published or given to third persons without 
removing your name. 
 

40 
 
 
 
Data management  
You - as a participant in the study - explicitly consent to the hospital transferring the necessary 
data to the data processing centre. 
 
Participant’s Rights 
Your participation is voluntary. You can choose not to take part or leave at any time without 
penalty or loss of benefits. Any new information that might affect your participation will be shared 
with you. 
 
Contact Information 
More information is available from the responsible physicians at your local hospital. 
Local responsible physician: 
[Name and Address of Hospital] 
[Name of Physician] 
[Telephone Number] 

41 
 
PHASE II MULTICENTER TRIAL: 
SINGLE-FRACTION VERY ACCELERATED PARTIAL BREAST IRRADIATION 
(sfVAPBI) IN LOW-RISK INVASIVE OR DUCTAL IN SITU BREAST CARCINOMA 
 
GEC-ESTRO BREAST CANCER WORKING GROUP. 
 
 
Declaration of Consent 
 
Of the patient after all questions regarding therapy and side effects are asked and answered. 
 
Dr. .......................................... informed me that I can participate in a scientific trial to clarify the 
role of “single-fraction very accelerated partial breast irradiation (sfVAPBI)” in breast cancer 
treatment. I had the opportunity to ask all my questions to the items I was interested in. 
 
I understand the concept of the study and declare my consent to participate. If I deny the planned 
treatment, I will not suffer from penalty or loss of benefit regarding the optimal medical treatment. 
I know that I can resign participation at any time and because of any cause. 
 
I was assured that my personal data will be kept anonymous and unpublished, except I declared 
my clear consent. 
 
I explicitly consent to the hospital transferring the necessary data to the data processing centre. 
 
 
I received a copy of this patient consent form and declaration of consent. 
 
 
 
 
Patient’s name: .................................................................................... 
 
ID-Number: ....................................................... 
 
 
 
 
....................................................................................................................... 
Place, date and signature of the patient 
 
 
 
 
....................................................................................................................... 
Place, date and signature of the responsible physician  

42 
 
Appendix III 
 
Eligibility Check 
 
Inclusion Criteria 
 
Criteria 
Eligible 
Exclusion 
Breast cancer stage ≤ st.II. 
• 
Yes 
• 
No 
Hystology 
• 
Invasive carcinoma of any 
subtype and grade or DCIS 
• 
No 
Vessel Invasion 
• 
Histopatholologically no or 
just focal lymph vessel 
invasion/ 
lymphangiosis 
(LVI+) 
• 
No blood vessel invasion/ 
hemangiosis (V0) 
• 
Extensive lymph vessel 
invasion/ 
lymphangiosis 
(LVI+) 
• 
Blood vessel invasion/ 
hemangiosis (V1) 
Tumor diameter  30 mm 
(histopathologically 
confirmed)  
• 
Yes 
• 
No 
Nodal status (invasive 
cancer) 
• 
Negative sentinel lymph 
node biopsy or 
micrometastasis (pN0 or 
pN1mi) 
• 
In case of ABD: pN0 or 
pN1mi (precondition: at 
least six lymph nodes 
histopathologically 
evaluated) 
 
(pts. with pN1mi status can 
be treated, but due to the 
limited clinical evidence, 
individual decision is 
needed) 
• 
Positive macrometastasis 
at sentinel lymph node 
biopsy (pN1) 
• 
In case of ABD: pN1 or 
<6 lymph nodes 
histopathologically 
evaluated) 
• 
no axillary staging 
Distant metastasis 
• 
No (M0) 
• 
Yes (M1) 
Safety Margins  
• 
Clear resection margins by 
NSABP definition (no 
tumor on ink) 
• 
Positive resection margins 
or surgical margins that 
cannot be microscopically 
assessed 
Luminal status 
• 
Luminal A or B tumors 
• 
HER2+ pts. who receiving 
postoperative anti-HER2 
systemic therapy 
• 
Triple negative tumors 
• 
HER2+ pts. not receiving 
postoperative anti-HER2 
systemic therapy 

43 
 
Growth pattern 
• 
unifocal (multifocality 
limited within 2 cm) 
• 
unicentric 
• 
multifocal over 2cm 
• 
multicentric 
Patient’s age > 40 years 
• 
Yes 
• 
No 
Interval between 
definitive breast 
conserving surgery and 
radiotherapy 
• 
≤ 84 days 
• 
≤ 28 days after completion 
of chemotherapy  
• 
> 84 days 
• 
> 28 days after 
completion of 
chemotherapy 
Signed informed consent 
• 
Yes 
• 
No 
 
 
 
 
 
 

44 
 
Appendix IV 
 
Exclusion Criteria 
 
Criteria 
Exclusion 
Eligible 
Breast cancer stage > stage II 
• 
Yes 
• 
No 
Safety margins histopathologically assessed 
• 
No 
• 
Yes 
Extensive intraductal component (EIC+) 
• 
Yes 
• 
No 
Extensive lymphovascular involvement (LVI+) 
• 
Yes 
• 
No 
Pagets disease 
• 
Yes 
• 
No 
Pathological skin involvement 
• 
Yes 
• 
No 
Synchronous or previous ipsilateral breast cancer 
• 
Yes 
• 
No 
Prior malignancy ( 5 years prior to enrollment in 
study) except non-melanoma skin cancer or 
cervical carcinoma FIGO I if patient is 
continuously disease-free 
• 
Yes 
• 
No 
Pregnant or lactating woman 
• 
Yes 
• 
No 
Collagen vascular disease 
• 
Yes 
• 
No 
The presence of congenital diseases with 
increased radiation sensitivity, for example Ataxia 
telangiectatica or similar 
• 
Yes 
• 
No 
Psychiatric disorders 
• 
Yes 
• 
No 
Patient with breast anatomy deemed technically 
unsatisfactory for brachytherapy 
• 
Yes 
• 
No 
Triple negative breast cancer 
• 
Yes 
• 
No 
BRCA 1-2 mutation 
• 
Yes 
• 
No 
HER2+ pts. not receiving postoperative anti-
HER2 systemic therapy 
• 
Yes 
• 
No 
Neoadjuvant systemic therapy 
• 
Yes 
• 
No 
 
 
 

45 
 
Appendix V 
 
Patient Data Form 
 
Patient Data 
• 
Initial name 
• 
Initial first name 
• 
Date of birth 
• 
Patient ID 
• 
Age at BCS 
• 
Karnofsky performance scale 
• 
ECOG performance scale 
• 
Informed consent 
• 
Study center 
• 
… 
• 
… 
• 
… 
• 
… 
• 
… 
• 
100,90,80,70,60,50,40,30,20,10,0 
• 
0,1,2,3,4 
• 
Yes/No 
• 
… 
Oncological history 
• 
Former neoplasia? 
• 
Specify 
• 
Former radiotherapy? 
• 
Specify 
• 
Yes/No 
… 
• 
Yes/No 
… 
Breast conserving surgery (BCS) 
• 
Date of BCS 
• 
BCS-type 
 
 
 
 
 
 
• 
Axilla surgery 
 
 
 
 
 
 
 
 
 
• 
Brachial lymphedema (post 
BCS, pre-RT) 
 
      
Specify: 
• 
… 
• 
quadrantectomy, segmentectomy, lumpectomy, 
tumorectomy 
• 
Conventional axillary dissection with at least six nodes 
removed, sentinel lymph node biopsy, no lymph node 
dissection 
• 
Yes/No  
 
 
 
 
 
 
 
 
 
 
 
 
     
… 
Pathology 
• 
Typing 
 
 
 
 
 
 
 
 
 
 
Specify, in case of ‘other’ 
• 
Grading 
• 
Breast side 
• 
Quadrant 
 
 
 
 
 
 
 
 
• 
Tumor-diameter in mm 
• 
Minimal safety margin in mm 
• 
pT-category 
• 
pN-category 
• 
Number of dissected nodes 
• 
Estrogene-receptor positive 
• 
Progesterone-receptor positive 
• 
C-erbB2 positive 
• 
Ki-67% 
• 
Invasive ductal carcinoma, Invasive papillary carcinoma, 
Invasive mucinous carcinoma, Invasive tubular carcinoma, 
Invasive medullary carcinoma, Invasive lobular carcinoma, 
DCIS, other … 
• 
G1, G2, G3, G4 
• 
Left, right 
• 
upper outer, upper inner, upper inner/outer, lower outer, 
lower inner, lower outer/inner, outer upper/lower, inner 
upper/lower, central 
• 
… 
• 
… 
• 
pT1 mic, pT1a, pT1b, pT1c 
• 
pN0, pN1mi, no axilla dissection 
• 
… 
• 
Yes/No 
• 
Yes/No  
• 
Yes/No 
• 
… 

46 
 
Adjuvant systemic therapy 
• 
Antihormonal therapy         
Specify:  
 
 
      
Start of treatment: 
• 
Chemotherapy                           
Specify:  
 
 
      
Start of treatment: 
• 
Anti-HER2 systemic therapy 
Specify:  
 
 
      
Start of treatment: 
• 
Yes/No 
 
 
 
 
 
     
…     
 
 
 
 
 
     
… 
• 
Yes/No                                                                                 
…                                                                                             
… 
• 
Yes/No                                                                                 
…                                                                                             
. 
Cosmetic result post BCS, pre radiotherapy 
• 
Bra cup size 
• 
Digital photography 
• 
Cosmesis – patient’s view 
• 
Cosmesis – doctor’s view 
• 
A, B, C, D or bigger 
• 
Yes/No 
• 
excellent, good, fair, poor 
• 
excellent, good, fair, poor  
Brachytherapy 
• 
Number of catheters 
• 
Number of implant planes 
• 
Reference isodose [%] 
• 
Total reference dose [Gy] 
• 
Mean Central Dose (MCD) [Gy] 
• 
Maximum dose Dmax (1,5 x 
MCD) [Gy] 
• 
Dose D150 (1.5 x Reference 
dose) [Gy] 
• 
Dose D90 (0.9 x Reference 
dose) [Gy] 
• 
Volume Vref [ml] 
• 
Volume V150 (D150) [ml] 
• 
Volume Vmax (Dmax) [ml] 
• 
Target definition 
 
 
 
 
 
 
 
 
• 
DNR 
• 
DHI 
• 
CI 
• 
COIN 
• 
… 
• 
… 
• 
… 
• 
… 
• 
… 
 
• 
… 
 
• 
…  
 
 
 
 
 
 
 
• 
…  
 
 
 
 
 
 
• 
…  
 
 
 
 
 
 
• 
… 
• 
… 
• 
with clips, without CT / with clips, with CT / with clips, 
with IBU / with clips, with US / without clips, with CT / 
without clips, with US / not possible, patient withdrawn 
• 
… 
• 
… 
• 
… 
• 
… 
Acute Toxicity (CTCAE v3.0) 
• 
Dermatitis associated with 
radiation 
• 
Hematoma  
• 
Infection (wound) 
• 
Intraoperative injury (breast) 
• 
Pain (breast) 
• 
Grade 0, Grade 1, Grade 2, Grade 3, Grade 4, Grade 5 
 
 
 
 
• 
Grade 0, Grade 1, Grade 2, Grade 3, Grade 4, Grade 5 
• 
Grade 0, Grade 1, Grade 2, Grade 3, Grade 4, Grade 5 
• 
Grade 0, Grade 1, Grade 2, Grade 3, Grade 4, Grade 5 
• 
Grade 0, Grade 1, Grade 2, Grade 3, Grade 4, Grade 5 
Comments 
… 
 
 
 

47 
 
Appendix VI 
 
Follow-up Form 
Patient Data 
• 
Initial name 
• 
Initial first name 
• 
Date of birth 
• 
Patient ID 
• 
Karnofsky performance scale 
• 
ECOG performance scale 
• 
Study center 
• 
… 
• 
… 
• 
… 
• 
… 
• 
100,90,80,70,60,50,40,30,20,10,0 
• 
0,1,2,3,4 
• 
… 
Follow-up status 
• 
Follow-up date 
• 
Follow-up period [months] 
• 
Free of disease 
• 
Status 
• 
Date of death 
• 
Cause of death 
                 
Specify: 
• 
… 
• 
… 
• 
Yes/No 
• 
Alive/Dead 
• 
… 
• 
breast cancer-related, not breast cancer-related                
… 
Tumor status 
• 
Tumor status                  
 
 
 
 
 
Specify in case of ‘other’:   
Specify in case of distant metastasis: 
• 
Secondary malignancy:              
Specify: 
 
 
 
• 
Meanwhile new therapy?           
Specify: 
 
           
Begin/end of new therapy: 
• 
free from disease, local recurrence in field, local 
recurrence field margin, local recurrence out of field, 
regional lymph node recurrence, distant metastasis, 
other … 
 
 
 
 
 
… 
• 
No / Yes, same organ / Yes, different organ                     
… 
• 
No / Yes                                                                            
…   
 
 
 
 
…  
Late toxicity 
• 
Late Toxicity? 
                 
Specify: 
• 
EORTC/RTOG Skin 
• 
EORTC/RTOG Subcutaneous tissue 
• 
Pain 
• 
Hyperpigmentation 
• 
Fibrosis 
• 
Teleangiectasia 
• 
Tube marks 
• 
Fat necrosis  
 
 
• 
Brachial lymphedema 
• 
No / Yes 
… 
• 
Grade 0, Grade 1, Grade 2, Grade 3, Grade 4 
• 
Grade 0, Grade 1, Grade 2, Grade 3, Grade 4 
• 
Grade 0, Grade 1, Grade 2, Grade 3, Grade 4 
 
• 
Grade 0, Grade 1, Grade 2, Grade 3, Grade 4 
• 
Grade 0, Grade 1, Grade 2, Grade 3 
• 
Grade 0, Grade 1, Grade 2, Grade 3 
• 
Grade 0, Grade 1, Grade 2, Grade 3 
• 
Grade 0, Grade 1, Grade 2, Grade 3, Grade 4 
• 
Grade 0, Grade 1, Grade 2, Grade 3, Grade 4 
Cosmetic result 
• 
Bra cup size 
• 
Digital photography 
• 
Cosmesis – patient’s view 
• 
Cosmesis – doctor’s view 
• 
A (small), B, C, D or bigger 
• 
Yes/No 
• 
excellent, good, fair, poor 
• 
excellent, good, fair, poor  
Comments 
… 
 

48 
 
Appendix VII 
 
Definitions of volumetric indices for brachytherapy 
 
- 
PD: prescribed dose 
- 
DNR (dose-nonuniformity ratio): ratio of the volumes encompassed by the 
isodose surfaces of the 150% and 100% of the PD 
- 
CI (coverage index): fraction of the PTV receiving dose equal to or greater 
than the PD 
- 
DHI (relative dose homogeneity index): fraction of the PTV receiving dose 
between 100% and 150% of the PD 
- 
COIN (conformal index) = c1 x c2, where c1 = CI and c2 = PTVref/Vref, 
where PTVref is the volume of the PTV receiving dose equal to or greater than 
the PD, and Vref is the volume encompassed by the isodose surface. 
 
 

49 
 
Appendix VIII 
 
Quality of Life Questionnaire EORTC QLQ- C30 

50 
 
 
 
 

51 
 
Quality of Life Questionnaire EORTC QLQ- BR23 
 
 

52 
 
 
 
 

53 
 
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