An Integrated Optimization of Surgery and Radiotherapy Techniques to Improve Cosmetic Outcome and Quality of Life in Breast Conserving Therapy for Breast Cancer Patients.
Conditions: Breast Fibrosis, Breast Cancer, Breast Cancer Female, Breast Neoplasms, Breast Carcinoma in Situ, Breast Carcinoma
Sponsor: Erasmus Medical Center

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STARLINGS Study Protocol 
An integrated optimization of surgery and radiotherapy techniques to improve cosmetic outcome 
and quality of life in breast conserving therapy for breast cancer patients (STARLINGS) – Study ID: 
NCT05263362) 
 
INTRODUCTION AND RATIONALE 
Approximately one in seven women will be diagnosed with breast cancer during their lifetime in the 
Netherlands. In other words, the lifetime cumulative risk of developing breast cancer in the 
Netherlands is approximately 14.3 %. The majority of breast cancer patients (60-70%) can be treated 
with breast-conserving therapy (BCT) which consists of a lumpectomy (instead of mastectomy) 
combined with a sentinel node procedure or an axillary lymph node dissection, followed by 
irradiation of the breast and systemic therapy if indicated (1-3). In patients with a (relatively) large 
tumor and/or small breast, chemotherapy precedes surgery with the aim to reduce tumor volume, 
and thereby making it possible to perform BCT (4). Our group has shown that survival after breast-
conserving therapy at least equals survival after mastectomy (5). Late adverse effects of the 
treatment affecting quality of life (QoL) have become increasingly important, due to the substantially 
longer life expectancy after BCT.  
In oncoplastic reconstructive surgery, an oncological resection is combined with plastic 
reconstructive techniques with the aim of improving cosmetic outcome without compromising 
oncological safety (6). Breast conserving surgery techniques can be divided into four groups: (1) 
standard lumpectomy (removal of the tumor without reshaping the breast) without closure of the 
glandular tissue, (2) simple oncoplastic surgery techniques (tissue displacement over a small area in 
order to reshape the breast without nipple displacement and with closure of the glandular tissue) 
and two groups of complex oncoplastic surgery techniques, namely (3) tissue displacement with 
nipple repositioning or breast reduction techniques and (4) volume replacement using tissue from 
outside of the breast (6). In this study we will use three groups, where group 1 and 2 as mentioned 
above are combined (1) standard and/or simple oncoplastic lumpectomy (2) tissue displacement 
techniques (breast reduction techniques) and (3) tissue replacement techniques using tissue from 
outside of the breast. We choose to combine the first and second group, because nowadays in 
clinical practice a standard lumpectomy is not conducted anymore in the participating hospitals. 
Adjuvant radiotherapy consists of partial or whole breast irradiation, which is dependent on patient 
and tumor-related factors as well as on the volume of the surgical area inside of the breast. Partial 
breast irradiation is an option in the case of favorable patient and tumor characteristics (i.e. age ≥ 50 
years with completely removed pre-invasive breast cancer (i.e. ductal carcinoma in situ (DCIS)) or 
invasive non-lobular unicentric unifocal carcinoma, tumor grade 1 or 2, diameter ≤ 3 cm and without 
triple negative receptor status) in combination with a limited radiation target volume (i.e. a surgical 
area that encompasses less than one-third of the breast) (7). In all other breast conserving therapy 
patients, the whole breast needs to be irradiated to reduce the risk of breast tumor recurrence. In 
patients with certain (combinations of) high risk features, an indication for a radiation boost at the 
surgical area (‘wound bed’) exists. High risk features are age ≤ 40 years, grade 3 tumor, triple 
negative tumor (e.g. estrogen receptor, progesterone receptor and Her2neu receptor negative 
tumors), the presence of lymph vascular invasion, the presence of extensive DCIS, and focally non-
complete tumor resection (8, 9). Unfortunately, breast fibrosis occurs as a late adverse event in a 

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substantial subset of patients (10-30%) after breast conserving therapy for DCIS or breast cancer (8, 
10, 11). Fibrosis can be painful and may result in poor cosmetic outcome (Figure 1) (12). Fibrosis as 
well as poor cosmetic outcome can negatively affect QoL (13, 14). Well-known risk factors for the 
development of fibrosis are:  
- 
Patient and tumor related: increasing age, larger breast volume and larger tumor size (15-
18)   
- 
Surgery related: larger excision volume and post-operative complications (e.g. seroma and 
hematoma) (10, 18) 
- 
Radiotherapy related: boost treatment, larger boost volume and higher maximum radiation 
dose (10, 11, 15, 19)  
In other words, besides patient and tumor related factors, both surgery and radiotherapy play a role 
in the risk of developing fibrosis. Of course, both surgical and radiation oncologists aim for the best 
cosmetic outcome and QoL of each breast cancer patient, without compromising oncological safety. 
However, especially in the light of current oncoplastic reconstructive surgery techniques, it has not 
yet been properly investigated how the different surgery and radiotherapy techniques interact. In 
order to avoid known risk factors for fibrosis, if possible, surgical techniques with the smallest 
chance of causing postoperative seroma and hematoma should be used. Furthermore, in patients 
who require a radiation boost or who are considered for partial breast irradiation, the surgical area 
should ideally be as small as possible, thereby reducing the radiotherapy target volume and the 
related risk of fibrosis on the long term (10). From a surgical perspective, a preference for 
oncoplastic reconstructive surgery may exist. However, if a radiation boost is indicated this approach 
might lead to an increased volume of the surgical area and thus may lead to a larger radiotherapy 
boost target volume and subsequently to a higher chance of fibrosis and a poorer cosmetic outcome 
than was initially aimed for by applying (complex) oncoplastic reconstructive surgery.  
In our region in the Netherlands, the surgical approach and preferences for surgical (oncoplastic 
reconstructive) techniques differ within and between hospitals. All breast cancer patients are 
referred to the Erasmus MC for adjuvant radiotherapy. Due to our close regional collaboration, we 
can use surgical as well as radiotherapeutic variables to analyze their effect on fibrosis, cosmetic 
outcomes and QoL in order to unravel the impact of different (possible) surgical and 
radiotherapeutic risk factors contributing to the development of fibrosis and to assess their 
interaction, after breast-conserving therapy for (pre-invasive) breast cancer. The primary focus will 
be on the role of different combinations of surgery and radiotherapy techniques as risk factors for 
fibrosis. From a patient perspective however, not primarily fibrosis, but QoL is usually what matters 
most. In a substantial subset of patients not only breast fibrosis, but also cosmetic outcomes may 
influence QoL (20). Therefore, we will not only focus on fibrosis, but also on cosmetic outcomes and 
QoL. 
Figure 1: Three women after breast-conserving therapy. No fibrosis (picture left) and severe fibrosis (middle 
and right picture). 

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OBJECTIVES 
The primary focus of this project will be to determine which different combinations of (oncoplastic 
reconstructive) surgery and radiotherapy techniques, in the context of BCT for (pre-invasive) breast 
cancer, contribute the most to the development of fibrosis as well as for moderate to poor cosmetic 
outcomes. 
Based on this knowledge, predictive models for the development of moderate to severe fibrosis and 
unfavorable cosmetic outcomes will be developed that allow for patient tailored treatment decision 
making in future breast cancer patients. 
The secondary endpoint will be to assess the relation between the presence and severity of fibrosis, 
cosmetic outcomes and different QoL domains and symptoms. With regard to QoL the specific focus 
will be on physical functioning, satisfaction with breast, psychosocial functioning, and breast 
symptoms. To this end health-related quality of life parameters will be captured. 
 
METHODS 
The STARLING study is a multi-center cross-sectional observational cohort study. Four Dutch hospitals 
will be participating (three large teaching hospitals: Albert Schweitzer hospital, Maasstad hospital 
and Franciscus hospital Gasthuis and Vlietland and one university hospital: Erasmus Medical Center). 
This study was prospectively registered February 21st 2022, at Clinical Trails.gov ID: NCT05263362. 
 
Study population 
The study population consists of breast cancer patients who were treated with breast-conserving 
therapy (BCT) at one of the four participating Dutch hospitals (Erasmus MC, Albert Schweitzer 
hospital, Maasstad hospital and Franciscus hospital Gasthuis and Vlietland), for non-metastatic, 
histological proven invasive breast cancer (pT1-3N0-2a) or DCIS between 2016 and 2020 (at time of 
inclusion in 2022 respectively 6,  to 2  years after treatment), and subsequently received adjuvant 
radiotherapy at the Erasmus MC as part of their BCT.  
In order to be eligible to participate in this study, a subject must meet all of the following criteria: 
female, aged ≥ 18 years, history of BCT with adjuvant radiation therapy for non-metastatic, 
histologically proven invasive breast cancer pT1-3N0-2a or DCIS. In light of BCT adjuvant systemic 
treatment (i.e. endocrine therapy, chemotherapy and immune therapy) is allowed. Furthermore, 
BCS between 1st of January 2016 and 31th of December 2020, and a patient must have been treated 
according to the currently applied dose fractionation schedules (START B trial), i.e. whole breast 
radiotherapy, with or without boost, and adequate understanding of the Dutch language and written 
informed consent 
A potential subject who meets any of the following criteria will be excluded from participation in this 
study: any breast surgery or re-irradiation on the breast area after BCT, progression of disease (and 
additional treatment) since BCT, patients who received partial breast irradiation, pregnancy or breast 
feeding at the time of recruitment.  

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Subjects can leave the study at any time for any reason if they wish to do so without any 
consequences. The investigator can decide to withdraw a subject from the study for urgent medical 
reasons. 
 
Recruitment and consent 
At the participating hospitals a list of all patients who had breast-conserving surgery in the period 
2016-2020 will be collected. These lists will be stored in a secure location at the hospital where the 
patient was treated, and only persons directly involved in subject recruitment, data collection, and 
data verification will have access to these lists. Also, a list of all irradiated patients in this period, 
meeting our inclusion criteria and operated on in the participating hospitals, will be collected at the 
Erasmus MC. In this way patients who are six years after surgery (and no longer have follow up 
appointments with their surgeon) will not be missed. 
After this, the outpatient clinic schedule will be checked for eligible patients. If so, the surgeon or 
assistant will be informed by phone or email and will be asked to inform the patient about our study 
at the outpatient clinic. Preceding their regular follow up visit, after a short explanation of the study 
by the surgeon or nurse, eligible patients will be asked by their treating surgeon or nurse if they want 
to participate. They will receive written information regarding this study. Patients can consider 
participation as long as needed to make a well-considered decision. The researcher will contact 
patients (or vice versa) to explain more about the study and answer the remaining questions. 
Patients will be enrolled after all questions are answered satisfactorily and after written informed 
consent is given. After written informed consent is given, a visit to the outpatient clinic of their own 
hospital will be planned. If it is more convenient for the patient, it is also possible to plan the hospital 
visit at the Erasmus MC. At this appointment, the researcher (MD) will perform a physical 
examination (to grade fibrosis), score the predefined list of adverse events and cosmetic outcomes, 
and take photographs of the breasts. The physical examination will consist of palpation of the 
breasts, axillary, and peri-clavicular regions. 
Patients will be informed at the outpatient clinic about the aim and the content of the study by the 
treating physician, but not all patients who are six years after surgery still have regular follow up 
anymore. In this case, the surgeon or radiotherapist (or colleague surgeon/radiotherapist, physician 
assistant, nurse practitioner from the team) who treated them will call these patients to notify them 
about the study. In the case of (permanent) absence of the primary treating physician, a colleague 
from the clinical team will call the patient. If the patient is open to this, they will be phoned by the 
researcher for more information. They will receive written information regarding this study and an 
informed consent form. Patients can consider participation as long as needed. The researcher will 
contact patients if necessary (or vice versa) to answer the remaining questions. Patients will be 
enrolled after written informed consent is given. 
Study procedures and endpoints 
Fibrosis 
A summary of all study procedures is displayed in Figure 2. After inclusion of eligible patients, 
fibrosis will be graded by the researcher using the CTCAE v5 scale (see Appendix A) during the one 
time visit at the outpatient clinic (21). Cosmetic outcomes will be evaluated by means of a 9-item 

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cosmetic patient questionnaire (filled out by the patient) with scoring on a four-point scale (range 
from ‘excellent’ to ‘poor’ per item) (22). We will also be using a physical examination form (see 
Appendix B) as used for the PBSI (Permanent Breast Seed Implant) study including the assessment of 
adverse events (such as redness of the skin, pigmentation), which will be an addition to the fibrosis 
grading, because these are also important factors which play a role in cosmetic outcomes. This form 
will be filled out by the researcher.  
Cosmetic outcomes 
Furthermore, patients’ photographs of the breasts (between collar bone and umbilicus) will be taken 
during this outpatient clinic visit, for asymmetry evaluations. Three color photographs of the breasts 
will be taken: two frontal views, one with arms along the body, one with arms lifted upwards and 
one profile view taken from the treated side with arms lifted upwards (19). With the use of the 
BCCT.core software from The Breast Research group (INESC TEC, the Faculdade de Medicina da 
Universidade do Porto) cosmetic outcomes will be assessed (23). With this software program, which 
we have been using and currently use in several studies (20, 22, 24, 25), various parameters can be 
extracted from the photographs. The three dimensionless asymmetry features known to be the most 
relevant variables that represent various aspects of breast fibrosis are Breast Retraction Assessment 
(BRA), Lower Breast Contour (LBC), and Breast Overlap Difference (BOD). These three parameters 
respectively represent nipple and breast retraction, ‘lifting’ of the breasts and contour and volume 
changes and will be used in our analyses (19).  
Quality of life 
Patient reported outcomes of QoL domains and symptoms will be assessed using the questionnaires 
that are proposed in the ICHOM breast cancer outcome set to evaluate breast cancer patients (26). 
The questionnaires we will be using are the Euro-QoL 5D- 5L (EQ 5D-5L version 2.0), the European 
Organization of Research and Treatment of Cancer QoL questionnaires (EORTC QLQ C30 version 3.0 
and EORTC QLQ-B23) and BREAST-Q breast conserving therapy (postoperative module version 2.0) 
and 9-item cosmetic patient questionnaire (22, 27-30). These questionnaires consist of psychosocial, 
sexual and physical well-being items, symptoms and satisfaction with outcome and breasts.  
A link to the electronic questionnaires will be sent to the participants by email after the patient has 
given explicit consent for transfer of personal data to the datacenter in coordinating institute (name, 
date of birth, email address and telephone number) and after inclusion in the trial. Some patients 
may already have completed some of the questionnaires that we are interested in (namely Breast-Q, 
EORTC QLQ-C30 and EORTC QLQ-B23), on behalf of the PROMs Citrien project (31). In the PROMs 
Citrien project, patients are asked to complete questionnaires after 6 months and then every year up 
until 5 years after treatment. If we include patients that filled in these questionnaires for the Citrien 
project already, we will ask the patient if we can use these questionnaires, in order to avoid having 
to fill in the same questionnaires twice. When filled out online, the questionnaires will automatically 
being transferred into our database. If the patient does not have an email address or cannot fill out 
the forms online for some reason, the questionnaires will be handed out on paper during the 
outpatient clinic visit at the referring site. Patients will then also receive a returning envelop, so that 
they are able to complete the questionnaires in their own time and space and send them to the 
Erasmus MC. All completed questionnaires will be stored by the Datacenter in the Erasmus MC and 
imported in the study database. 

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The site will be responsible for collection of questionnaires at the time point as defined in the study 
protocol. Every site may delegate the distribution and collection of online questionnaires to the 
Datacenter by sending a form containing the full name, date of birth, telephone number and email 
address of the patient and including a written consent for providing these data to the employees in 
Erasmus MC who are directly involved in the distribution and collection of digital questionnaires. 
Without this written consent form for digital collection of questionnaires, the distribution and 
collection of questionnaires cannot be delegated to the Datacenter in Erasmus MC and will remain a 
site responsibility. 
All patient and tumor characteristics, as well as surgical techniques, will be collected 
(retrospectively) from (digital) records in the four hospitals. All radiation treatment data is available 
at the department of Radiotherapy at Erasmus MC and will be collected by the study staff in 
Erasmus MC. All technical radiation parameters can be retracted fully automated because of the 
extended information technology (IT) infrastructure at the department. Due to the excellent 
multidisciplinary collaboration, complete collection of clinical, surgical and radiotherapeutic data will 
be realistic. 
The study ends when the last included patient has her photographs taken and has completed the 
questionnaires. There will be no follow-up of patients in the context of this study. Patients will 
continue with their regular follow-up. 
If patients are withdrawn from the study, the standard care and follow-up will be continued. We do 
not expect a reason to terminate the study prematurely since only minimal to no risks are associated 
with participating in the study. 
 
Data collection  
The main goal of this project is to determine risk factors and their interaction contributing to the 
development of fibrosis and cosmetic outcome, after breast-conserving therapy for (pre-invasive) 
breast cancer. The primary focus will be on the role of different combinations of (oncoplastic 
reconstructive) surgery and radiotherapy techniques as risk factors for the development of fibrosis, 
as well as for moderate to poor cosmetic outcome and QoL. To be more specific: 
1. To determine prognostic risk factors for moderate to severe fibrosis, moderate to poor cosmetic 
outcome and QoL, especially in the light of current oncoplastic surgery techniques. 
2. To develop prediction models for the risk of moderate to severe fibrosis stratified for (oncoplastic) 
surgery and radiotherapy parameters 
3. To develop prediction models for cosmetic outcome stratified for (oncoplastic) surgery and 
radiotherapy parameters 
To this end clinical, surgical and radiotherapeutic related parameters will be captured: 
Patient characteristics such as age at time of inclusion; age at time of diagnosis of breast cancer; 
length, weight, body mass index (BMI; kg/m2); diabetes; menopausal status, smoking; allergies; 
hypertension; presence of connective tissue disorders; presence or history of autoimmune or auto-

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inflammatory disorders; history of malignancies and received treatments, previous operations of the 
breast(s). 
Tumor characteristics: clinical tumor size (cm) on X-mamma/echo/MRI, tumor location (lateral upper 
quadrant, lateral lower quadrant, medial upper quadrant, medial lower quadrant, central), 
macroscopic size (cm) of the tumor (in the pathology report), tumor to breast volume ratio, tumor 
histology, ER, PR and Her2neu expression, tumor grade, presence of complementary DCIS (in the 
case of invasive breast cancer), size and location of DCIS, lymphovascular space invasion (LVSI). 
 
 
Figure 2: Study Flowchart 
 
Surgery characteristics: weight of tissue of specimen (pathology report) or macroscopic size (cm) of 
the tissue specimen (if available in the pathology report), post-operative complications, type of 

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surgery (1. standard/simple lumpectomy, 2. tissue displacement techniques 3. tissue replacement 
techniques), re-resection (yes/no), axillary dissection (yes/no). 
Radiotherapy characteristics: Technical, volumetric and dosimetric data will be collected. On this 
basis the relevant parameters can be extracted. 
In case of systemic therapy: use of Aromatase inhibitor and Chemotherapy (type, timing: neo-
adjuvant or adjuvant); use of antimicrobial, anti-inflammatory, biological and cardiovascular agents; 
duration of Aromatase inhibitor therapy and Chemotherapy, use of Hormonal therapy, use of 
Trastuzumab; use of Hyperbaric Oxygen Therapy. 
The secondary endpoint will be to assess the relation between the presence and severity of fibrosis, 
cosmetic outcome and different QoL domains and symptoms. With regard to QoL the specific focus 
will be on physical functioning, satisfaction with breast, psychosocial functioning and breast 
symptoms. To this end health related quality of life parameters will be captured: 
- 
Health Related Quality of Life: pain (NRS scale 0-10), use of medication for pain  
(yes/no). Patient reported outcomes will be used to evaluate the health-related quality of life, which 
are measured by different questionnaires about quality of life and symptoms. This includes: 
o European Organization for Research and Treatment of Cancer QoL Questionnaire–
Core 30 (EORTC QLQ-C30, version 3) (28) 
o Postoperative BCT of the BREAST-Q (version 2)(only postoperative items) (27) 
o EuroQol Group 5-level EQ-5D (EQ 5D-5L) (29)  
o European Organization for Research and Treatment of Cancer QoL 
o Questionnaire BR23 (EORTC QLQ-BR23 version 1.0) (30) 
o 9-item cosmetic patient questionnaire (22) 
 
These questionnaires (in Dutch) consist of psychosocial, sexual and physical well-being items, as well 
as symptoms, and satisfaction with breasts. All scales and single item measures range in a score of 
0-100 after transformation. A higher score means better functioning and QoL, whereas for the 
symptom domains higher scores represent more symptoms. The results of these questionnaires of 
our participants will be used to measure the impact of cosmetic outcomes and fibrosis on the HRQoL. 
To this end the participants will be asked to fill out the questionnaires during their one-time study 
visit. Fibrosis will be prospectively graded using the CTCAE v5 scale (see appendix A) (21) together 
with a predefined list of adverse events / cosmetic outcomes (see appendix B), and patients’ breast 
photographs will be made to assess objective cosmetic outcomes.  
 
Sample size calculation 
Between 2016-2020 approximately 1600 patients underwent simple or complex oncoplastic 
lumpectomy (6) (Figure 1) at one of the four hospitals and subsequently received adjuvant 
radiotherapy at the Erasmus MC as part of their BCT. Considering data of 2016, we can conclude that 
approximately 50% was treated with a simultaneously integrated boost (SIB), roughly 15% got a 
sequential boost and the rest only received the elective dose. A radiation boost dose to the surgical 
area was delivered as a SIB in 49% of the patients and directly after the elective radiation dose 
(sequentially) in 17%. The 1600 eligible patients will be asked to participate in this study at their 

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planned standard follow-up appointment during the 1 to 1.5 years of patient inclusion at their 
follow-up appointment 2-, 3-, 4-, 5- or 6-years after treatment. However, not all patients who are six 
years after surgery still have regular follow up anymore. In this case the surgeon or radiotherapist 
who treated them will call to notify about the study. Earlier studies showed that an inclusion rate of 
70% is feasible (21). In our experience, at least 50% of the patients agrees to participate in the study. This 
means that approaching 1600 patients should be sufficient to result in a cohort of at least 750 patients. 
It is expected that approximately 20% (11) of these patients will have moderate or severe fibrosis in 
the breast, including the boost area. That means that the sample size of 750 will provide sufficient 
information to develop a model with approximately 7-15 degrees of freedom (DF) (using the rule of 
thumb of the effective sample size of 10-20 per DF). It is expected that the percentage of patients 
with unsatisfactory cosmetic outcomes will be approximately 30%, so according to the same 
reasoning as above, there will also be sufficient information to develop a model to predict cosmetic 
outcomes. 
 
Statistical analysis  
All statistical analyses will be performed using SPSS (current version 25.0, Statistical Package for 
Social Sciences, Chicago, IL, USA) and the latest R version. Statistical tests will be two-sided and 
differences are considered significant if p<0.05. 
 
Primary study parameter(s)  
The primary aim of this study is to develop prediction models for fibrosis and moderate to poor 
cosmetic outcome after treatment with different combinations of (oncoplastic) surgery and 
radiotherapy techniques. It will be investigated whether the type of surgical technique (standard / 
simple oncoplastic lumpectomy; complex oncoplastic technique with tissue displacement, or 
complex oncoplastic technique with tissue replacement) is associated most with cosmetic outcome 
and the risk of fibrosis, or whether it is one or more radiotherapeutic parameter(s), or both. These 
analyses will be adjusted for other patient and tumor characteristics (e.g., age, breast volume, tumor 
size), and factors related to radiotherapy (e.g., boost treatment, boost volume, maximum radiation 
dose).  
The surgical techniques with tissue displacement and replacement will be compared to determine 
whether they should be analysed separately or could be considered as one treatment. The analysis 
will be supported by a comparison of the post-operative complications (e.g., seroma and 
hematoma), because these are known to be associated with fibrosis. 
If there are differences between the surgical techniques, then it will be useful to develop models that 
predict their outcome for individual patients. The treatment options actually consist of combinations 
of surgical techniques and radiotherapy. Therefore, the interaction will be tested between surgical 
technique and whether a radiation boost dose was given (and volume of the boost). The interaction 
will be included in the model if it is found to be relevant. Patient and tumor characteristics and 
factors related to radiotherapy treatment will be considered as candidate variables to be included in 
the model. But factors will not be considered candidate variables if they are related to the success of 
the surgery procedure itself (e.g., excision volume, post-operative complications seroma and 

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hematoma), because it is expected that any differences between the surgical techniques on 
outcome may be caused via these factors. However, whether this is the case will be investigated. 
If no clinically relevant differences are found between the surgical techniques, then it may be more 
worthwhile to focus the research on the role of radiotherapy techniques. In that case, it will be 
important to investigate correlations between the candidate predictor variables, and resolve 
multicollinearity issues if possible, when developing a model. The model may then be used to 
identify radiotherapy parameters that can be taken into consideration during radiotherapy 
treatment planning. These parameters could then be investigated in a future planning study, with 
the aim of optimizing radiotherapy treatment plans. For such a model, factors related to surgery are 
candidate covariates (along with patient and tumor characteristics, and radiotherapy parameters), 
because in practice the results of the surgery will be known at the time of radiotherapy planning. 
The endpoints will be modeled as follows: 
- 
Fibrosis will be dichotomized into no/mild and moderate/severe fibrosis and modeled using 
logistic regression. 
- 
Overall cosmetic outcome derived from patient questionnaires will be dichotomized into 
excellent/good outcome (“satisfactory cosmetic outcome”) and moderate/poor 
(“unsatisfactory cosmetic outcome”) and modeled using logistic regression.  
Prediction models will be developed by means of a multivariable logistic regression using variable 
selection criteria and supported by univariable analysis.  
Furthermore, the parameters that will be found in our literature search for the review will also be 
added. Internal validation of the models will be investigated using a bootstrap or cross-validation 
procedure. External validation will not be part of this study but can be done in the future by means 
of a validation study or a replication cohort (for example Breastcenter ZuidHollandZuid or Umbrella 
cohort, University Medical Center Utrecht). Details of the methods will be described in a statistical 
analysis plan. 
 
Secondary study parameter(s) 
The secondary objectives are to describe the presence and severity of fibrosis, cosmetic outcomes, 
and QoL according to the different patient and tumor characteristics and the different surgery and 
radiotherapy techniques. Second, to assess the relation between the presence and severity of 
fibrosis, cosmetic outcome and the different QoL domains and symptoms. With regard to QoL, the 
specific focus will be on physical functioning, satisfaction with breast, psychosocial functioning and 
breast symptoms.  
Summary statistics and tables of patient characteristics will be produced. Participants will be asked 
to fill out five questionnaires. The results of each domain from the EORTC QLQC30, EORTC QLQ-B23, 
Breast-Q, 9-item questionnaire and EQ 5D-5L questionnaires, will be converted to a numeric score 
(range 0-100) by the use of manual scoring tables. All statistical tests will be two-sided and 
differences are considered significant if p<0.05.  
Univariate logistic regression analysis will be used to assess whether there is a relation between 
fibrosis and BCCT.core. parameters (treated as continuous variables), and whether fibrosis or the 
BCCT.core parameters were associated with patient reported unsatisfactory cosmetic outcome. In 

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order to evaluate whether fibrosis or unsatisfactory cosmetic outcome lead to a worse QoL, linear 
regression will be used. A separate model will be built for each of the QoL scales/single items. 
 
Future plans 
If the findings of this project lead to changes in shared decision-making, it will be important to 
explore which risk factors and specific (sub)domains of cosmetic outcomes and QoL are most 
relevant to patients during treatment decision-making, and how these aspects relate to one another. 
This may also include consideration of lifestyle interventions, such as quit smoking, aimed at 
reducing the risk of postoperative complications and subsequent fibrosis. 
If our study demonstrates that certain patients have a choice regarding the type of (oncoplastic) 
lumpectomy, a patient decision aid (PDA) will be developed. This will be carried out in close 
collaboration with Dutch breast cancer patient advocates (Borstkankervereniging Nederland) and 
with the use of the International Patient Decision Aid Standards (IPDAS) checklist (32). 
The next step will be to assess its effect on quality of care and QoL of our breast cancer patients. Our 
prospective registration of patient-reported outcome measures (PROMs) within the Citrien project 
will be of great value to evaluate this in a prospective manner (31). If future research demonstrates 
that such a decision aid improves quality of care, it will become more widely available. 
 
Acknowledgements  
The authors would like to thank the INESC Porto Breast Research Group for the use of the BCCT.core 
software. 
 
Funding  
This study was partially funded by Stichting BeterKeten (Dutch: Stichting BeterKeten). 
 
Ethics approval and consent to participate  
The study is in compliance with the Helsinki declaration. Ethical approval has been granted by the 
Institutional Review Board of the Erasmus University Medical Centre, Rotterdam, the Netherlands 
(reference-number: MEC-2021-0829) and of the institutional Review Board of all participating 
hospitals. This trial is registered before the start of the inclusion. Upon inclusion, a written informed 
consent is obtained from all participants. 
 
 
 

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Appendices 
 
Appendix A: CTCAE v5 
 
CTCEA Term 
Superficial soft tissue fibrosis / Fibrosis deep connective tissue 
Grade 0 
Not applicable 
Grade 1 
Mild induration, able to move skin parallel to plane (sliding) and perpendicular 
to skin (pinching up) 
Grade 2 
Moderate induration, able to slide skin, unable to pinch skin; limiting 
instrumental ADL 
Grade 3 
Severe induration; unable to slide or pinch skin; limiting joint or orifice 
movement (e.g., mouth, anus); limiting self-care ADL 
Grade 4 
Generalized; associated with signs or symptoms of impaired breathing or 
feeding 
Grade 5 
Death 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 

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Appendix B: Physical examination form STARLINGS study 
 
Patiënt name  
 
PID nr 
 
 
Date of assessment primary endpoint  
 
Physician who scored primary endpoint  
 
 
Teleangiectasia score (Bentzen) 
| 
| 0 = 
none 
 
1 = grade I – less than 1cm2 
2 = grade II – 1 to 4 cm2 
3 = grade III – over 4cm2 
Distance of teleangiectasia from 
reference point (nipple lowerinner) 
 
 mm 
 
Angle of teleangiectasia from 
reference point (nipple lowerinner) 
 
 degree 
 
Teleangiectasia in which 
skin projection location? 
| 
| 0 = 
none 
 
 
1 = central 
2 = mediocranial quadrant 
3 = mediocaudal quadrant 
4 = laterocaudal quadrant 
5 = laterocranial quadrant 
 
 
Primary endpoint evaluable 
| 
| 0 = no 
1 = 
yes 
 
If non-evaluable, reason: 
| 
| 
1 = re-irradiation on ipsilateral breast/chestwall < 
2yrs post-treatment 
Physical Examination Form STARLING STUDY 
formulier ten behoeve van medisch dossier 

Version 3.0 d.d. 27-01-2023 
14 
 
2 = re-surgery on ipsilateral breast/chestwall 
< 2 yrs post-treatment 
5 = other, specify below 
 
Comments: 
 
 
 
 
 
Naam + Handtekening:  
 

Version 3.0 d.d. 27-01-2023 
15 
 
  
 
Patient name  
 
Date of AE assessment 
 
 
PID nr 
 
 
 
 
Pain in breast 
| 
| 0 = none 
1 = occasional and minimal – hypersensation – 
pruritus 
2 = intermittent and tolerable 
3 = persistent and intense 
Redness 
4 = refractory and excruciating 
| 
| 0 = no 
1 = yes, but no effect on ADL 
2 = yes and effect on ADL 
 
Pigmentation 
| 
| 0 = none 
1 = transitory – slight; 
2 = permanent marked 
Skin induration 
| 
| 0 = none 
1 = mild induration / able to move skin parallel to 
plane 
(sliding) and perpendicular to skin (pinching up) 
2 = moderate induration / able to slide skin / unable to 
pinch skin / limiting instrumental ADL 
3 = Severe induration / unable to slide or pinch skin / 
limiting self-care ADL 
4 = generalized 
 
Subcutaneous induration 
| 
| 
0 = none 
1 = slight induration and loss of subcutaneous fat 
2 = moderate fibrosis but asymptomatic 
3 = severe induration and loss of subcutaneous tissue / field 
contracture 
4 = necrosis 
 
Distance of clinical max skintoxicity from reference point (nipple lowerinner) 
 
 
 mm Angle of clinical max skintoxicity from 
Physical Examination Form STARLING STUDY 
formulier ten behoeve van medisch dossier 

Version 3.0 d.d. 27-01-2023 
16 
 
reference point (nipple lowerinner) 
 
degree Max skin toxicity in wich skin 
projection location: | 
| 
0=none 
1=central 
2=mediocanial 
quadrant 
3=medialcaudal 
quadrant 
4=laterocaudal 
quadrant 
5=laterocranial 
quadrant 
 
Any other radiotherapy induced adverse events? | 
| 0 = no; 1 = yes 
If yes, specify: 
 
 
 
 
 
Naam + Handtekening:  
 

 
 
 
 
Appendix C: Dutch questionnaires 
 
 
9-item cosmetische vragenlijst: 
 
Beoordeel het uiterlijk van uw behandelde borst met betrekking tot: 
Operatie-litteken 
uitstekend 
goed 
matig 
slecht 
Grootte van de borst 
uitstekend 
goed 
matig 
slecht 
Vorm van de borst 
uitstekend 
goed 
matig 
slecht 
Positie van de tepel 
uitstekend 
goed 
matig 
slecht 
Kleur van de huid 
uitstekend 
goed 
matig 
slecht 
Hoe de borst er als geheel uitziet 
uitstekend 
goed 
matig 
slecht 
Asymmetrie / verschil tussen de behandelde en onbehandelde borst 
helemaal niet 
een beetje nogal 
heel erg 
Tevredenheid met hoe de borst er als geheel uitziet 
uitstekend 
goed 
matig 
slecht 
Tevredenheid met de keuze voor borstsparende operatie ten opzichte 
van niet-borstsparende operatie 
uitstekend 
goed 
matig 
slecht 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
EQ-5D-5L: 
 
 
 
 
 
 
 
 

 
 
 
 
 
 

 
 
References 
 
 
1. 
Fisher B, Anderson S, Bryant J, Margolese RG, Deutsch M, Fisher ER, et al. Twenty-
year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy 
plus irradiation for the treatment of invasive breast cancer. N Engl J Med. 2002;347(16):1233-
41. 
2. 
Litiere S, Werutsky G, Fentiman IS, Rutgers E, Christiaens MR, Van Limbergen E, et al. 
Breast conserving therapy versus mastectomy for stage I-II breast cancer: 20 year follow-up of 
the EORTC 10801 phase 3 randomised trial. Lancet Oncol. 2012;13(4):412-9. 
3. 
Veronesi U, Cascinelli N, Mariani L, Greco M, Saccozzi R, Luini A, et al. Twenty-year 
follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy 
for early breast cancer. N Engl J Med. 2002;347(16):1227-32. 
4. 
Alberro JA, Ballester B, Deulofeu P, Fabregas R, Fraile M, Gubern JM, et al. Long-term 
outcomes for neoadjuvant versus adjuvant chemotherapy in early breast cancer: meta-analysis 
of individual patient data from ten randomised trials. Lancet Oncology. 2018;19(1):27-39. 
5. 
Lagendijk M, van Maaren MC, Saadatmand S, Strobbe LJA, Poortmans PMP, Koppert 
LB, et al. Breast conserving therapy and mastectomy revisited: Breast cancer-specific survival 
and the influence of prognostic factors in 129,692 patients. Int J Cancer. 2018;142(1):165-75. 
6. 
De La Cruz L, Blankenship SA, Chatterjee A, Geha R, Nocera N, Czerniecki BJ, et al. 
Outcomes After Oncoplastic Breast-Conserving Surgery in Breast Cancer Patients: A 
Systematic Literature Review. Ann Surg Oncol. 2016;23(10):3247-58. 
7. 
Correa C, Harris EE, Leonardi MC, Smith BD, Taghian AG, Thompson AM, et al. 
Accelerated Partial Breast Irradiation: Executive summary for the update of an ASTRO 
Evidence-Based Consensus Statement. Pract Radiat Oncol. 2017;7(2):73-9. 
8. 
Bartelink H, Maingon P, Poortmans P, Weltens C, Fourquet A, Jager J, et al. Whole-
breast irradiation with or without a boost for patients treated with breast-conserving surgery for 
early breast cancer: 20-year follow-up of a randomised phase 3 trial. Lancet Oncol. 
2015;16(1):47-56. 
9. 
Vrieling C, van Werkhoven E, Maingon P, Poortmans P, Weltens C, Fourquet A, et al. 
Prognostic Factors for Local Control in Breast Cancer After Long-term Follow-up in the EORTC 
Boost vs No Boost Trial: A Randomized Clinical Trial. JAMA Oncol. 2017;3(1):42-8. 
10. 
Collette S, Collette L, Budiharto T, Horiot JC, Poortmans PM, Struikmans H, et al. 
Predictors of the risk of fibrosis at 10 years after breast conserving therapy for early breast 
cancer: a study based on the EORTC Trial 22881-10882 'boost versus no boost'. Eur J Cancer. 
2008;44(17):2587-99. 
11. 
Brouwers P, van Werkhoven E, Bartelink H, Fourquet A, Lemanski C, van Loon J, et al. 
Predictors for poor cosmetic outcome in patients with early stage breast cancer treated with 
breast conserving therapy: Results of the Young boost trial. Radiother Oncol. 2018;128(3):434-
41. 
12. 
Brouwers PJ, van Werkhoven E, Bartelink H, Fourquet A, Lemanski C, van Loon J, et al. 
Factors associated with patient-reported cosmetic outcome in the Young Boost Breast Trial. 
Radiother Oncol. 2016;120(1):107-13. 
13. 
Hau E, Browne L, Capp A, Delaney GP, Fox C, Kearsley JH, et al. The impact of breast 
cosmetic and functional outcomes on quality of life: long-term results from the St. George and 
Wollongong randomized breast boost trial. Breast Cancer Res Treat. 2013;139(1):115-23. 
14. 
Waljee JF, Hu ES, Ubel PA, Smith DM, Newman LA, Alderman AK. Effect of esthetic 
outcome after breast-conserving surgery on psychosocial functioning and quality of life. J Clin 
Oncol. 2008;26(20):3331-7. 
15. 
Hammer C, Maduro JH, Bantema-Joppe EJ, van der Schaaf A, van der Laan HP, 
Langendijk JA, Crijns AP. Radiation-induced fibrosis in the boost area after three-dimensional 

 
 
conformal radiotherapy with a simultaneous integrated boost technique for early-stage breast 
cancer: A multivariable prediction model. Radiother Oncol. 2017;122(1):45-9. 
16. 
Lilla C, Ambrosone CB, Kropp S, Helmbold I, Schmezer P, von Fournier D, et al. 
Predictive factors for late normal tissue complications following radiotherapy for breast cancer. 
Breast Cancer Res Treat. 2007;106(1):143-50. 
17. 
Murphy C, Anderson PR, Li T, Bleicher RJ, Sigurdson ER, Goldstein LJ, et al. Impact of 
the radiation boost on outcomes after breast-conserving surgery and radiation. Int J Radiat 
Oncol Biol Phys. 2011;81(1):69-76. 
18. 
Vrieling C, Collette L, Fourquet A, Hoogenraad WJ, Horiot JH, Jager JJ, et al. The 
influence of patient, tumor and treatment factors on the cosmetic results after breast-conserving 
therapy in the EORTC 'boost vs. no boost' trial. EORTC Radiotherapy and Breast Cancer 
Cooperative Groups. Radiother Oncol. 2000;55(3):219-32. 
19. 
Immink JM, Putter H, Bartelink H, Cardoso JS, Cardoso MJ, van der Hulst-Vijgen MHV, 
et al. Long-term cosmetic changes after breast-conserving treatment of patients with stage I-II 
breast cancer and included in the EORTC 'boost versus no boost' trial. Ann Oncol. 
2012;23(10):2591-8. 
20. 
Lagendijk M, Vos EL, Nieboer D, Verhoef C, Corten EML, Koppert LB. Evaluation of 
cosmetic outcome following breast-conserving therapy in trials: panel versus digitalized analysis 
and the role of PROMs. Breast J. 2018;24(4):519-25. 
21. 
Available at: National Cancer Institute. Common terminology criteria for adverse events, 
v5.0. 2017. 2017. 
22. 
Vos EL, Koning AHJ, Obdeijn IM, van Verschuer VMT, Verhoef C, van der Spek PJ, et 
al. Preoperative Prediction of Cosmetic Results in Breast Conserving Surgery. J Surg Oncol. 
2015;111(2):178-84. 
23. 
Cardoso JS, Cardoso MJ. Towards an intelligent medical system for the aesthetic 
evaluation of breast cancer conservative treatment. Artif Intell Med. 2007;40(2):115-26. 
24. 
Lagendijk M, Vos EL, Koning AHJ, Hunink MGM, Pignol JP, Corten EML, et al. TUmor-
volume to breast-volume RAtio for improving COSmetic results in breast cancer patients 
(TURACOS); a randomized controlled trial. BMC Cancer. 2017;17(1):336. 
25. 
Vos E, Koppert L, van Lankeren W, Verhoef C, Koerkamp BG, Hunink M. A preliminary 
prediction model for potentially guiding patient choices between breast conserving surgery and 
mastectomy in early breast cancer patients; a Dutch experience. Qual Life Res. 2018;27(2):545-
53. 
26. 
Ong WL, Schouwenburg MG, van Bommel ACM, Stowell C, Allison KH, Benn KE, et al. 
A Standard Set of Value-Based Patient-Centered Outcomes for Breast Cancer: The 
International Consortium for Health Outcomes Measurement (ICHOM) Initiative. JAMA Oncol. 
2017;3(5):677-85. 
27. 
Pusic AL, Klassen AF, Scott AM, Klok JA, Cordeiro PG, Cano SJ. Development of a new 
patient-reported outcome measure for breast surgery: the BREAST-Q. Plast Reconstr Surg. 
2009;124(2):345-53. 
28. 
Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. The 
European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life 
instrument for use in international clinical trials in oncology. J Natl Cancer Inst. 1993;85(5):365-
76. 
29. 
Herdman M, Gudex C, Lloyd A, Janssen M, Kind P, Parkin D, et al. Development and 
preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res. 
2011;20(10):1727-36. 
30. 
Tan ML, Idris DB, Teo LW, Loh SY, Seow GC, Chia YY, Tin AS. Validation of EORTC 
QLQ-C30 and QLQ-BR23 questionnaires in the measurement of quality of life of breast cancer 
patients in Singapore. Asia Pac J Oncol Nurs. 2014;1(1):22-32. 

 
 
31. 
Organisatie van kwaliteitsindicatoren Waardegedreven zorg: Ontwikkeling regionaal 
platform en dashboard Borstkanker. Available at: 
https://www.oncologienetwerken.nl/nieuws/artikel/project-de-organisatie-van-
kwaliteitsindicatoren-pilot-borstkanker. 
32. 
Vromans R, Tenfelde K, Pauws S, van Eenbergen M, Mares-Engelberts I, Velikova G, et 
al. Assessing the quality and communicative aspects of patient decision aids for early-stage 
breast cancer treatment: a systematic review. Breast Cancer Res Treat. 2019;178(1):1-15.