General considerations
RT should start preferably within 8 weeks from the last breast surgical procedure and not later than 12 weeks. In case chemotherapy is applied, RT should start within 6 weeks after the end of the last cycle of chemotherapy and not later than 8 weeks.
All patients undergo adjuvant whole-breast irradiation after breast-conserving surgery or chest-wall irradiation after mastectomy. After breast-conserving surgery, a boost to the tumor bed is recommended for all patients of ≤ 50 years of age and considered for patients > 50 years with increased risk of local recurrence (e.g., G3, HER2-pos, triple-negative, accompanying DCIS, LVI, R1/narrow R0) [
87‐
89]. All patients receive regional nodal irradiation, excluding the dissected axilla as a target volume in arm A (levels (II)/III; medial supraclavicular; internal mammary lymph nodes) and including the full axilla (levels I–III; medial supraclavicular; internal mammary lymph nodes) as a target volume in arm B. In case of extensive nodular involvement in arm A, the target volume includes the area at risk of the dissected levels. Inclusion of internal mammary nodes is recommended irrespective of treatment arm [
42].
In case of assumed residual or recurrent macroscopic axillary disease after axillary surgery (TAS or ALND) detected by imaging, i.e., performed for RT treatment planning or staging, confirmation with fine-needle aspiration and adjustment of axillary treatment is allowed. The decision whether to apply additional surgery or nodal boost irradiation or irradiation without a nodal boost has to be made interdisciplinary.
Volumes of interest
The CTV, PTV, nodal levels, and OAR must be outlined on all CT slices in which these structures are visible. Standardization of target volume delineation will be generally based on the ESTRO Consensus guideline on target volume delineation [
90,
91]. Delineation of all lymph node levels separately and independently from the actual defined nodal CTV will be required for all patients to perform a distinct evaluation of dose distribution within the prospectively planned quality assurance program.
The lymph node levels are in summary:
n-L1(level-I nodes):
Part of the axilla located lateral of the pectoralis minor muscle and more caudally lateral of the thoracic wall. Cranially, the axillary vein should be included with a margin of 5 mm. Laterally, the n-L1 should be limited by a margin of 1 cm around the humeral head (humerus-PRV) in the cranial part and by a line between the lateral edges of the pectoralis major muscle and the deltoid muscle. Caudally, this level ends around the level of costae 4–5 and the dorsal limit is set by the ventral parts of the subscapular and deltoid muscles and more caudally by the ventral edge of the latissimus dorsi muscle.
n-L2 (level-II nodes):
Part of the axilla located dorsal to the minor pectoral muscle. The axillary vein with a 5-mm margin should be embedded including, cranially, the axillary artery. The caudal limit is the caudal border of the minor pectoral muscle. Medially and laterally the volume adjoins level 1 and level III.
n-L3 (level-III nodes):
Volume located medially to the minor pectoral muscle and n-L2. The subclavian vein with a 5-mm margin should be embedded, cranially including the subclavian artery. It is located dorsal the pectoralis minor muscle and ventral to the costae and intercostal muscles. In medial direction the volume is connected to the n-L4.
n-L4 (medial supraclavicular nodes):
This volume represents the supraclavicular volume. Laterally, it connects with the n-L3 including the anterior scalene muscles. Caudally the subclavian vein is embedded with a margin of 5 mm and connects to the n-IMN. The jugular vein is included medially without a margin, excluding the thyroid gland and the common carotid artery. The cranial border is the cranial level of the subclavian artery arch including the subclavian vein with a margin of 5 mm. In case of pathological nodes in level III, the cranial border may be shifted further cranially (maximally below the cricoid cartilage as specified by the Radiation Therapy Oncology Group guidelines).
n-interpect:
These lymph nodes are located ventral to the minor pectoral muscle and dorsal to the major pectoral muscle, while the cranial, caudal, lateral, and medial limits largely reflect the limits of n-L2.
n-IMN (internal mammary nodes):
This volume connects cranially to the n-L4 volume and includes both the internal mammary vein and artery with a 5-mm margin. The dorsal border is the pleura. Caudally, this volume ends from the cranial edge of the fourth rib; in case of a caudally/medially located tumor the cranial side of the fifth rib is allowed to be included.
Clinical target volume of breast/chest wall (CTVp_breast/CTVp_chestwall)
The target volume of the breast includes the total glandular breast tissue. The dorsal border of the CTVp_breast is the ventral side of the major pectoral muscle and, where that is not present, the exterior side of the ribs and intercostal muscles. The ventral border is 5 mm under the skin surface. The cranial border extends usually maximally up to the level of the caudal edge of the sterno-clavicular joint. The caudal border is the lowest CT slice with breast shape still visible. The medial border extends maximally to the ipsilateral edge of the sternum. For the lateral border, the breast should be delineated ventral/medial to the lateral thoracic artery. Care should be taken that the CTVp breast encompasses the primary tumor bed.
The boundaries of the CTVp_chestwall are similar to those of the CTVp_breast as described above. Expanders and implants will be included in the CTV. In case of a very thin chest wall, the ventral border of the CTVp_chestwall may be reduced to 2–3 mm under the skin surface for practicability reasons. In case of skin involvement, the ventral border in the respective regions should expand to the skin surface.
CTV of the tumor bed boost (CTVp_boost)
The tumor bed should be delineated based on all available information from pre-operative imaging, surgical report, pathology report and the localization of the surgical clips. If oncoplastic surgery was done a close collaboration between surgeon and radiation oncologist is important. The CTVp_boost should include the tumor bed with a margin of 5 mm in all directions to encompass potential microscopic disease extension without exceeding CTVp_breast.
CTV of regional nodal irradiation in arm A (CTVn_RNI-A)
The CTV of the regional nodal irradiation in arm A includes the not surgically approached parts of the axilla. This will be in general level III (n-L3), the supraclavicular lymph nodes (n-L4) and the internal mammary lymph nodes (n-IMN). Thus, the final CTV of regional nodal radiation (RNI) should be restricted to include the summation of levels III (n-L3), level IV (n-L4 and the internal mammary lymph nodes (n-IMN). Level II or cranial parts of level II (n-L2) should be included in the nodal CTVn_RNI-A in case the surgical procedure did presumably not include the whole of level II, leaving the lateral and inferior border of the CTV at the discretion of the radiation oncologist. In case clips are used to mark the medio-cranial dissection border of axillary dissection the CTV will be restricted accordingly. There should be no gap between the target volumes of RNI and the resulting target volume of the breast/thoracic wall.
In case of limited nodular involvement (more than three lymph nodes) and biologically low-risk disease (G1- and ER-positive or lateral location and postmenopausal), RNI could be omitted. In case of extensive nodular involvement (e.g., ≥ 50% of removed lymph nodes) and suspected residual disease, the target volume may include the area at risk of the dissected levels. The reason for omitting RNI or including the complete axilla will be queried in the RT CRF.
CTV of regional nodal irradiation in arm B (CTVn_RNI-B)
The CTV of the regional nodal irradiation in arm B will be defined like in arm A (n-L3 + n-L4 + n-IMN) but will in addition always include the axillary nodal levels I and II (n-L1 and n-L2).
In case of biologically low-risk disease (G1- and ER-positive and postmenopausal) and lateral tumor location, the irradiation of the internal mammary nodes (n-IMN) may be omitted if the risk of cardiac side effects is considered disproportionately high compared to the benefit of RT to the internal mammary nodes. The reason for omitting internal mammary nodes in the nodal target volume will be queried in the RT CRF. In case of additional complete axillary dissection in arm B target volume will be modified accordingly and spare out the completely approached levels.
CTV of nodal boost (CTVn_boost)
In case of assumed residual or recurrent macroscopic disease and decision for a nodal boost without additional surgery, the lymph node tissue visible in imaging and an additional margin of 5 mm should be defined as CTVn_boost.
Planning target volume (PTVp_breast/chestwall; PTVn_RNI-A/B)
For the planning target volume (PTV) an additional margin is to be added to the respective CTV in order to take intra-fraction, inter-fraction motion and machine uncertainty into account.
These margins depend on institutional standards. Generally, the minimum of 5 mm CTV-to-PTV expansion is recommended. PTVp_breast/chestwall and PTVn_RNI will be joined to create the PTV, which will be the target volume for treatment planning.
For planning reasons the PTV should be cropped 2–3 mm beneath the skin in case of breast-conserving surgery and 2 mm beneath the skin in case of PMRT. In case of skin involvement the ventral border expands to the skin surface.
Organs at risk (OAR)
The lungs should be contoured separately ipsilaterally (Lung_ipsilat) and contralaterally (Lung_contralat) as well as a whole organ as a sum of both (Lung).
Superiorly, the whole heart (Heart) starts just inferior to the left pulmonary artery. For simplification, a round structure to include the great vessels as well can be delineated. Inferiorly, the heart blends with the diaphragm. Since cardiac vessels run in the fatty tissue within the pericardium, this should be included in the contours, even if there is no heart muscle visible in that area. The superior vena cava can be included [
92].
The humeral head should be contoured (humeral head) and in addition a planning risk volume including a margin of 1 cm around the humeral head (humeral head_PRV) should be created to help sparing high doses from the humeral head and surrounding tissue by cropping the CTVn_RNI.
The spinal cord should be delineated and in addition a planning risk volume including the margin used for the set-up error CTV-PTV expansion should be created (spinal cord_planning risk volume (PRV)).
The contralateral breast should be contoured 5 mm below the skin to the fascia of the pectoralis muscle. The medial border of the organ should end at least 20 mm from the midline including apparent glandular breast tissue.
There is no need to routinely delineate the brachial plexus since keeping the maximal doses of target volumes within the per-protocol constraints accounts for a low risk of brachial plexopathy. However, in case of deviations from these constraints, or if a nodal boost should be performed, the commonly accepted constraints for brachial plexus in the site should be respected.
External-beam equipment and techniques
Treatment must be delivered on a linear accelerator with a photon beam quality of 4 to 15 MV. Three-dimensional CRT (3D-CRT) techniques or IMRT can be used to configure the irradiation fields. Rotational techniques, such as Tomotherapy®, RapidArc®, IMAT, and VMAT, will also be eligible. For 3D-CRT planning it is recommended to use a technique based on tangential fields with parallel posterior-field edges to cover the PTVp_breast/PTVp_chestwall. For regional nodal irradiation field arrangements are left to the discretion of the investigators to produce an optimal dose distribution for PTV and OAR. Wedges, multileaf collimator (MLC) compensation or field-within-field techniques may be used to optimize dose distribution and compensate for inhomogeneity throughout the PTV.
Treatment using the deep inspiration breath-hold technique is allowed and recommended for left-sided patients and also for right-sided patients if essential for the reduction of cardiac dose and ipsilateral lung dose and at the same time assuring sufficient dose coverage.
The tumor bed boost may be administered using electrons or megavoltage photons at the discretion of the radiation oncologist. Brachytherapy boost is permitted.
Dose prescription, fractionation, recording, and reporting
The prescribed dose to the breast/thoracic wall as well as the regional nodal pathways is 50 Gy in 25 fractions of 2 Gy or 50.4 Gy in 28 fractions of 1.8 Gy treated on a daily basis, 5 days a week.
Alternatively, a hypofractionated schedule applying 40 Gy in 15 fractions of 2.67 Gy to the same volume is allowed. Treatment centers must define before attending the study which fractionation schedule will be followed throughout the trial to allow for stratification.
As modulated techniques are also permitted in this trial, the definition of volumes and the dose reporting should be in accordance with the ICRU (International Commission on Radiation Units and measurements) report 83 [
93]. Dose prescription and normalization will be done to the median dose D50% of the PTV.
Treatment plans will be computed using modern type-B dose calculation algorithms, such as convolution/superposition, Monte Carlo, collapsed cone or equivalent algorithms. Dose calculations will be performed using density heterogeneity corrections.
The boost to the tumor bed if indicated should be delivered sequentially immediately after the completion of whole-breast RT. The fractionation schedule of the boost is left to the discretion of the treating radiation oncologist (e.g., 16 Gy in eight fractions of 2 Gy or 10.7 Gy in five fractions of 2.67 Gy). Mixture of photons and electrons are the preferred modality. Megavoltage photons may be used as single modality if an electron energy of > 12 MeV is necessary to deliver an adequate dose at depth to boost PTV coverage because of the higher skin dose. Details of the boost are left to the discretion of the center and will not be part of the quality assurance of the trial but doses and techniques should be reported.
If indicated, a boost to the lymph node (PTVn_boost) may be delivered sequentially or simultaneously as integrated boost at the discretion of the treating radio-oncologist. A dose of 60 Gy in case of normofractionation is recommended but depends on the individual case.
The use of a skin bolus in case of mastectomy either on the scar or the whole chest wall is left to the discretion of the treating radio-oncologist and will be documented and evaluated within the QA program of the study. If using a bolus the skin dose must follow the constraints for the CTVp_chestwall and the CTV should expand in the area of the bolus to the skin surface.
The goal of treatment planning in both arms is to provide the best possible coverage of the breast/chest wall and nodal PTVs and at the same time minimize inclusion of the heart and lungs. The following dose-volume constraints will be used for dose specification and dose reporting in CTV and OAR (Values in parenthesis refer to the hypofractionated schedule if different from normofractionation) [
94].
Target volumes:
Structure | Dosimetric parameter | Per protocol | Minor deviation (acceptable) variation) | Major deviation |
CTVp_breast CTVp_chestwall CTVn_RNI-A/B | D95% | ≥ 95% of the prescribed dose | 90–94% of the prescribed dose | < 90% of the prescribed dose |
D2% | ≤ 107% (≤ 105%) of the prescribed dose | 108–110% (106–108%) of the prescribed dose | > 110% (> 108%) of the prescribed dose |
Dmax | ≤ 110% | 110–115% | > 115% |
Organs at risk (OAR):
Structure | Dosimetric parameter | Per protocol | Minor deviation (acceptable) variation) | Major deviation |
Lung_ipsilat | V20 Gy (V17 Gy) | < 25% | 25–30% | > 30% |
Mean | < 15 Gy (< 13 Gy) | 15–18 Gy (13–16 Gy) | > 18 Gy (> 16 Gy) |
Lung_total | V5 Gy | < 60% | 60–70% | > 70% |
Heart | Mean | < 4 Gy | 4–6 Gy | > 6 Gy |
V20 Gy (V17 Gy) | < 8% | 8–10% | > 10% |
V40 Gy (V35 Gy) | ≤ 5% | > 5% | – |
Humeral head | D95% | < 50% of prescribed dose | ≥ 50% of prescribed dose | – |
Spinal cord_PRV | Max | ≤ 40 Gy (≤ 33 Gy) | 41–45 Gy (34–38 Gy) | > 45 Gy (> 38 Gy) |
Breast_contra | Mean | < 6 Gy | ≥ 6 Gy | – |
Treatment planning will aim to reach the planning aims for the CTV and OAR as defined above with priorities in descending order:
1.)
Keep CTV and OAR within “per-protocol” limits
2.)
Keep CTV in “per-protocol” limits and OAR within “acceptable variation”
3.)
Keep CTV and OAR within “acceptable variation”
4.)
Keep OAR within “acceptable variation” and CTV coverage as good as possible
Despite the above-mentioned specification of an accepted dose, it is the responsibility of the treating radiation oncologist to achieve as low doses as possible to the organs at risk (see section “
Organs at risk (OAR)”) and the medial cervical/mediastinal organs (e.g., thyroid, trachea, esophagus) while achieving sufficient doses to the targets. For organs not mentioned in the table above the constraints commonly used in the site should be applied.
In addition to the dosimetric parameters of the target volumes and the OARs, the DVH parameters will be reported for the nodal levels.
Quality assurance of radiotherapy
A quality assurance (RT-QA) program will accompany this multicenter trial.
For each participating site, this RT-QA consists of completing the following prior to opening for accrual:
-
A facility questionnaire,
-
Including an external dosimetry audit (EDA),
-
A dummy run
During the trial conduct, the following RT-QA patient-specific procedure must be performed:
-
Submission of treatment plans for the first three patients in each treatment arm
-
Submission of one randomly selected treatment plan / year and site
-
Reporting of relevant treatment parameters for every patient
The “Trial-specific Agreement” explicitly contains a commitment to comply with the QA requirements defined in the protocol.
A dedicated RT-QA website for file download and upload is set up
The facility questionnaire, dummy run, and treatment plans will be reviewed by a group of reviewers under the responsibility of the contact persons for the RT-QA.
Facility questionnaire and external dosimetry audit
All sites being opened for accrual must have completed a facility questionnaire that is collecting information about the participating institution and about the methods to be applied for this specific trial. This facility questionnaire can be found at the RT-QA website (see section “
RT-QA website and transmission process”) and will preferably be submitted online via the same website. In case of technical difficulties, a paper copy or a CD/DVD-ROM (compact disk/digital versatile disk – read-only memory) may be sent.
All sites being opened for accrual must have a valid EDA (not older than as defined in the applicable national law). This EDA will be submitted online via the RT-QA website. An updated EDA will be submitted at the end of its validity. In case of technical difficulties, a paper copy or a CD/DVD-ROM may be sent.
Dummy run
Before opening for accrual, each institution wishing to participate in this trial has to successfully participate in a dummy run. For this purpose, one anonymous case including a CT dataset will be made available. The data exchange will be done in electronic form via the RT-QA website (see section “
RT-QA website and transmission process”). The participants will delineate CTV, PTV, and OAR (heart/LADA, lungs, humeral head, spinal cord, contralateral breast) according to the trial protocol. In addition, they will provide a treatment plan fulfilling the requirements defined in the protocol. It will use the fractionation that the institution will use during the trial. The reviewer will evaluate delineation and treatment planning. The results, including eventual corrections, will be communicated back to the institution before its opening for accrual can take place. In case of major deviations, delineation or the treatment plan will be submitted until no major deviations persist.
Submission of treatment plans for the first three patients in each treatment arm
Coded treatment plans of the first three patients in each treatment arm will be provided within 1 week after the start of the RT treatment.
The information must include:
-
CT data with OAR, nodal levels, CTV, and PTV delineated
-
Beam geometry
-
Dose distribution
-
Dose-volume histogram data for OAR, CTV, and PTV
Patients will be identified by their unique patient number only. It is mandatory for the sites to submit the data to the RT-QA website within 1 week after the start of the RT treatment. The reviewers will check the data and, if necessary, propose changes directly to the QA-responsible radiotherapist. In case of continuously insufficient adherence to the protocol guidelines, the reviewer informs the QA-responsible radiotherapist and the SAKK CC that the next patient of the respective site will be also reviewed, etc. until the plans fulfill the guidelines.
Note: all simulation and portal films and/or digital images will be kept by the institution and only submitted upon request
Procedure for other patients
For each site, a RT-QA will be performed randomly for at least one patient / year. The SAKK CC will inform both the QA-responsible radiotherapist at the site and the responsible reviewers which unique patient number was chosen for review. The material must be submitted after the chosen patient has terminated RT. The reviewer will inform the QA-responsible radiotherapist at the site about the outcome of the review. In case of inconsistency or inadequate treatment parameters, additional RT-QAs may be performed.
The QA-responsible radiotherapist is responsible for reporting of treatment-relevant parameters for every patient by completing the RT CRF within 4 weeks after the end of RT.
RT-QA website and transmission process
RT-QA website and transmission of data
Data must be submitted electronically via a secure web-based file transfer system (
https://swiss-dataspace.ch/). This is a server located in Switzerland. Hypertext Transfer Protocol Secure (HTTPS) provides encryption and secure identification of the server. It is a combination of the Hypertext Transfer Protocol with the SSL/TLS (secure sockets layer/transport layer security) protocol. Participating sites will receive a password for access and instructions for data transfer from the reviewer.
Format used
RT treatment plans are contained in DICOM-RT files. DICOM files contain medical images (standard for handling, storing, printing, and transmitting information in medical imaging). The RT-specific extensions to the DICOM format contain information including the delineated structures, the treatment plan, and the dose distribution within the body; this format is referred to as DICOM-RT.
Coding and encryption
DICOM-RT files contain patient-specific tags that allow identification of the patient. Each tag is stored at a specific address within the files. Before any transmission of DICOM-RT files, coding must be performed by the site. It is the responsibility of the site to ensure that patient name and date of birth will be removed from the DICOM-RT files and be replaced by the unique patient number to enable easy identification within the trial. Identifiers that do not allow patient identification outside the participating institution are permitted (e.g., department-specific patient ID).
Before uploading data to the trial server, the site must code the data and pack them into an encrypted zip-file. Only the respective site and the reviewers have access to these files. In case corrections are necessary, the reviewer will inform the site concerning actions to be taken.
Compliance with radiotherapy protocol
Deviations from the RT protocol will be divided in major and minor deviations.
Major deviations:
-
D95% < 90% (dose to 95% of volume < 90% of the prescribed dose)
-
D2% > 110% of the prescribed dose
-
Exceedance of normal tissue dose restriction for major deviation
-
Largely inadequate volumes of interest (CTV, PTV, nodal tissue, OAR):
Delineation of specified contouring volumes deviates significantly from protocol guidelines and the protocol-intended volumes are not adequately covered by the prescribed doses
Minor deviations:
-
Any deviations not fulfilling the criteria of major deviations
-
Inadequate volumes of interest (CTV, PTV, nodal levels, OAR):
Delineation of specified contouring volumes deviates from protocol guidelines but the protocol-intended volumes are adequately covered by the prescribed dose.