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Tricks and tips for target volume definition and delineation in breast cancer: Lessons learned from ESTRO breast courses

      Abstract

      Delineation of target and ‘organ at risk’ volumes is a critical part of modern radiation therapy planning, the next essential step after deciding the indication, patient discussion and image acquisition. Adoption of volume-based treatment planning for non-metastatic breast cancer has increased greatly along with the use of improved planning techniques, essential for modern therapy. However, identifying the volumes on a planning CT is no easy task. The current paper is written by ESTRO’s breast course faculty, providing tricks and tips for target volume definition and delineation for optimal postoperative breast cancer irradiation.

      Keywords

      Contouring workshops have formed part of the topic-oriented courses of the European SocieTy for Radiotherapy & Oncology (ESTRO) since 2009. In 2013, ESTRO formed a partnership with RadOnc eLearning Center, Inc (https://www.educase.com) to create a multifunctional platform for contouring and delineation, known as Fellowship in Anatomic deLineation and CONtouring (FALCON). This platform has served thousands of professionals and has included live hands-on delineation and online/virtual delineation workshops to encourage interaction of participants with the teachers and members of the FALCON contouring team. FALCON offers a variety of courses and workshops, which are constantly updated and include an online database of delineation exercises, expert delineations, and guidelines [
      • Eriksen J.G.
      • Salembier C.
      • Rivera S.
      • De Bari B.
      • Berger D.
      • Mantello G.
      • et al.
      Four years with FALCON – an ESTRO educational project: achievements and perspectives.
      ].
      Volume-based treatment planning is now incorporated in most fields of radiation oncology. In recent years, treatment planning for breast cancer has gone through major developments allowing for image-based planning, fusion of diagnostic imaging with acquired planning-based images, movement tracking, and volume-based irradiation delivery and guidance.
      In the 2-dimensional (2D) -era, the size and shape of treatment fields were determined using bony landmarks, and ‘organ at risk’ (OAR) protection was obtained mostly by physical shielding or by shrinking of the field/s after a specified dose, guided only by film or portal images with limited soft-tissue visibility for radiation delivery. In sharp contrast to this, three-dimensional conformal radiation therapy (3DCRT) incorporates the use of technologies to generate 3D images to allow accurate planning and treatment delivery such as image guided radiation (IGRT).
      3DCRT allows a much-improved appreciation of patient anatomy, routes of tumour spread and proximity of target volume/s to other organs and tissues. The use of 3DCRT supported the transition from large tangential fields determined according to bony landmarks and clinical palpation to field-in-field (FiF) and intensity modulated irradiation (IMRT), all aiming to reduce OAR exposure, homogenize target volume doses, shape irradiated volumes closer to the planning target volume (PTV), and avoid compromising PTV coverage.
      Historically, bony landmarks were considered to be reasonable surrogate anatomical boundaries in breast irradiation and have therefore been used for decades to define 2D-fields aimed to cover regional nodal volumes assuming that the vessels and lymphatic system will be enclosed within these borders. In 2015 and 2016, ESTRO published consensus guidelines for target volume delineation in early breast cancer based on the vascular and lymphatic drainage of the breast as identified on planning CT [
      • Offersen B.V.
      • Boersma L.J.
      • Kirkove C.
      • Hol S.
      • Aznar M.C.
      • Biete Sola A.
      • et al.
      ESTRO consensus guideline on target volume delineation for elective radiation therapy of early stage breast cancer.
      ,
      • Offersen B.V.
      • Boersma L.J.
      • Kirkove C.
      • Hol S.
      • Aznar M.C.
      • Sola A.B.
      • et al.
      ESTRO consensus guideline on target volume delineation for elective radiation therapy of early stage breast cancer, version 1.1.
      ]. These guidelines were based on the work performed by the ESTRO’s breast workshop teachers and extended to an international consensus group. However, identifying target volumes and OAR during CT planning is not straightforward [
      • Offersen B.V.
      • Boersma L.J.
      • Kirkove C.
      • Hol S.
      • Aznar M.C.
      • Biete Sola A.
      • et al.
      ESTRO consensus guideline on target volume delineation for elective radiation therapy of early stage breast cancer.
      ,
      • Offersen B.V.
      • Boersma L.J.
      • Kirkove C.
      • Hol S.
      • Aznar M.C.
      • Sola A.B.
      • et al.
      ESTRO consensus guideline on target volume delineation for elective radiation therapy of early stage breast cancer, version 1.1.
      ] and ESTRO breast workshops using the FALCON platform aim to promote this important medical task. The courses involve careful study of patient anatomy and an iterative comparison and discussion of participants’ and teachers’ delineations to improve accuracy and reduce inter-observer variability and inconsistency [
      • Eriksen J.G.
      • Salembier C.
      • Rivera S.
      • De Bari B.
      • Berger D.
      • Mantello G.
      • et al.
      Four years with FALCON – an ESTRO educational project: achievements and perspectives.
      ]. Importantly, by having a multidisciplinary team at the course, including a radiation therapist (RTT), a medical physicist and surgeons with expertise in breast radiation planning, the adverse dosimetric consequences of inaccurate target volume and OAR delineation can be illustrated. Additionally, the trade-offs involved in using different radiation techniques (such as FiF compared to IMRT) are discussed.
      Since the publication of ESTRO guidelines [
      • Offersen B.V.
      • Boersma L.J.
      • Kirkove C.
      • Hol S.
      • Aznar M.C.
      • Biete Sola A.
      • et al.
      ESTRO consensus guideline on target volume delineation for elective radiation therapy of early stage breast cancer.
      ,
      • Offersen B.V.
      • Boersma L.J.
      • Kirkove C.
      • Hol S.
      • Aznar M.C.
      • Sola A.B.
      • et al.
      ESTRO consensus guideline on target volume delineation for elective radiation therapy of early stage breast cancer, version 1.1.
      ], we noticed significant improvement in the delineations done by the course participants. A recent survey by the EUropean Breast cancer REsearch Association of Surgical Trialists (EUBREAST) distributed to radiation oncologists reported that 93% of the radiation oncologists use delineation guidelines for elective nodal irradiation (60.6% use the ESTRO guidelines and 32.4% use the RTOG guidelines), 7% are using field-based volumes without nodal volumes (personal communication, Dr. Maria Luisa Gasparri, the full results of the EUBREAST survey are planned to be published).
      In this manuscript, we address lessons learned from the ESTRO breast courses and the FALCON breast workshops and include tricks and tips for target volume definition and delineation in breast cancer as well as evidence to support the recommended ESTRO volumes.

      Defining the target volumes prior to delineation

      There is a need to understand the anatomy and lymphatic drainage pathways, patterns of tumour spread, pre-operative imaging, extent of surgery, and potential harms and benefits to minimize and balance the risk of recurrence against the risk of treatment-related morbidity. Currently, the use of sentinel lymph node biopsy (SLNB) for clinically and radiologically node negative disease is common practice, while patients with positive clinical nodes are often referred for primary systemic therapy (PST) where the extent of both breast and axillary surgery is often determined according to the response to PST. Axillary lymph node dissection is performed less frequently following publication of the ACOSOG Z0011 (Alliance) [

      Giuliano AE, Ballman K, McCall L et al. Locoregional Recurrence After Sentinel Lymph Node Dissection With or Without Axillary Dissection in Patients With Sentinel Lymph Node Metastases: Long-term Follow-up From the American College of Surgeons Oncology Group (Alliance) ACOSOG Z0011 Randomized Trial. Ann Surg 2016; 264: 413–420.

      ,
      • Giuliano A.E.
      • Ballman K.V.
      • McCall L.
      • Beitsch P.D.
      • Brennan M.B.
      • Kelemen P.R.
      • et al.
      Effect of axillary dissection vs no axillary dissection on 10-year overall survival among women with invasive breast cancer and sentinel node metastasis: the ACOSOG Z0011 (alliance) randomized clinical trial.
      ] and AMAROS (EORTC 10981–22023) [
      • Donker M.
      • van Tienhoven G.
      • Straver M.E.
      • Meijnen P.
      • van de Velde C.J.H.
      • Mansel R.E.
      • et al.
      Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer (EORTC 10981–22023 AMAROS): a randomised, multicentre, open-label, phase 3 non-inferiority trial.
      ] trials and subsequent studies including those on targeted axillary management.
      Disease stage, tumour location, extent of lymph node involvement, pre-treatment imaging, pathology including molecular characteristics, muscle invasion, distance to skin or thoracic wall, extent of lymphovascular invasion, surgical margins, extent of surgery and response to therapy all have implications for defining the target volumes for regional nodal irradiation [
      • Belkacemi Y.
      • Kaidar-Person O.
      • Poortmans P.
      • Ozsahin M.
      • Valli M.-C.
      • Russell N.
      • et al.
      Patterns of practice of regional nodal irradiation in breast cancer: results of the European Organization for Research and Treatment of Cancer (EORTC) NOdal Radiotherapy (NORA) survey.
      ,
      • Beaton L.
      • Nica L.
      • Tyldesley S.
      • Sek K.
      • Ayre G.
      • Aparicio M.
      • et al.
      PET/CT of breast cancer regional nodal recurrences: an evaluation of contouring atlases.
      ].
      Careful review of available diagnostic imaging (not only the report but the images themselves), accurate description of the surgery (degree of oncoplastic reshaping, relative position of skin incision compared to the tumour bed, clip placement) and a detailed pathology report are essential for planning post-operative irradiation. Discussion in a multidisciplinary team is recommended to allow for better clarification of the extent of disease and previous treatment. The radiation oncologist should be involved at diagnosis and prior to surgery. Any relevant history of comorbidities (e.g., cardiovascular, respiratory disorders, concomitant drugs, smoking) and a physical examination that reflects the potential challenges in post-operative irradiation is invaluable. This includes an appreciation of size and shape of the breasts/chest wall, skin folds, limitation in arm mobility and musculoskeletal abnormalities that may limit the ability of accurate daily positioning. Patients’ understanding and comorbidities may affect their likely compliance and the potential reproducibility of for example respiratory control techniques. Ideally, the treating breast radiation oncologist should be available, if needed, at the time of CT-scan for treatment planning, especially for challenging cases. A detailed note and pre/post treatment diagnostic imaging (e.g., prior to surgery/primary systemic therapy) should be available at the time of volume delineation for proper definition of targets, especially if volume delineation is not done by the clinician who saw the patient at their initial visit for radiation planning.
      A clear written departmental protocol for planning CT (e.g., treatment position, deep inspiration breath hold) is advised. Deviations for protocol should be limited to selected cases, such as patients with difficulties laying still in treatment position, or, in selected cases, that patient’s anatomy is a major obstacle for safe irradiation, and coverage of the clinical target volume (CTV) should be weighed against the potential harms from OAR exposure (Fig. 1).
      Figure thumbnail gr1
      Fig. 1A patient with severe scoliosis, cardiac anomaly who was planned for left breast irradiation due to breast cancer. The CT scan shows unfavourable cardiac location regardless of breath hold technique. Wide Arrow indicates the location of the lumpectomy scar. Thin arrow shows the clip at the site of previous cardiothoracic surgery, clip is unrelated to breast cancer lumpectomy cavity.
      At the time of CT- scanning, it is recommended that the patient lays with both arms raised symmetrically. This will allow to look at the unaffected site (contralateral chest) for assistance in delineation. Although delineation guidelines are based on vascular landmarks, we do not recommend the routine use of intravenous contrast for delineation. Parts of the vessels are usually easily seen on the planning- CT without the use of contrast. Intravenous contrast, or even a PET-CT (Fig. 2), may be considered, especially in cases where a nodal boost is relevant, or to detect additional nodes in case of extensive nodal involvement. If diagnostic imaging is fused with the planning CT, it should be reviewed carefully for different position, misregistration and possible flaws of using deformable registration for certain areas. Of note, the CT images shown in the current paper are without contrast.
      Figure thumbnail gr2
      Fig. 2Fusion of diagnostic PET-CT with radiation planning CT for nodal volume delineation to assist in identifying the site of level 1 lymph node involvement.

      Defining the volumes on the planning CT

      As most radiation planning is done via a planning CT, the recommended Hounsfield Unit interval for contouring is the soft-tissue and breast tissue window. At the time of contouring and defining the volumes, we recommend adherence to a standard nomenclature and preferably fix the choice of colours (many planning systems allow for creation of templates) for individual volumes. This should be followed by all team members, and eventually will facilitate pattern recognition when approving delineation. Using nomenclature and colours similar to the ESTRO guidelines and the international harmonisation nomenclature is advised. [
      • Offersen B.V.
      • Boersma L.J.
      • Kirkove C.
      • Hol S.
      • Aznar M.C.
      • Biete Sola A.
      • et al.
      ESTRO consensus guideline on target volume delineation for elective radiation therapy of early stage breast cancer.
      ,
      • Offersen B.V.
      • Boersma L.J.
      • Kirkove C.
      • Hol S.
      • Aznar M.C.
      • Sola A.B.
      • et al.
      ESTRO consensus guideline on target volume delineation for elective radiation therapy of early stage breast cancer, version 1.1.
      ,
      • Santanam L.
      • Hurkmans C.
      • Mutic S.
      • van Vliet-Vroegindeweij C.
      • Brame S.
      • Straube W.
      • et al.
      Standardizing naming conventions in radiation oncology.
      ].

      Delineation of the breast clinical target volume (CTVp_breast)

      To assure correct delineation of the CTVp_breast, always start delineation at a level where you clearly see the limits of the breast and then move cranially/caudally (see the 2015, 2016 ESTRO guidelines) [
      • Offersen B.V.
      • Boersma L.J.
      • Kirkove C.
      • Hol S.
      • Aznar M.C.
      • Biete Sola A.
      • et al.
      ESTRO consensus guideline on target volume delineation for elective radiation therapy of early stage breast cancer.
      ,
      • Offersen B.V.
      • Boersma L.J.
      • Kirkove C.
      • Hol S.
      • Aznar M.C.
      • Sola A.B.
      • et al.
      ESTRO consensus guideline on target volume delineation for elective radiation therapy of early stage breast cancer, version 1.1.
      ]. In some cases, especially in patients with small breasts, no inframammary fold can be noted on planning CT, and correct placement of the markers during the CT can assist in identifying the border with the fine structures of glandular breast tissue on CT. Incorrect marking in these cases might result in unnecessary large volumes and exposure of OARs as shown in Fig. 2 of abdominal OARs (Fig. 3). Marking of skin scars related to the breast surgery can be helpful, as long as it does not cause artefacts that might result in poor images.
      Figure thumbnail gr3
      Fig. 3Patient without an inframammary fold on CT (A) Planning CT sagittal view showing the markers of breast edge and scar (B) Axial view on planning CT.
      It is recommended to delineate the tumour bed, according to the pre-treatment/diagnostic imaging, even if a boost is not planned. A publication from Veronesi’s group [
      • Botteri E.
      • Bagnardi V.
      • Rotmensz N.
      • Gentilini O.
      • Disalvatore D.
      • Bazolli B.
      • et al.
      Analysis of local and regional recurrences in breast cancer after conservative surgery.
      ] analysed the sites of local and locoregional recurrences in 2784 patients who underwent quadrantectomy and postoperative radiation. At a median of 72 months follow up, a total 33 out of 40 in-breast recurrences were regarded as true local recurrences because of the proximity to the primary tumour bed (5-year cumulative incidence of 1.1%). These data were supported by several studies that showed that 71% of in-breast recurrences were near or at the lumpectomy site [
      • Chang J.S.
      • Byun H.K.
      • Kim J.W.
      • Kim K.H.
      • Lee J.
      • Cho Y.
      • et al.
      Three-dimensional analysis of patterns of locoregional recurrence after treatment in breast cancer patients: Validation of the ESTRO consensus guideline on target volume.
      ,
      • Fowble B.
      • Solin L.J.
      • Schultz D.J.
      • Rubenstein J.
      • Goodman R.L.
      Breast recurrence following conservative surgery and radiation: patterns of failure, prognosis, and pathologic findings from mastectomy specimens with implications for treatment.
      ,
      • Luini A.
      • Gatti G.
      • Zurrida S.
      • Talakhadze N.
      • Brenelli F.
      • Gilardi D.
      • et al.
      The evolution of the conservative approach to breast cancer.
      ]. Therefore, even if a tumour bed boost is not planned, delineation of the tumour bed can assure that the CTVp_breast will include the primary tumour bed inside the CTVp_breast. If the tumour bed is located at the edge of the CTVp_breast, (eg very cranially or medially), the CTVp_breast should include the CTV_tumour bed, being the tumour bed with a 1.5 cm margin (minus the tumour-free margins) to allow for full coverage of the area that is at high risk of recurrence. Apart from this, delineation of surgical clips positioned at the time of lumpectomy are useful for IGRT [

      Harris EJ, Mukesh M, Jena R et al. In A multicentre observational study evaluating image-guided radiotherapy for more accurate partial-breast intensity-modulated radiotherapy: comparison with standard imaging technique. Southampton (UK): 2014.

      ].
      For defining the tumour bed volumes, we recommend using the GEC-ESTRO recommendations [
      • Strnad V.
      • Hannoun-Levi J.-M.
      • Guinot J.-L.
      • Lössl K.
      • Kauer-Dorner D.
      • Resch A.
      • et al.
      Recommendations from GEC ESTRO Breast Cancer Working Group (I): Target definition and target delineation for accelerated or boost Partial Breast Irradiation using multicatheter interstitial brachytherapy after breast conserving closed cavity surgery.
      ].

      Delineation of the thoracic wall clinical target volume (CTVp_thoracic wall).

      Whereas the contralateral breast, if intact, can serve as a landmark for delineation if the breasts were symmetrical and the patient laying symmetrically in the treatment position (Fig. 4), as mastectomy routinely involves removal of part of the overlying skin and pulling adjacent skin and subcutaneous tissue in to close the defect, the size of the CTVp_thoracic wall (also termed CTVp_chest wall) can be reduced compared to the intact breast in case of most indications of chest wall RT, where only the subcutaneous lymphatic plexus, potential residual glandular breast tissue and high risk areas adjacent to the primary tumour are the targets. However, to ensure inclusion of the deep lymphatic plexus in the CTV_thoracic wall, care should be taken not to excessively decrease the CTV [
      • Offersen B.V.
      • Boersma L.J.
      • Kirkove C.
      • Hol S.
      • Aznar M.C.
      • Biete Sola A.
      • et al.
      ESTRO consensus guideline on target volume delineation for elective radiation therapy of early stage breast cancer.
      ,
      • Offersen B.V.
      • Boersma L.J.
      • Kirkove C.
      • Hol S.
      • Aznar M.C.
      • Sola A.B.
      • et al.
      ESTRO consensus guideline on target volume delineation for elective radiation therapy of early stage breast cancer, version 1.1.
      ].
      Figure thumbnail gr4
      Fig. 4(A) Asymmetry of the breasts noticed on planning CT (B) Humerus head might imply of asymmetry in patient’s position.
      Moreover, the mastectomy scar may extend laterally beyond the breast tissue, for example in women with a large axillary skin fold to allow this to be reduced. This means that the CTV may not need to include the entire scar. Indeed, for radiation treatment planning the part of the scar outside the breast region is not part of the target volume except in very medial or lateral tumour locations. In cases that the skin/scar is at high risk for breast cancer recurrence, in cases such as extensive dermal involvement and inflammatory cancer the entire mastectomy scar should be covered. The use of bolus for all postmastectomy irradiation has been challenged [

      Dahn H, Boersma, L, de Ruysscher, D, Meattini, I, Offersen, BV, Pignol, JP, et al. The use of bolus in postmastectomy radiation therapy for breast cancer: A systematic review. Crit Rev Oncol/Hematol 2021; Accepted for publication.

      ], but should be considered in cases that the high risk region for recurrence includes the skin or within the “dose build up region”.
      Following skin sparing/nipple sparing mastectomy, the target volume includes any residual breast tissue and the subcutaneous layer of the native skin breast which is preserved as part of the skin sparing mastectomy procedure. [
      • Kaidar-Person O.
      • Hermann N.
      • Poortmans P.
      • Offersen B.V.
      • Boersma L.J.
      • de Ruysscher D.
      • et al.
      A multidisciplinary approach for autologous breast reconstruction: A narrative (re)view for better management.
      ,
      • Kaidar-Person O.
      • Offersen B.V.
      • Boersma L.J.
      • de Ruysscher D.
      • Tramm T.
      • Kühn T.
      • et al.
      A multidisciplinary view of mastectomy and breast reconstruction: Understanding the challenges.
      ]

      Delineation of nodal volumes

      The logic behind the ESTRO lymph node volumes is that lymphatic drainage to levels 1–3 drain subsequently to level 4, following a regular, progressive pattern [
      • Pigott J.
      • Nichols R.
      • Maddox W.A.
      • Balch C.M.
      Metastases to the upper levels of the axillary nodes in carcinoma of the breast and its implications for nodal sampling procedures.
      ,
      • Veronesi U.
      • Rilke F.
      • Luini A.
      • Sacchini V.
      • Galimberti V.
      • Campa T.
      • et al.
      Distribution of axillary node metastases by level of invasion. An analysis of 539 cases.
      ,
      • Keskek M.
      • Balas S.
      • Gokoz A.
      • Sayek I.
      Re-evaluation of axillary skip metastases in the era of sentinel lymph node biopsy in breast cancer.
      ]. In general, skip metastases, defined as the involvement of nodes at level 2, or 3, or both, but not at level 1, are uncommon, occurring at a rate of 3%–10% dependent on the histopathological evaluation of the nodes [
      • Pigott J.
      • Nichols R.
      • Maddox W.A.
      • Balch C.M.
      Metastases to the upper levels of the axillary nodes in carcinoma of the breast and its implications for nodal sampling procedures.
      ,
      • Veronesi U.
      • Rilke F.
      • Luini A.
      • Sacchini V.
      • Galimberti V.
      • Campa T.
      • et al.
      Distribution of axillary node metastases by level of invasion. An analysis of 539 cases.
      ,
      • Keskek M.
      • Balas S.
      • Gokoz A.
      • Sayek I.
      Re-evaluation of axillary skip metastases in the era of sentinel lymph node biopsy in breast cancer.
      ,

      Rosen PP, Lesser ML, Kinne DW, Beattie EJ. Discontinuous or “skip” metastases in breast carcinoma. Analysis of 1228 axillary dissections. Ann Surg 1983;197:276–83.

      ].
      However, the internal mammary vessels connect with the subclavian/brachiocephalic vessels, causing internal mammary nodes (IMN) involvement to drain directly into level 3–4 without affecting level 1–2. Table 1 summarizes sentinel node drainage in clinical node negative breast cancer according to tumour location and depth within the breast, all can influence drainage to IMNs.
      Table 1Sentinel node drainage using gamma-ray detection probe and patent blue dye in clinical node negative breast cancer according to tumour location and palpable in-breast lesion
      • Estourgie S.H.
      • Tanis P.J.
      • Nieweg O.E.
      • Valdés Olmos R.A.
      • Rutgers E.J.T.
      • Kroon B.B.R.
      Should the hunt for internal mammary chain sentinel nodes begin? An evaluation of 150 breast cancer patients.
      Lesion location within the breastPalpable & nonpalpable lesionsPalpable lesionsNonpalpable lesions
      AxillaIMNAxillaIMNAxillaIMN
      UOQ95.8%10.4%97.7%6.9%89.2.%23%
      UIQ93.1%32.4%94.1%31.4%88.9%37%
      LOQ97.7%29.5%97.1%26.1%100%42.1%
      LIQ88%52%91.7%50%78.6%57.1%
      UOQ-upper outer quadrant; UIQ- upper inner quadrant; LOQ- Lower outer quadrant; LIQ- Lower inner quadrant; IMN- Internal mammary node chain. Please do note that drainage of the lymphatic fluid depends not only on the tumour location per quadrant, but also the position between skin and chest wall, tumour stage and the injection site (peritumoral or periareolar). Drainage does not always translate into tumoural involvement.
      Level 4 was historically called the supraclavicular region; however, contouring according to ESTRO guidelines [
      • Offersen B.V.
      • Boersma L.J.
      • Kirkove C.
      • Hol S.
      • Aznar M.C.
      • Biete Sola A.
      • et al.
      ESTRO consensus guideline on target volume delineation for elective radiation therapy of early stage breast cancer.
      ,
      • Offersen B.V.
      • Boersma L.J.
      • Kirkove C.
      • Hol S.
      • Aznar M.C.
      • Sola A.B.
      • et al.
      ESTRO consensus guideline on target volume delineation for elective radiation therapy of early stage breast cancer, version 1.1.
      ], this volume does not need to include supraclavicular nodes, as in most patients it remains at the level of the clavicular head without any clear cranial extension. As it is 5 mm cranial to the subclavian vein, the volume extends no more than 2 CT slices (usually 6 mm) above this, largely remaining behind the clavicle [
      • Offersen B.V.
      • Boersma L.J.
      • Kirkove C.
      • Hol S.
      • Aznar M.C.
      • Sola A.B.
      • et al.
      ESTRO consensus guideline on target volume delineation for elective radiation therapy of early stage breast cancer, version 1.1.
      ]. Involvement of level 4 without involvement of levels 2 and 3 or high IMNs is thought to be rare based on Estourgie’s mapping study in node negative patients. Direct drainage to level 4 was reported to be 0–3% depending on tumour location and whether the lesion was palpable or not [

      Estourgie SH, Nieweg OE, Olmos RA et al. Lymphatic drainage patterns from the breast. Ann Surg 2004;239:232–37.

      ,
      • Estourgie S.H.
      • Tanis P.J.
      • Nieweg O.E.
      • Valdés Olmos R.A.
      • Rutgers E.J.T.
      • Kroon B.B.R.
      Should the hunt for internal mammary chain sentinel nodes begin? An evaluation of 150 breast cancer patients.
      ]. Additionally, none had level 4 only drainage (without other levels). Therefore, the cranial border of level 4 in ESTRO guidelines is caudal to that recommended by the RTOG for elective nodal irradiation. This will allow for a reduction in dose to the thyroid gland, internal carotid, and other head & neck OARs [
      • Yaney A.
      • Ayan A.S.
      • Pan X.
      • Jhawar S.
      • Healy E.
      • Beyer S.
      • et al.
      Dosimetric parameters associated with radiation-induced esophagitis in breast cancer patients undergoing regional nodal irradiation.
      ]. Furthermore, as reported by Chang et al, all level 4 failures were located <6 mm cranial to the subclavian artery [
      • Chang J.S.
      • Byun H.K.
      • Kim J.W.
      • Kim K.H.
      • Lee J.
      • Cho Y.
      • et al.
      Three-dimensional analysis of patterns of locoregional recurrence after treatment in breast cancer patients: Validation of the ESTRO consensus guideline on target volume.
      ,
      • Chang J.S.
      • Lee J.
      • Chun M.
      • Shin K.H.
      • Park W.
      • Lee J.H.
      • et al.
      Mapping patterns of locoregional recurrence following contemporary treatment with radiation therapy for breast cancer: A multi-institutional validation study of the ESTRO consensus guideline on clinical target volume.
      ], ESTRO’s guideline does recommend extending the cranial border according to nodal tumour load in patients with nodal disease at level 2–3 to cover potential areas that are at high risk for nodal recurrence.
      Lymphatic obstruction caused by scarring (e.g., previous breast/chest surgery), irradiation or high tumour load can result in tumour spread into pathways beyond the locoregional treated area such as superior neck and arm or contralateral side. In the case of metastatic involvement of lymph nodes, the pattern of spread in the axilla usually follows a progressive pattern and retrograde involvement is likely to relate to a high tumour load. In these cases, the delineation should be adapted according to disease spread with appropriate margins to cover the extent of disease.

      ESTRO vs RTOG vs RADCOMP and delineation in locoregionally advanced breast cancer

      The ESTRO consensus guidelines were designed for elective nodal irradiation in early breast cancer [
      • Offersen B.V.
      • Boersma L.J.
      • Kirkove C.
      • Hol S.
      • Aznar M.C.
      • Biete Sola A.
      • et al.
      ESTRO consensus guideline on target volume delineation for elective radiation therapy of early stage breast cancer.
      ,
      • Offersen B.V.
      • Boersma L.J.
      • Kirkove C.
      • Hol S.
      • Aznar M.C.
      • Sola A.B.
      • et al.
      ESTRO consensus guideline on target volume delineation for elective radiation therapy of early stage breast cancer, version 1.1.
      ]. The guidelines are based on the finding that in early breast cancer the involved nodal regions are mainly situated within 5-mm around the blood vessels, usually the veins [
      • Offersen B.V.
      • Boersma L.J.
      • Kirkove C.
      • Hol S.
      • Aznar M.C.
      • Biete Sola A.
      • et al.
      ESTRO consensus guideline on target volume delineation for elective radiation therapy of early stage breast cancer.
      ,
      • Offersen B.V.
      • Boersma L.J.
      • Kirkove C.
      • Hol S.
      • Aznar M.C.
      • Sola A.B.
      • et al.
      ESTRO consensus guideline on target volume delineation for elective radiation therapy of early stage breast cancer, version 1.1.
      ,
      • Verhoeven K.
      • Weltens C.
      • Remouchamps V.
      • Mahjoubi K.
      • Veldeman L.
      • Lengele B.
      • et al.
      Vessel based delineation guidelines for the elective lymph node regions in breast cancer radiation therapy - PROCAB guidelines.
      ]. Conversely, RTOG defined target volumes are based on a consensus of experts (https://www.nrgoncology.org/Portals/0/Scientific%20Program/CIRO/Atlases/BreastCancerAtlas_corr.pdf?ver=2018-04-18-144201-270) and mainly based on the volumes enclosed by the 2D-based radiation fields (based on bony landmarks).
      A comparison between the two different approaches has been performed by a few groups and this has included mapping of location of recurrences. For some components of nodal target volumes, ESTRO volumes tend to be larger than RTOG volumes as a result of the ESTRO recommendation of adding a 5 mm margin lateral and medial (cropping the volume onto the lung surface) to the internal mammary vessels, and adding a volume to interpectoral nodal CTVn between the pectoralis major and minor [
      • Loganadane G.
      • Truong P.T.
      • Taghian A.G.
      • Tešanović D.
      • Jiang M.
      • Geara F.
      • et al.
      Comparison of nodal target volume definition in breast cancer radiation therapy according to RTOG versus ESTRO atlases: a practical review from the transatlantic radiation oncology network (TRONE).
      ,
      • Gentile M.S.
      • Usman A.A.
      • Neuschler E.I.
      • Sathiaseelan V.
      • Hayes J.P.
      • Small W.
      Contouring guidelines for the axillary lymph nodes for the delivery of radiation therapy in breast cancer: evaluation of the RTOG breast cancer atlas.
      ,
      • Jing H.
      • Wang S.-L.
      • Li J.
      • Xue M.
      • Xiong Z.-K.
      • Jin J.
      • et al.
      Mapping patterns of ipsilateral supraclavicular nodal metastases in breast cancer: rethinking the clinical target volume for high-risk patients.
      ,
      • Duma M.
      An update on regional nodal irradiation: indication, target volume delineation, and radiotherapy techniques.
      ]. Conversely, ESTRO volumes tend to be smaller at CTVn_level 1 toward the arm and back muscles and the CTVn_level 4 where the cranial border is reduced from the cricoid cartilage to 5 mm cranial to the subclavian vein. Studies focusing on regional relapse patterns demonstrated that, in pT1-2 pN0-1 breast cancer patients, only 4% of regional recurrences were situated outside ESTRO and inside RTOG defined lymph nodes CTVs and up to 28% out of field recurrences occurred in patients with pT3-pT4 or pN2-N3 disease [
      • Chang J.S.
      • Byun H.K.
      • Kim J.W.
      • Kim K.H.
      • Lee J.
      • Cho Y.
      • et al.
      Three-dimensional analysis of patterns of locoregional recurrence after treatment in breast cancer patients: Validation of the ESTRO consensus guideline on target volume.
      ]. Additionally, even though ESTRO CTVn_level 1 is significantly smaller than RTOG level 1 volume, 87% of the recurrences were within ESTRO volumes compared to 91% of the recurrences within those defined by RTOG [
      • Beaton L.
      • Nica L.
      • Tyldesley S.
      • Sek K.
      • Ayre G.
      • Aparicio M.
      • et al.
      PET/CT of breast cancer regional nodal recurrences: an evaluation of contouring atlases.
      ]. It is unclear if these only occurred with locally advanced disease. However, the location of recurrences within RTOG and outside ESTRO CTVn_level 1 was not demonstrated [
      • Beaton L.
      • Nica L.
      • Tyldesley S.
      • Sek K.
      • Ayre G.
      • Aparicio M.
      • et al.
      PET/CT of breast cancer regional nodal recurrences: an evaluation of contouring atlases.
      ]. The differences in level 2 recurrences were more significant between the atlases, favouring the ESTRO CTVn_level 2 with 78% of the recurrences within its volumes compared to only 68% within the RTOG volumes [
      • Beaton L.
      • Nica L.
      • Tyldesley S.
      • Sek K.
      • Ayre G.
      • Aparicio M.
      • et al.
      PET/CT of breast cancer regional nodal recurrences: an evaluation of contouring atlases.
      ]. Other studies have also compared recurrence patterns in relation to the ESTRO versus RTOG volumes [
      • Beaton L.
      • Nica L.
      • Tyldesley S.
      • Sek K.
      • Ayre G.
      • Aparicio M.
      • et al.
      PET/CT of breast cancer regional nodal recurrences: an evaluation of contouring atlases.
      ,
      • Chang J.S.
      • Byun H.K.
      • Kim J.W.
      • Kim K.H.
      • Lee J.
      • Cho Y.
      • et al.
      Three-dimensional analysis of patterns of locoregional recurrence after treatment in breast cancer patients: Validation of the ESTRO consensus guideline on target volume.
      ,
      • Chang J.S.
      • Lee J.
      • Chun M.
      • Shin K.H.
      • Park W.
      • Lee J.H.
      • et al.
      Mapping patterns of locoregional recurrence following contemporary treatment with radiation therapy for breast cancer: A multi-institutional validation study of the ESTRO consensus guideline on clinical target volume.
      ,
      • Borm K.J.
      • Voppichler J.
      • Düsberg M.
      • Oechsner M.
      • Vag T.
      • Weber W.
      • et al.
      FDG/PET-CT-based lymph node atlas in breast cancer patients.
      ] but these studies can be misleading: some studies compared the volumes of primary presentation of disease, some did not indicate the primary stage of disease or treatment (extent of surgery, systemic therapy, radiation volumes) and included relapse-only cases and others used deformable registration to reproduce the site of recurrence which may lead to a false evaluation [
      • Beaton L.
      • Nica L.
      • Tyldesley S.
      • Sek K.
      • Ayre G.
      • Aparicio M.
      • et al.
      PET/CT of breast cancer regional nodal recurrences: an evaluation of contouring atlases.
      ,
      • Chang J.S.
      • Byun H.K.
      • Kim J.W.
      • Kim K.H.
      • Lee J.
      • Cho Y.
      • et al.
      Three-dimensional analysis of patterns of locoregional recurrence after treatment in breast cancer patients: Validation of the ESTRO consensus guideline on target volume.
      ,
      • Chang J.S.
      • Lee J.
      • Chun M.
      • Shin K.H.
      • Park W.
      • Lee J.H.
      • et al.
      Mapping patterns of locoregional recurrence following contemporary treatment with radiation therapy for breast cancer: A multi-institutional validation study of the ESTRO consensus guideline on clinical target volume.
      ,
      • Borm K.J.
      • Voppichler J.
      • Düsberg M.
      • Oechsner M.
      • Vag T.
      • Weber W.
      • et al.
      FDG/PET-CT-based lymph node atlas in breast cancer patients.
      ].
      One of the most important issues that is indicated in the ESTRO guidelines and is taught in the Breast courses and FALCON workshops is that the borders of the nodal CTVs are for elective nodal irradiation only and these should be individually adapted for locally advanced tumours (pT3-pT4 or pN2-N3) with a margin of 10–20 mm around confirmed areas of pathological nodes. Therefore, if delineated correctly, it will include the volumes that were shown to be outside the ESTRO volumes for early breast cancer while not overtreating patients who are not at such high risk for locoregional recurrence. The ESTRO guideline is currently being clinically validated as part of the DBCG Skagen 1 (NCT02384733) and Hypo-G01 (NCT 03127995) trials, where loco-regional RT is provided to more than 4000 high-risk breast cancer patients.
      A recent atlas [
      • Bekelman J.E.
      • Lu H.
      • Pugh S.
      • Baker K.
      • Berg C.D.
      • de Gonzalez A.B.
      • et al.
      Pragmatic randomised clinical trial of proton versus photon therapy for patients with non-metastatic breast cancer: the Radiotherapy Comparative Effectiveness (RadComp) Consortium trial protocol.
      ] created for a multicentre trial [NCT02603341] comparing proton versus photon-based planning named The Radiotherapy Comparative Effectiveness (RADCOMP) added an additional volume to those proposed by RTOG and ESTRO which includes the posterior neck lymphatics. This is considered an optional volume that may be drawn contiguously with the supraclavicular volume of the RTOG. The investigators indicated that this volume was added according to patterns of locoregional recurrence [https://www.nrgoncology.org/About-Us/Center-for-Innovation-in-Radiation-Oncology/Breast/RADCOMP-Breast-Atlas]. The publication by Beaton et al.[
      • Beaton L.
      • Nica L.
      • Tyldesley S.
      • Sek K.
      • Ayre G.
      • Aparicio M.
      • et al.
      PET/CT of breast cancer regional nodal recurrences: an evaluation of contouring atlases.
      ], compared patterns of 226 PET-CT nodal recurrences according to the RTOG, ESTRO and RADCOMP volumes. Regional nodal recurrences were centred 70% inside, 4% marginal and 27% outside RTOG defined nodal volumes. Addition of the RADCOMP Posterior Neck volume increased complete coverage to 48% additional regional recurrences compared to both ESTRO and RTOG volumes. Regional node recurrences were centred 73% inside, 2% marginal and 25% outside ESTRO defined CTVn. Most importantly, the sites of nodal recurrences were 28% within CTVn_level 1, 16% within level 2, 15% within level 4 15% and 15% within IMNs. Only 9% were within the posterior neck volume. There was no significant association between geographic miss for the baseline variables such as grade and lymphovascular invasion. The authors of this study indicated that even though the analysis did not reach statistical significance, patients with stage III breast cancer were more likely than stage I and II patients to have regional node recurrences in these regions [
      • Beaton L.
      • Nica L.
      • Tyldesley S.
      • Sek K.
      • Ayre G.
      • Aparicio M.
      • et al.
      PET/CT of breast cancer regional nodal recurrences: an evaluation of contouring atlases.
      ]. These studies provide important spatial understanding for the location of nodal recurrence, volumes that should be taken into consideration while delineating and planning. However, important information about identifying the population that is at risk for recurrence in these volumes is lacking. The number needed to treat and potential toxicity from more extensive radiation volumes could be substantial and over-irradiation should be avoided [
      • Poortmans P.M.P.
      • Arenas M.
      • Livi L.
      Over-irradiation.
      ]. Where data is lacking with respect to primary disease risk factors, molecular subtype, systemic therapies and extent of surgery, it is difficult to determine the best balance between the chances benefit and the risk of toxicity.
      In a patient population of >95% pT1-2 and ~85% pN0-2 stage, the EORTC 22922-10925 trial reported that the rate of regional recurrence was 3% in the IMN-RT group compared to 5% in the control group at a median follow up of 15.7 years. Axillary recurrences (levels 1–3) occurred in 1.7% of patients in the IMN-RT group compared to 2.4% in the control group and the risk of level 4 recurrence was 1.6% in the IMN-RT compared to 2.5% in the control group [
      • Poortmans P.M.
      • Weltens C.
      • Fortpied C.
      • Kirkove C.
      • Peignaux-Casasnovas K.
      • Budach V.
      • et al.
      Internal mammary and medial supraclavicular lymph node chain irradiation in stage I-III breast cancer (EORTC 22922/10925): 15-year results of a randomised, phase 3 trial.
      ]. Importantly, this low rate of regional recurrence was observed in an era of pre-current systemic therapies, including taxanes, anti-HER2 therapy and more effective endocrine strategies. Therefore, it is our recommendation to consider case by case, and restrict including larger volumes as suggested by the RADCOMP atlas to locoregionally advanced (pT3-pT4 and/or pN2-N3) disease, as these patients are at risk for aberrant lymphatic drainage. Furthermore, the RADCOMP atlas was created for a trial evaluating proton beam irradiation, that allow for less exposure of normal tissue outside the target volumes.
      Table 2 summarizes the anatomical boundaries of breast and chest wall according to ESTRO and RTOG atlases and Table 3 summarized the anatomical boundaries of regional node volumes according to ESTRO and RTOG atlases. For comparison to the RADCOMP volumes, we refer the reader to the publication by the TransAtlantic Radiation Oncology Network (TRONE) [
      • Loganadane G.
      • Truong P.T.
      • Taghian A.G.
      • Tešanović D.
      • Jiang M.
      • Geara F.
      • et al.
      Comparison of nodal target volume definition in breast cancer radiation therapy according to RTOG versus ESTRO atlases: a practical review from the transatlantic radiation oncology network (TRONE).
      ].
      Table 2Anatomical boundaries of breast and chest wall according to ESTRO and RTOG atlases.
      ESTRORTOGAuthors’ comments
      Breast
      Cranial<Sterno-clavicular jointSterno-clavicular joint (2nd rib) + clinical referenceESTRO defines the upper border as the clinically visible/palpable one, adding that it should never exceed the sternoclavicular joint. Thereby, in general the cranial border is quite lower according to ESTRO guidelines.
      CaudalLowest slide of visible breast contourLoss of breast on CTThis is about identical
      Ventral5 mm below the skinSkinNot identical
      DorsalPectoral muscles/thoracic wall (not including)

      *Areas that are not covered by pectoralis in particular in obese patients with a thick subcutaneous tissue layer – since this rather represents subcutaneous fat extending from the abdominal wall which is not part of the CTV
      Anterior border of pectoral muscles/thoracic wall. In case of locally advanced cancer include pectoralis muscles and ribsThis is identical. ESTRO 2016 guidelines is for elective early-stage RT and recommends to individualise in case of locally and/or regionally advanced disease
      Medial<Ipsilateral edge of the sternum/<vessels: rami mammarii (thoracic internal vessels)SternumThis is, especially at older age, a major difference
      LateralLateral side of the visible breast contour/<lateral thoracic vs./≪<mid-axillary lineMidaxillary line (exclude latissimus dorsi)This is a clear difference
      Offersen BV, et al., 2016;118(1):205-208https://www.nrgoncology.org
      Chest wall
      Cranial<Sterno-clavicular jointSterno-clavicular joint (~2nd rib) + clinical referenceESTRO defines the upper border as the clinically visible/palpable one, adding that it should never exceed the sternoclavicular joint. Thereby, in general the cranial border is quite lower according to ESTRO guidelines
      CaudalLowest side of visible breast contourLoss of contralateral breast on CTThis is an important difference, especially if the patient is positioned asymmetrically (only 1 arm up), with the RTOG border being much more caudally located
      Ventral5 mm below the skin (Unless T4b,c,d- than the skin is targeted)SkinNot identical
      DorsalPectoral muscles/thoracic wall (not including)Include pectoralis muscles and ribsThis is a major difference
      Medial<Ipsilateral edge of the sternum/<vessels: rami mammarii (thoracic internal vessels)SternumThis is, especially at older age, a major difference
      LateralLateral side of the visible breast contour/<lateral thoracic vs./≪<mid-axillary lineMid-axillary line (exclude latissimus dorsi)This is a clear difference
      Table 3Anatomical boundaries of regional node volumes according to ESTRO and RTOG atlases.
      ESTRORTOGAuthors’Comments
      Level 1
      CranialMedial: 5-mm cranial to the axillary vein

      lateral: max up to 1 cm below the edge of the humeral head, 5 mm around the axillary vein
      Axillary vessels lateral edge of pectoral minor muscleMinor difference
      CaudalTo the level of rib 4–5, taking into account the visible effects of the SLNBPectoralis major muscle insert into ribMinor difference but more variation of insertion of the pectoral muscle insertion
      VentralPectoralis major and minor musclesPlane defined anteriorly by surface of pectoralis major muscle and latissimus dorsi muscleMinor difference
      DorsalCranially up to the thoracodorsal vessels and more caudally up to an imaginary line between the anterior edge of the latissimus dorsi muscle and the intercostal musclesAnterior surface of subscapularis muscleMore dorsally for RTOG, thereby including drainage coming from the back/shoulder region.
      MedialLevel II, the interpectoral level, and the thoracic wallLateral border of pectoralis minor muscleMinor difference
      LateralCranially up to an imaginary line between the major pectoral and latissimus dorsi musclesMedial border of latissimus dorsi muscleMinor difference
      Level 2
      CranialIncludes the cranial extent of the axillary artery (i.e., 5 mm cranial to axillary vein)Axillary vessels cross medial edge of pectoralis minor muscleMinor difference
      CaudalThe caudal border of the minor pectoral muscle if appropriate: top of surgical ALNDAxillary vessels cross lateral edge of pectoralis minor muscleMinor difference
      VentralMinor pectoral muscleAnterior surface of pectoralis minor muscleIdentical
      DorsalUp to 5 mm dorsal to axillary vein or to costae and intercostal musclesRibs and intercostal musclesIdentical
      MedialMedial edge of minor pectoral muscleMedial border of pectoralis minor muscleIdentical
      LateralLateral edge of minor pectoral muscleLateral border of pectoralis minor muscleIdentical
      Level 3
      CranialIncludes the cranial extent of the subclavian artery (i.e., 5 mm cranial to subclavian vein)Pectoralis minor muscle insertion on coracoidESTRO is far less cranial
      Caudal5 mm caudal to the subclavian vein if appropriate: top of surgical axillary surgeryAxillary vessels cross medial edge of pectoralis minor muscleMinor difference
      AnteriorMajor pectoral musclePosterior surface of pectoralis majorIdentical
      PosteriorUp to 5 mm dorsal to axillary vein or to costae and intercostal muscleRibs and intercostal musclesIdentical
      MedialJunction of subclavian and internal jugular veins, level 4Thoracic inletMinor difference
      LateralMedial side of the minor pectoral muscleMedial border of pectoralis minor muscleIdentical
      Level 4
      CranialIncludes the cranial extent of the subclavian artery (i.e., 5 mm cranial to subclavian vein)Caudal to the cricoid cartilageESTRO is far less cranial
      CaudalIncludes the subclavian vein with 5-mm margin, thus connecting to the cranial border of CTVn IMNJunction of brachiocephalic axillary veins/caudal edge clavicle headMinor difference
      Ventralsternocleidomastoid muscle, dorsal edge of the claviclesternocleidomastoid muscleMinor difference
      DorsalPleuraAnterior aspect of the scalene muscleMinor difference
      MedialIncludes the jugular vein without margin; excludes the thyroid gland and common carotid arteryExcludes thyroid and tracheaESTRO far less medial
      LateralIncludes the anterior scalene muscles and connects to the medial border of the level 3Cranial: lateral edge of sternocleidomastoid muscle, caudal: junction first rib-clavicleMinor difference
      Coronal view taken from the ESTRO delineation guidelines (Offersen BV, et al., 2016;118(1):205–208.)Coronal view taken from the RTOG atals at https://www.nrgoncology.org
      Internal mammary nodes
      CranialCaudal limit of the level 4Superior aspect of the medial first ribMajor difference in cranial part
      CaudalCranial side of the fourth ribCranial aspect of the fourth ribIdentical
      VentralVentral limit of the vascular areaRibs and intercostal spacesIdentical
      DorsalPleuraPleuraIdentical
      Medial5 mm from the internal mammary artery
      Lateral5 mm from the internal mammary vein (artery in cranial part down to and including first intercostal space)

      Organs at risk

      Organs at risk delineation became an integral part of radiation planning with the implementation of planning CT and volumetric delineation for both target volumes and OARs. Correct delineation of OARs is essential for improving treatment outcome and reducing toxicity. This enables a quantitative analysis of normal tissue effects and defining the ability to deliver treatment within constraints objectives. Recently, the RT Quality Assurance (RTQA) Global Harmonization Group (GHG), defined the consensus guidelines for OAR delineation for RT clinical trials, along with AAPM TG263 and the American Society for Radiation Oncology (ASTRO) [
      • Mir R.
      • Kelly S.M.
      • Xiao Y.
      • Moore A.
      • Clark C.H.
      • Clementel E.
      • et al.
      Organ at risk delineation for radiation therapy clinical trials: Global Harmonization Group consensus guidelines.
      ]. For visualization and OAR recognition on planning CT it is recommended to use specified window width (WW) and window level (WL) for better identification of soft tissue (in many planning systems these are predefined such as “lung window”, “breast window”). There are several available atlases for OARs delineation, including for cardiac contouring [
      • Duane F.
      • Aznar M.C.
      • Bartlett F.
      • Cutter D.J.
      • Darby S.C.
      • Jagsi R.
      • et al.
      A cardiac contouring atlas for radiotherapy.
      ].
      It should be noted that normal organs exposure and dose distribution within the OARs can be significantly different if IMRT or VMAT (Volumetric-modulated arc therapy or vIMRT) are used compared to FiF -based planning [
      • Kaidar-Person O.
      • Nissen H.D.
      • Yates E.S.
      • Andersen K.
      • Boersma L.J.
      • Boye K.
      • et al.
      Postmastectomy radiation therapy planning after immediate implant-based reconstruction using the European society for radiotherapy and oncology-advisory committee in radiation oncology practice consensus guidelines for target volume delineation.
      ,
      • Kaidar-Person O.
      • Kostich M.
      • Zagar T.M.
      • Jones E.
      • Gupta G.
      • Mavroidis P.
      • et al.
      Helical tomotherapy for bilateral breast cancer: clinical experience.
      ]. For example, planning bilateral breast irradiation with Helical tomotherapy resulted in lung and liver toxicity [
      • Kaidar-Person O.
      • Kostich M.
      • Zagar T.M.
      • Jones E.
      • Gupta G.
      • Mavroidis P.
      • et al.
      Helical tomotherapy for bilateral breast cancer: clinical experience.
      ]. Therefore, care should be given to delineate all potentially OARs that might be exposed to radiation (including the contralateral uninvolved breast) and the doses to these OARs should be evaluated, otherwise treatment might result in increased or unexpected toxicity [
      • Kaidar-Person O.
      • Kostich M.
      • Zagar T.M.
      • Jones E.
      • Gupta G.
      • Mavroidis P.
      • et al.
      Helical tomotherapy for bilateral breast cancer: clinical experience.
      ].

      Dose coverage

      Delineation and dose coverage for breast cancer target volumes can be challenging. These challenges can be related to patient’s body habitus. In patients with a high BMI, surgery, delineation, and dose coverage for regional nodes may be challenging, and it is probably one of the main reasons for higher rates of locoregional failure and worse distant recurrence-free interval and overall survival in these patients [
      • Bergom C.
      • Kelly T.
      • Bedi M.
      • Saeed H.
      • Prior P.
      • Rein L.E.
      • et al.
      Association of locoregional control with high body mass index in women undergoing breast conservation therapy for early-stage breast cancer.
      ,

      de Blacam C, Ogunleye AA, Momoh AO et al. High body mass index and smoking predict morbidity in breast cancer surgery: a multivariate analysis of 26,988 patients from the national surgical quality improvement program database. Annals of Surg 2012;255.

      ]. In case of CTVp (breast or chest wall), treatment objective is that the doses in the range 95%-105% of the prescription dose and Dmax ≤ 110% [
      • Thomsen M.S.
      • Berg M.
      • Zimmermann S.
      • Lutz C.M.
      • Makocki S.
      • Jensen I.
      • et al.
      Dose constraints for whole breast radiation therapy based on the quality assessment of treatment plans in the randomised Danish breast cancer group (DBCG) HYPO trial.
      ]. The volume that receives a dose between 105% and 107% of the prescription dose should be limited to 2% of the CTV volume (V105%–V107% ≤ 2%) [
      • Donovan E.
      • Bleakley N.
      • Denholm E.
      • Evans P.
      • Gothard L.
      • Hanson J.
      • et al.
      Randomised trial of standard 2D radiotherapy (RT) versus intensity modulated radiotherapy (IMRT) in patients prescribed breast radiotherapy.
      ]. These recommendations are important to reduce the risk of toxicity, as dose inhomogeneity was found to be associated with acute complications and poor aesthetic outcome in case of breast irradiation. It is recommended that no part of the CTVp except for build-up regions (within 5 mm from the skin) should be covered with doses <95% of the prescription dose (V95% ≥ 95%). Further consideration for dose coverage/planning in the setting of moderate hypofractionation for breast cancer treatment were recently published from the quality assessment of the treatment plans in the Danish Breast Cancer Group (DBCG) HYPO trial [
      • Thomsen M.S.
      • Berg M.
      • Zimmermann S.
      • Lutz C.M.
      • Makocki S.
      • Jensen I.
      • et al.
      Dose constraints for whole breast radiation therapy based on the quality assessment of treatment plans in the randomised Danish breast cancer group (DBCG) HYPO trial.
      ]. For different radiation dose protocols, example, centres using the FAST FORWARD regimen [
      • Murray Brunt A.
      • Haviland J.S.
      • Wheatley D.A.
      • Sydenham M.A.
      • Alhasso A.
      • Bloomfield D.J.
      • et al.
      Hypofractionated breast radiotherapy for 1 week versus 3 weeks (FAST-Forward): 5-year efficacy and late normal tissue effects results from a multicentre, non-inferiority, randomised, phase 3 trial.
      ], we recommend reading the section for radiation planning within the trial protocol.
      In the era of 3D-based planning and dose volume histogram, the dose objectives for all target volumes and organs at risk should be clearly defined prior to planning. Borm et al [
      • Borm K.J.
      • Oechsner M.
      • Düsberg M.
      • Buschner G.
      • Weber W.
      • Combs S.E.
      • et al.
      Irradiation of regional lymph node areas in breast cancer – Dose evaluation according to the Z0011, AMAROS, EORTC 10981–22023 and MA-20 field design.
      ] estimated the lymph node volume dose distribution from radiation therapy according to treatment planning protocols in the MA.20 [
      • Whelan T.J.
      • Olivotto I.A.
      • Parulekar W.R.
      • Ackerman I.
      • Chua B.H.
      • Nabid A.
      • et al.
      Regional nodal irradiation in early-stage breast cancer.
      ], EORTC 22922-10925 [
      • Poortmans P.M.
      • Collette S.
      • Kirkove C.
      • Van Limbergen E.
      • Budach V.
      • Struikmans H.
      • et al.
      Internal mammary and medial supraclavicular irradiation in breast cancer.
      ], AMAROS [
      • Donker M.
      • van Tienhoven G.
      • Straver M.E.
      • Meijnen P.
      • van de Velde C.J.H.
      • Mansel R.E.
      • et al.
      Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer (EORTC 10981–22023 AMAROS): a randomised, multicentre, open-label, phase 3 non-inferiority trial.
      ] and the Z0011 [

      Giuliano AE, Ballman K, McCall L et al. Locoregional Recurrence After Sentinel Lymph Node Dissection With or Without Axillary Dissection in Patients With Sentinel Lymph Node Metastases: Long-term Follow-up From the American College of Surgeons Oncology Group (Alliance) ACOSOG Z0011 Randomized Trial. Ann Surg 2016; 264: 413–420.

      ,
      • Giuliano A.E.
      • Hunt K.K.
      • Ballman K.V.
      • et al.
      Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial.
      ] trials – all of which enrolled patients in the pre-target volumes-based era. When these volumes were compared to regional node volumes according to ESTRO guidelines, nodal volumes were not always effectively covered. None of the trial treatment planning protocols provided adequate dose coverage to the lymphatic drainage system. High tangential irradiation (used in the Z0011) resulted in a similar dose distribution in level 1–2 compared to the AMAROS field design [
      • Borm K.J.
      • Oechsner M.
      • Düsberg M.
      • Buschner G.
      • Weber W.
      • Combs S.E.
      • et al.
      Irradiation of regional lymph node areas in breast cancer – Dose evaluation according to the Z0011, AMAROS, EORTC 10981–22023 and MA-20 field design.
      ]. The lymphatic volumes included in these trials were based on old planning techniques of bony landmarks and old prescription recommendations (eg., dose of level 3–4 was prescribed at 3 cm depth). Moreover, it was shown that there was not full dose coverage to elective volumes according to the ESTRO atlas. Thus, the use of more extensive target volumes for level 4 such as those recommended by the RTOG is likely not necessary for patients requiring elective nodal irradiation as these trials already had very low rates of regional recurrence, despite the shortcomings mentioned above. It is also important to recognise that many nodal recurrences are not identified or recorded because of a lack of nodal evaluation after a diagnosis of metastatic disease and because the threshold for reliably detecting nodal recurrences via imaging (MRI or PET-CT) requires the presence of deposits of about 25 × 106 tumour cells (i.e., ~3 mm lesion).
      Although some of these trials in the pre-CT-based treatment planning era had radiation quality assurance, current 3DCRT based planning systems allow for clear identification of the anatomical target volumes and visualisation of the dose distribution, setting treatment objectives that permit appropriate coverage. The EORTC trial, enrolled patients from 1996 till 2004 and only a few institutions used CT-based treatment planning, most often based on just a few CT-slices using a CT-extension mounted on a conventional simulator.
      Extensive nodal irradiation may result in increased doses to OARs, mostly the heart and the lungs, but also the thyroid gland and the shoulder joint, which might result in higher toxicity [
      • Donker M.
      • van Tienhoven G.
      • Straver M.E.
      • Meijnen P.
      • van de Velde C.J.H.
      • Mansel R.E.
      • et al.
      Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer (EORTC 10981–22023 AMAROS): a randomised, multicentre, open-label, phase 3 non-inferiority trial.
      ]. This is noted in the AMAROS trial, in which the dose to the axilla lateral to the coracoid process was prescribed to full patient thickness, limited to 3 cm depth at level 3–4 [
      • Donker M.
      • van Tienhoven G.
      • Straver M.E.
      • Meijnen P.
      • van de Velde C.J.H.
      • Mansel R.E.
      • et al.
      Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer (EORTC 10981–22023 AMAROS): a randomised, multicentre, open-label, phase 3 non-inferiority trial.
      ,
      • Borm K.J.
      • Oechsner M.
      • Düsberg M.
      • Buschner G.
      • Weber W.
      • Combs S.E.
      • et al.
      Irradiation of regional lymph node areas in breast cancer – Dose evaluation according to the Z0011, AMAROS, EORTC 10981–22023 and MA-20 field design.
      ]. The inclusion of the humeral head in the radiation fields resulted in an unexpected nonsignificant trend towards more early shoulder movement impairment in the experimental (RT) arm. As the AMAROS population consisted of early breast cancer patients, delineating according to ESTRO guidelines creating a 1 cm planning OAR volume (PRV) around the humeral head, will likely reduce the risk for arm/shoulder morbidity [
      • Offersen B.V.
      • Boersma L.J.
      • Kirkove C.
      • Hol S.
      • Aznar M.C.
      • Biete Sola A.
      • et al.
      ESTRO consensus guideline on target volume delineation for elective radiation therapy of early stage breast cancer.
      ,
      • Offersen B.V.
      • Boersma L.J.
      • Kirkove C.
      • Hol S.
      • Aznar M.C.
      • Sola A.B.
      • et al.
      ESTRO consensus guideline on target volume delineation for elective radiation therapy of early stage breast cancer, version 1.1.
      ]. As both the ESTRO and RTOG atlases were shown to provide equivalent coverage to areas at high risk for recurrence [
      • Borm K.J.
      • Oechsner M.
      • Düsberg M.
      • Buschner G.
      • Weber W.
      • Combs S.E.
      • et al.
      Irradiation of regional lymph node areas in breast cancer – Dose evaluation according to the Z0011, AMAROS, EORTC 10981–22023 and MA-20 field design.
      ], we recommend using the ESTRO guidelines for early breast cancer with adaptation of the volume in cases of locoregionally advanced disease as this is likely to offer a superior balance between disease control and toxicity compared to using more extensive fields for all patients [
      • Duma M.
      An update on regional nodal irradiation: indication, target volume delineation, and radiotherapy techniques.
      ].

      Final note on irradiated levels and volumes

      Delineation is not the only challenge, but also the decision which nodal volumes to include in the CTVn [
      • Belkacemi Y.
      • Kaidar-Person O.
      • Poortmans P.
      • Ozsahin M.
      • Valli M.-C.
      • Russell N.
      • et al.
      Patterns of practice of regional nodal irradiation in breast cancer: results of the European Organization for Research and Treatment of Cancer (EORTC) NOdal Radiotherapy (NORA) survey.
      ]. The un-operated lymph nodes are the most common site of recurrence [
      • Chang J.S.
      • Byun H.K.
      • Kim J.W.
      • Kim K.H.
      • Lee J.
      • Cho Y.
      • et al.
      Three-dimensional analysis of patterns of locoregional recurrence after treatment in breast cancer patients: Validation of the ESTRO consensus guideline on target volume.
      ,
      • Chang J.S.
      • Lee J.
      • Chun M.
      • Shin K.H.
      • Park W.
      • Lee J.H.
      • et al.
      Mapping patterns of locoregional recurrence following contemporary treatment with radiation therapy for breast cancer: A multi-institutional validation study of the ESTRO consensus guideline on clinical target volume.
      ]. Chang and colleagues [
      • Chang J.S.
      • Byun H.K.
      • Kim J.W.
      • Kim K.H.
      • Lee J.
      • Cho Y.
      • et al.
      Three-dimensional analysis of patterns of locoregional recurrence after treatment in breast cancer patients: Validation of the ESTRO consensus guideline on target volume.
      ,
      • Chang J.S.
      • Lee J.
      • Chun M.
      • Shin K.H.
      • Park W.
      • Lee J.H.
      • et al.
      Mapping patterns of locoregional recurrence following contemporary treatment with radiation therapy for breast cancer: A multi-institutional validation study of the ESTRO consensus guideline on clinical target volume.
      ] reported that lymph node level 4 was the most common site of regional recurrence (33.8% of all lesions). Other regions of axillary lymph nodes failure were mostly in level 1 (28.3%), level 2 (14.3%), and level 3 (8.9%) [
      • Chang J.S.
      • Byun H.K.
      • Kim J.W.
      • Kim K.H.
      • Lee J.
      • Cho Y.
      • et al.
      Three-dimensional analysis of patterns of locoregional recurrence after treatment in breast cancer patients: Validation of the ESTRO consensus guideline on target volume.
      ,
      • Chang J.S.
      • Lee J.
      • Chun M.
      • Shin K.H.
      • Park W.
      • Lee J.H.
      • et al.
      Mapping patterns of locoregional recurrence following contemporary treatment with radiation therapy for breast cancer: A multi-institutional validation study of the ESTRO consensus guideline on clinical target volume.
      ].
      This was the leading concept in the EORTC 22922-10925 trial [
      • Poortmans P.M.
      • Weltens C.
      • Fortpied C.
      • Kirkove C.
      • Peignaux-Casasnovas K.
      • Budach V.
      • et al.
      Internal mammary and medial supraclavicular lymph node chain irradiation in stage I-III breast cancer (EORTC 22922/10925): 15-year results of a randomised, phase 3 trial.
      ,
      • Poortmans P.M.
      • Collette S.
      • Kirkove C.
      • Van Limbergen E.
      • Budach V.
      • Struikmans H.
      • et al.
      Internal mammary and medial supraclavicular irradiation in breast cancer.
      ] with the aim to reduce the toxicity associated with dissection combined with nodal irradiation without compromising oncological outcomes. If appropriate axillary surgery was performed, the elective nodal volumes were limited to the undissected parts of the axilla. Radiation therapy of the dissected part was only allowed in circumstances where there was a high risk of residual disease (as stated by surgeon or pathologist). Lymphoedema rates did not differ between treatment arms. In contrast, in the MA.20 trial [
      • Whelan T.J.
      • Olivotto I.A.
      • Parulekar W.R.
      • Ackerman I.
      • Chua B.H.
      • Nabid A.
      • et al.
      Regional nodal irradiation in early-stage breast cancer.
      ], radiation to the operated part of the axilla was advised for patients who had fewer than 10 axillary nodes removed or more than 3 positive axillary nodes. In these cases, the field was extended laterally to include the level 1 and 2 axillary lymph nodes, and it was recommended that a nondivergent posterior field should match the anterior field or that a smaller patch field be used to cover the axilla. The lymphoedema rates were almost doubled after adding radiation to surgery [
      • Whelan T.J.
      • Olivotto I.A.
      • Parulekar W.R.
      • Ackerman I.
      • Chua B.H.
      • Nabid A.
      • et al.
      Regional nodal irradiation in early-stage breast cancer.
      ]. Importantly, reported rates of lymphoedema vary depending on the scoring system, but these are clearly higher if lymph node dissection is combined with comprehensive regional node irradiation [
      • Byun H.K.
      • Chang J.S.
      • Im S.H.
      • et al.
      Risk of lymphedema following contemporary treatment for breast cancer: an analysis of 7617 consecutive patients from a multidisciplinary perspective.
      ] (Table 4).
      Table 4The rates of lymphedema according to type of axillary intervention and radiation.
      TrialMedian follow up (years)ALND (%)SLNB + RT (%)ALND + RT (%)Authors’ comments
      Z0011

      Giuliano AE, Ballman K, McCall L et al. Locoregional Recurrence After Sentinel Lymph Node Dissection With or Without Axillary Dissection in Patients With Sentinel Lymph Node Metastases: Long-term Follow-up From the American College of Surgeons Oncology Group (Alliance) ACOSOG Z0011 Randomized Trial. Ann Surg 2016; 264: 413–420.

      ,
      • Giuliano A.E.
      • Ballman K.V.
      • McCall L.
      • Beitsch P.D.
      • Brennan M.B.
      • Kelemen P.R.
      • et al.
      Effect of axillary dissection vs no axillary dissection on 10-year overall survival among women with invasive breast cancer and sentinel node metastasis: the ACOSOG Z0011 (alliance) randomized clinical trial.
      ,
      • Giuliano A.E.
      • Hunt K.K.
      • Ballman K.V.
      • et al.
      Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial.
      1*196High tangential irradiation included level 1 and part of level 2
      AMAROS
      • Donker M.
      • van Tienhoven G.
      • Straver M.E.
      • Meijnen P.
      • van de Velde C.J.H.
      • Mansel R.E.
      • et al.
      Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer (EORTC 10981–22023 AMAROS): a randomised, multicentre, open-label, phase 3 non-inferiority trial.
      52813.6RT to levels 1–4, extensive fields larger than recommended by ESTRO, including the lymphatics draining the arm
      EORTC 22922/10925
      • Poortmans P.M.
      • Weltens C.
      • Fortpied C.
      • Kirkove C.
      • Peignaux-Casasnovas K.
      • Budach V.
      • et al.
      Internal mammary and medial supraclavicular lymph node chain irradiation in stage I-III breast cancer (EORTC 22922/10925): 15-year results of a randomised, phase 3 trial.
      ,
      • Poortmans P.M.
      • Collette S.
      • Kirkove C.
      • Van Limbergen E.
      • Budach V.
      • Struikmans H.
      • et al.
      Internal mammary and medial supraclavicular irradiation in breast cancer.
      10.99.8-11.1Elective nodal volumes to the undissected parts, level 3–4 and IMNs

      *Incomplete ALND, RT was to all LN levels
      MA-20
      • Whelan T.J.
      • Olivotto I.A.
      • Parulekar W.R.
      • Ackerman I.
      • Chua B.H.
      • Nabid A.
      • et al.
      Regional nodal irradiation in early-stage breast cancer.
      9.54.5-8.4Elective nodal volumes to the undissected parts, level 3–4 and IMNs

      *Three or more involved LNs, or incomplete ALND, RT was to all LN levels
      ALND- axillary lymph dissection; SLNB- sentinel lymph node dissection; RT- radiation therapy; IMN – internal mammary nodes chain; LN – Lymph nodes. *The toxicity was reported at 1 year follow up, the median long term follow up was 9.3 years.
      Although the EORTC 22922-10925 trial limited the elective nodal volumes to the undissected parts of the axilla regardless of the tumour nodal burden or features such as extracapsular invasion or fat deposits, the regional recurrence rates were low at 3.2 % at 15 years and so were the lymphoedema rates. Other guidelines do address features that are considered as high risk for recurrence and recommend irradiation of the operated axilla. These include ratio of lymph node involvement (number of involved lymph nodes/total number of dissected lymph nodes). The guidelines in the Netherlands recommend irradiation of the dissected axilla if pathology report shows involved margins, suspicion of residual disease, and very rarely if extensive lymphovascular invasion or tumour in fat is present. The DBCG recommends RT to axilla level 1 if six or more macrometastases are present irrespective of number of removed nodes. However, using the ESTRO guideline, the CTVn_L1 is small compared to earlier guidelines, and even when not aiming to include level 1 in the target, this volume may receive full dose of RT in >10% of the cases treated with loco-regional RT with no indication for level 1 irradiation [
      • Francolini G.
      • Thomsen M.S.
      • Yates E.S.
      • Kirkove C.
      • Jensen I.
      • Blix E.S.
      • et al.
      Quality assessment of delineation and dose planning of early breast cancer patients included in the randomized Skagen Trial 1.
      ].
      Importantly, the extent of axillary surgery has changed. Axillary dissection is less commonly performed; therefore, levels 1–2 are not treated surgically in patients with low burden nodal disease. Based on the AMAROS trial, radiation volumes should include these levels in case of nodal involvement based on SLNB only [
      • Donker M.
      • van Tienhoven G.
      • Straver M.E.
      • Meijnen P.
      • van de Velde C.J.H.
      • Mansel R.E.
      • et al.
      Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer (EORTC 10981–22023 AMAROS): a randomised, multicentre, open-label, phase 3 non-inferiority trial.
      ]. If axillary dissection is performed, we recommend reviewing the pathological report and carefully examining the preoperative and postoperative (mostly planning CT) images to understand which levels were involved and which levels were operated upon. Often dissection includes level 1 and only the lateral part of level 2, thus planning according to the old-2D fields for “apex and supra” fields could miss part of the unoperated axilla which can result in recurrences (Fig. 5).
      Figure thumbnail gr5
      Fig. 5(A, B) beam arrangement and colour wash showing doses >65% of prescribed dose at initial time of radiation. The radiation was aimed to treat only the unoperated axilla and supraclavicular nodes, however, part of rotter nodes and level 2 that were not dissected were not included in the therapeutic isodose line. Arrow shows the clips at the level of the operated axilla, and medial to it are level 2 and rotter nodes that were not dissected and not within the therapeutic isodose line. (C) A PET-Scan 10 years later, isolated lymph node recurrence at edge of level 2 that was untreated with radiation.
      It should be noted that radiation techniques are constantly evolving (e.g., deep inspiration breath hold, vIMRT, proton therapy), and special considerations should be taken to determine the pro and cons of each technique such as OARs exposure and target volume coverage. Delineation of volumes of interests (OARs, target volumes) are essential for evaluation of radiation plans, and comparison between different techniques. This will allow for proper estimation of the plan and dealing with unexpected changes from the usual tangential based dose distribution. Example, if level 1–2 and rotter nodes are not delineated (and are part of the target volume), techniques such as deep inspiration breath hold, or even planning according to breast delineation-only as opposed to bony-landmarks, might lead to reduce dose to these nodal areas [
      • Borm K.J.
      • Oechsner M.
      • Combs S.E.
      • Duma M.-N.
      Deep-inspiration breath-hold radiation therapy in breast cancer: a word of caution on the dose to the axillary lymph node levels.
      ]. Furthermore, the use of new radiation techniques might define a need for a different image guidance protocols and adapting the planning treatment volume (PTV) to assure correct delivery to the target.

      Summary

      It is time to base radiation therapy on the volumes at high risk for tumour recurrence. Aggressive tumour subtypes and high tumour burden, extensive lymphovascular invasion or extracapsular extension, are strong predictors of locoregional recurrence, providing valuable information for defining the nodal target volumes to cover areas of potential subclinical spread. The current paper does not define the indications for nodal irradiation and nodal levels according to disease stage, risk factors, and response to therapy. We should aim for better risk stratification to allow tailoring of local–regional management strategies according to the risks of local–regional recurrence, ideally by nodal subsite. Keeping also in mind that the diagnosed rates of regional recurrences are now very low at 5% at 15 years in cases where regional radiation is not performed and without effective current systemic therapies. In most cases, ESTRO volumes for elective nodal irradiation will be sufficient to include the volumes at risk without increasing toxicity whereas at extremes, with a high tumour burden, there is relatively little controversy, that volumes should be individually adapted to cover all areas at risk.
      In the meantime, we recommend the collection of data, especially when using new radiation techniques such as IMRT or proton beam therapy that will allow reduction of the incidental dose to axillary levels that are not targeted. In the future this will allow for a better understanding of the volumes that need to be targeted, further improve the efficacy, and minimize the toxicity of adjuvant breast irradiation.

      Declaration of Competing Interest

      Icro Meattini reports occasional advisory boards supported by Eli Lilly, Novartis, Pfizer, and Roche, outside the submitted work, Philip Poortmans is medical advisor of Sordina IORT Technologies, S.p.A. outside the submitted work and other authors declared that no conflict of interest.

      Acknowledgments

      We would like to thank all the participants in ESTRO/FALCON courses that inspire us to write this paper and we hope that the workshops will continue to be interactive and thought provoking.

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