Dose–Volume Constraints fOr oRganS At risk In Radiotherapy (CORSAIR): An “All-in-One” Multicenter–Multidisciplinary Practical Summary

Background: The safe use of radiotherapy (RT) requires compliance with dose/volume constraints (DVCs) for organs at risk (OaRs). However, the available recommendations are sometimes conflicting and scattered across a number of different documents. Therefore, the aim of this work is to provide, in a single document, practical indications on DVCs for OaRs in external beam RT available in the literature. Material and Methods: A multidisciplinary team collected bibliographic information on the anatomical definition of OaRs, on the imaging methods needed for their definition, and on DVCs in general and in specific settings (curative RT of Hodgkin’s lymphomas, postoperative RT of breast tumors, curative RT of pediatric cancers, stereotactic ablative RT of ventricular arrythmia). The information provided in terms of DVCs was graded based on levels of evidence. Results: Over 650 papers/documents/websites were examined. The search results, together with the levels of evidence, are presented in tabular form. Conclusions: A working tool, based on collected guidelines on DVCs in different settings, is provided to help in daily clinical practice of RT departments. This could be a first step for further optimizations.


Introduction
Radiation therapy (RT) is an effective cancer treatment. However, like any other therapy, RT is associated with the risk of side effects. In particular, RT can produce both early (acute) and delayed (late) damage to organs at risk (OaRs). Therefore, since the early applications of RT, interest has grown in ways to reduce radiation-induced toxicity.
In particular, starting from the 1970s, progressively more detailed indications on safe dose limits became available in the literature. In fact, after the pioneering work of Rubin and Cassaret [1] and the historical so-called Emami's paper [2], the Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC) guidelines [3][4][5], based on dose/volume constraints (DVCs), were published in 2010. Subsequently, with the growing interest in hypofractionated treatments, especially delivered with stereotactic techniques, several recommendations were published on DVCs to be used with this dose fractionation [6][7][8][9][10]. In addition, specific DVC guidelines were published in particular clinical settings, such as Hodgkin's lymphomas [11], breast carcinomas [12][13][14], and pediatric cancers [15][16][17][18][19][20]. Finally, in the last few years, in parallel with the introduction of stereotactic ablative RT of ventricular arrythmia (STAR) [21][22][23], specific DVCs for this treatment were also proposed [6,8,21,22,24]. Therefore, a large number of guidelines or recommendations is now available to guide RT prescription and treatment plan evaluation and comparison.
Unfortunately, this information is contained in a plethora of sometimes conflicting publications. Therefore, a quick consultation to find clear and unambiguous indications is not always easy. Therefore, the aim of this work is to present, in a single document, practical indications on DVCs for different clinical settings and dose fractionations.

Materials and Methods
For the purposes of this project (CORSAIR: dose-volume constraints for organs at risk in radiotherapy), a multidisciplinary working group was established, including radiation oncologists, medical physicists, and radiologists. Colleagues from other Italian, American, African, and Asian centers were added to a first original nucleus made up of staff from our center (Bologna University). In particular, the contribution of some colleagues from developing countries was requested in order to verify the possibility of clearly and correctly interpreting the recommendations also in low-medium-resourced settings.
A literature search was performed in March 2022, using PubMed and without time limits, with different combinations of the following keywords: "dose/volume", "constraints", "organs at risk", and "radiotherapy". Only papers in English were considered. Moreover, the bibliographic list of one hundred and twenty publications was screened in order to identify other relevant sources. Furthermore, for convenience, only recommendations based on simple indications of dose and volume limit values (or percentages) were included in this collection. In addition, we consulted the National Comprehensive Cancer Network (NCCN) guidelines in all cases in which, in the indication of radiotherapy, the DCVs of specific OaRs were presented and precisely in the case of lymphomas [11], lung cancers [25] and tumors of the esophagus [26], stomach [27], and anus [28]. The Global Quality Assurance of Radiation Therapy Clinical Trials Harmonization Group (GHG) contouring guidelines were used as the reference list and nomenclature system of the OaRs [29]. Furthermore, the OaR anatomical descriptions and landmarks were extracted from the same document and shown with the DVCs in tabular form. The anatomical descriptions were classified by level of reliability in their use for DVC evaluation. The classification was performed as follows: α: international guidelines or expert consensus in RT contouring, β: validated anatomical description for RT contouring from single institution, γ: anatomical or radiological descriptions from dedicated books or papers, δ: anatomical definition for RT contouring used in planning studies.
The results recorded during this research were independently verified by three authors from different centers and then summarized in tabular form. In the tables we referred to a different modality of fractionation and in particular to conventional fractionation, moderate hypofractionation, and ultra-hypofractionation. However, it should be considered that the definitions of fractionation refer to the dose per fraction administered to the tumor, which is generally different from that to the OaRs. Therefore, particular caution is required in the use of information contained in the tables, as well as the radiobiological knowledge on the impact of the different fractions and the clinical experience in this topic. In particular, six different tables related to different RT treatment settings were drawn up. In addition, together with the recommended DVC values, we reported the grade of recommendation (for example: mandatory, recommended, optimal, or acceptable) if included in the reference publication. Moreover, the optimal imaging technique for delineating the specific OaR was included in the tables if included in the selected publications. In addition, in order to provide users with a critical assessment of the DVCs, we categorized the source of recommendation as follows: (A) international guidelines; (B) literature reviews on clinical or planning studies; (C) data from the results of clinical or planning studies; (D) expert opinions or DVCs used in prospective trials. Moreover, when different sources presented different values of the same DVC, we included in the tables only the one with the highest level of evidence. Therefore, we included recommendations with "B-D" source of recommendation only in case of lack of level "A" DVCs.
Finally, common abbreviations in the literature were used in the tables: V = volume receiving a dose ≥ Gy, D = dose received by % of the organ volume, D = dose received by γ cm 3 (the cubic centimeters) of the organ volume, DMAX = maximum dose received by the organ, DMEAN = mean dose received by the organ. Volumes and doses were expressed as percentage (%) or absolute values (cm 3 or Gy, respectively).

Anal Canal {Canal_Anal}
Consider from the anorectal junction to the anal verge [62] [γ]. Include the internal and external anal sphincters.
-Internal anal sphincter: thin muscle, which encircles the anal canal from anal mucosa (inner) to external anal sphincter (outer).

Anterior Descending Artery {A_LAD}
Descending in the anterior inter-ventricular groove to the apex of the heart. Proximal: The proximal 1/5th of the vessel, from the end of the left main coronary artery passing anteriorly behind the pulmonary artery. Mid: The mid 2/5th of the vessel descending anterolaterally in the anterior interventricular groove. Distal: The distal 2/5th of the vessel running in the interventricular groove and extending to the apex [29,63,64] [α].

Aortic valve
The aortic valve is located between the left ventricle and aorta. It is a semilunar valve, posterior to the pulmonary valve. It is composed of three cups: the left posterior (origin of left coronary), anterior (origin of the right coronary), and right posterior [62] [γ].

Bichat's Fat pad
It is located on either side of the face, between the buccinator muscle and the masseter, the zygomaticus major, and the zygomaticus minor muscles. Composed in three lobes, anterior, intermediate, and posterior. It also has four extensions: sublevator, melolabial, buccal, and pterygoid, whose names derived from their location and proximal muscles [65] [γ].  Contour each structure separately. Include the intercostal muscles and other muscles, from lateral edge of the sternum, until the lateral edge of vertebral body. Exclude the skin from the contour. Consider a possible auto-segmentation from the corrected lung edges with a 2 cm expansion in the lateral, anterior, and posterior directions. Chestwall may be also considered as sum of the two volumes [29,73] [α].

CT-bone windows
Consider each structure separately. Located in a bony cavity in the petrous portion of the temporal bone. It has a spiral structure and continues cranially with the semicircular canals, laterally with the internal auditory canal. Cochlea may also be considered as sum of the two volumes [29,37,39] [α].

Femur
The femur is the only bone in the upper leg. It is classified as a long bone and is normally divided into diaphysis (or body) and two epiphyses (ends). The proximal end contains the head, neck, two trochanters, and adjacent structures. The body of the femur is thick and almost cylindrical in shape. The lower end of the femur is the thickest and ends with two condyles that articulate with the tibia. [62] [γ] The diaphysis cross-sectioned by the beam entrances. Reduce the femur dose using VMAT [77] [δ].

Genitals {Genitals} MRI
In males: include the penis, scrotum, and area including skin and fat anterior to the pubic symphysis.
In females: include the clitoris, labia majora and minora, and area including skin and fat anterior to pubic symphysis.

CT-lung windows
Limit the contour to the air-inflated lung parenchyma without inclusion of any fluid visible on CT. Include small sized vessels (<1 cm or beyond the hilar region); exclude the proximal bronchial tree. Do not include the trachea/bronchus. Automated contouring tools may be used, with reviewing and editing of the auto-contoured structure often required. Considered lungs as sum of structures. Normally, the lung dose limits are referred to DVHs of both lungs, with exclusion of the target volume [29,73] [α].

Mitral valve
It is a bicuspid valve and it is located between the left atrium and the left ventricle of the heart. It is composed by two cusps (or leaflets): an anteromedial leaflet and a posterolateral leaflet. A fibrous ring (anulus) surrounds the structure [

T2-weighted MR
Contour each ovary separately. Located in the ovarian fossae, proximate to the lateral pelvic wall. The right ovary is usually medial to ileocaecal junction, caecum, and appendix. The left ovary is adjacent to the sigmoid colon. Posteriorly they face the peritoneum. Ovaries may be considered as a sum of the two structures [29,66] [α] [82,83] [γ].

Pancreas {Pancreas}
Located at the level of the L1-L3 vertebral bodies. The pancreatic head can be identified to the right of the superior mesenteric artery. The uncinate process is placed posteriorly to the superior mesenteric vein. The pancreatic body lays between the coeliac trunk and superior mesenteric artery, anterior to the aorta [29,69]  Pericardium It is called also pericardial sac; it is a fibro-serous sac containing the heart and the roots of the great vessels. It is composed by an outer layer (fibrous pericardium) and an inner layer (serous pericardium) [62] [γ].

Pituitary Fossa {Fossa_Pituitary}
It is defined as the inner bony limit of the sella turcica and can be considered as an alternative anatomical structure for the pituitary gland [29,37,67]

Pulmonary valve
It is also called pulmonic valve, a semilunar valve, located between the right ventricle and pulmonary artery. It is composed by three semilunar cusps-two anterior and one posterior, projecting into the lumen of pulmonary trunk [62] [γ].

Rectum {Rectum}
Cranial: consider sigmoid junction when the rectum loses its round shape in the axial plane and connects with the sigmoid. Caudal: the anorectal junction, at the lowest level of the ischial tuberosity (right or left) [29,66] [α].

Retina {Retina_L Retina_R Retinas}
Contour each structure separately. It is structure located in the posterior wall of the eye. Consider the posterior wall of the eye and contour from the insertion of the lateral rectus muscle to the contralateral medial rectus muscle. Retinas can be considered as sum of two volumes [29] [α].

Right Coronary Artery (RCA)
Proximal: from the exit of LMCA, it runs in the atrioventricular groove between right ventricle and right atrium, with caudal limit before it reaches the position near the pericardium. Middle: from the distal part of proximal-RCA, it runs in the atrioventricular groove, to the acute heart border. Distal: from the acute hearth border, continues in the atrioventricular groove posteriorly to the crux cordis. Posterior descending artery: from distal RCA it continues between left and right ventricles [64,80] [α].

Sigmoid Colon {Colon_Sigmoid}
Consider the last part of the colon, caudal to descending colon. Cranial border: where the descending colon turns toward the left to reach the middle line at the level of the third piece of the sacrum. Caudal border: recto-sigmoid junction. Contour the outer boundary of the bowel and includes any bowel contents [29] [α] [62] [γ].

Skin {Skin}
The skin is the 5mm inner rind of the external body contour. Please note actual skin thickness will vary dependent on region of interest [29,37]

Tricuspid valve
It is also called right atrioventricular valve and it is located at the superior portion of the right ventricle. It is composed by three cusps or leaflets: anterior, posterior, and septal cusps. Each leaflet is connected through chordae tendineae to the papillary muscles of the right ventricle [62] [γ].

Ureters {Ureter_L Ureter_R Ureters}
Defined from the ureteropelvic junction of the kidneys. In the abdomen they are located in the retroperitoneum and they lay anteriorly to the psoas muscle. At the level of the ischial spine, the ureter turns anterior and medial and enter the bladder on the posterior bladder aspect in the trigone (ureterovesical junction). Ureters can be considered as volume sum [29] [29], where present, is given in {..}. The anatomical descriptions were classified by level of reliability in their use for DVC evaluation as follows: α-international guidelines or expert consensus in RT contouring, β-validated anatomical description for RT contouring from single institution, γ-anatomical or radiological descriptions from dedicated books or papers, δ-anatomical definition for RT contouring used in planning studies.

Discussion
The initial aim of this work was to produce practical guidelines within our institution and, thus, to provide radiation oncologists with a quick and user-friendly synopsis without (or with little) ambiguity. We subsequently decided to share this work and to involve a multidisciplinary and international team of authors to write this paper.
In drafting these guidelines, we avoided entering different values (from different sources) for the same DVC. For this reason, we identified criteria for selecting the data to be included. Therefore, we scored the source of recommendation as previously reported.
Obviously, this choice reduced the amount of the presented information but we hope that the tables will be used as an index to the literature where further relevant details can easily be found. Furthermore, grading the evidence provides the reader with an estimate of the single recommendation relevance.
Obviously, the use of these recommendations cannot be "automatic" but necessarily requires management by operators with knowledge and experience on the details needed for an informed and expert use of dose/volume constraints. For example, the evaluation of dose/volume histograms for OaRs must take into account various aspects, such as patient age and comorbidities, spatial characteristics of the radiotherapy dose distribution, treatment aims, and any symptoms that are manageable or not with other treatments.
This collection of DVCs for OaRs has obvious limitations. Not all available information was included, only some has been selected. To this end we used well-defined objective criteria which, however, were inevitably the result of a subjective and somehow arbitrary choice for the authors. Therefore, we are aware that different criteria would have led to recommendations different from those presented here. In addition, many DVCs came from publications, such as the QUANTEC guidelines, based on the results of clinical studies where RT was mainly delivered with the 3D technique. However, it is known that different and new techniques may require different and new DVCs. For example, in the Allen et al. experience, where the DVC V 20 Gy was met, 6 out of 13 patients with pleural mesothelioma undergoing intensity-modulated RT died from radiation-induced pneumonitis. From the analysis of their data, the authors concluded that in the setting of thoracic irradiation with modulated RT, the V 5 Gy parameter must be evaluated in addition to the DVCs established at the time of their publication [86]. Therefore, great caution is required when using "new" RT techniques with "old" DVCs. Furthermore, our bibliographic research only included papers, thus, excluding other potentially useful sources, as in the case of the textbook published by Rancati and Fiorino in 2019 [87], which offers an in-depth update of the QUANTEC initiative. In addition, other potentially useful bibliographic sources, such as those relating to the HyTEC initiative (Hygh dose per fraction, hypofractionated treatment effects in the clinic) [88,89], were deliberately excluded. In fact, our choice was to provide the most practical indications and, therefore, to include only recommendations based on dose and volume limit values or percentages.
Furthermore, both the recommendations from guidelines and from other sources may be based on previous publications and it is difficult, and sometimes impossible, to verify that these references are completely correct and, above all, provide precise indications on the clinical reference setting.
Similarly, Ferini et al. effectively summarized a large series of ever-changing dosimetric issues about the rectum, including contradictory perspectives on how to consider such an OAR (parallel vs. serial) and, consequently, conflicting DVCs [90]. In this scenario, there is also the need to understand whether some medical interventions can improve the rectal tolerance to high-radiation exposure [91,92].
Furthermore, the introduction of new algorithms to calculate dose distribution can also lead to unexpected OaR overdosing [93]. On the other hand, new techniques can improve the tolerance of some tissues. For example, Table 1 reports 72 Gy as the D max value for the brain. Instead, some studies based on intensity-modulated RT or volumetric-modulated arc therapy showed the brain's tolerability of doses up to 80 Gy [94,95]. Furthermore, many indications have rather low levels of evidence and have to be simply considered as "expert opinions". For example, all suggestions presented in Supplementary Table S3 for breast cancers have the minimum level of evidence (D). More generally, the categorization of the source of recommendation we propose has further limitations. In fact, we arbitrarily considered recommendations from guidelines as those with the highest level of evidence, considering this, even if a compromise, the best possible choice. However, as is well known, the same guidelines can be based on levels of evidence that we classify as of lower level and it is not certain that the recommendations of the guidelines are updated based on the latest data from the literature.
Finally, the "practical" choice of producing "synoptic" guidelines further limited the presented information. For example, only the DVCs for RT delivered in one, three, five, and eight fractions were arbitrarily selected for ultra-hypofractionated treatments.
Additionally, no DVC indication is made for RT schedules combining different radiation dose sizes, as in the cases of a stereotactic boost to a limited tumor site after a more extended normofractionated irradiation [96,97] or of a large spatially fractionated dose administration before a homogeneously delivered hypofractionated palliative course [98].