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ESTRO ACROP guidelines for target volume definition in pancreatic cancer

      Highlights

      • This guideline aims to help radiation oncologists to delineate target volumes for patients with ductal adenocarcinoma for conventionally fractionated and for stereotactic body radiotherapy.
      • Elective nodal areas are not recommended to be included for definitive treatment.
      • Consensus recommendations are given for adjuvant and neoadjuvant therapy ± the inclusion of nodal areas.
      • Organs of risk are defined and dose constraints are given.

      Abstract

      Despite of the predominant role of chemotherapy and surgery in pancreatic ductal adenocarcinoma (PDAC), radiotherapy (RT) still has a place in multimodal management of this disease where local tumour sequelae are fatal in about 40% of the patients. RT (chemoradiotherapy and stereotactic body radiotherapy) is used and investigated in the non-metastatic setting as part of definitive treatment strategies, in (neo)adjuvant settings and for locally recurrent disease. The ACROP committee was delegated by ESTRO to recommend target volume delineation for these clinical situations. The guidelines of this document are a result of a structured evaluation of the best available evidence by a panel of international experts in the field. Guidance for treatment planning including diagnostic imaging is provided. Recommendations are given for GTV delineation. The role and the definition of CTV volumes are critically discussed. Aspects of motion management and patient positioning are taken into account for PTV definition. Furthermore, aspects of delineation of organs at risk and of dose constraints are described in both, standard and hypofractionated, settings. This guideline has the purpose to support standardised and optimised processes of RT treatment planning for both, clinical practice and prospective studies.

      Keywords

      Pancreatic RT has been used in the neo-adjuvant and adjuvant setting, and for the management of locally advanced or recurrent pancreatic tumours. The techniques, target volume definitions and fractionation schemes vary considerably in the published literature, even for the same indication. The aim of this technical RT guideline is to provide clinicians with consensus recommendations for target volume delineation (including imaging and patient-set up) for the treatment of pancreatic cancer in different clinical situations according to the used technique. A writing committee consisting of six European radiation oncologists with specialisation and experience in GI cancers produced the guideline draft. The guidelines were further refined after being reviewed by a review committee consisting of three different European radiation oncologists specialized in GI cancers. All points issued by the review committee have been discussed and were refined in accordance with the writing committee after consensus has been reached. It must be noted that the primary focus of this guideline is to discuss the technical aspects of pancreatic RT. Discussing the evidence-base for RT indications and specific RT technique (e.g. CRT versus SBRT) was considered to be beyond the scope of this guidance.

      Anatomy

      The pancreas and its relationship to surrounding structures

      The pancreas is situated retroperitoneally extending from the duodenum (pancreatic head) to the splenic hilum (pancreatic tail).
      The head of the pancreas lies in the loop of the duodenum, as it exits the stomach. The tail of the pancreas lies near the splenic hilum. Two key structures are traversing the pancreatic head, the common hepatic duct and the excretory pancreatic main duct (Wirsung), additionally (if present) the accessory duct (Santorini) all of which enter into the descending duodenum. The body is located dorsal of the stomach.
      The neck of the pancreas is intercalated by the superior mesenteric artery (SMA) and vein (SMV). The pancreatic tail is found in close proximity to the splenic hilum where the splenic vein originates, which runs along the backside of the pancreatic tail and body until it finally forms the confluence of the portal vein (PV) dorsally of the pancreatic head by converging with the SMV. The pancreas superimposes the large retroperitoneal vessels, in particular the inferior vena cava (IVC), the abdominal Aorta (Ao) and the renal vessels. Superiorly of the pancreas the celiac axis (CA) leaves the Aorta dividing into the common hepatic artery (CHA), the right gastric artery and the splenic artery (SA), which runs along the superior edge of the pancreatic body and tail to the splenic hilum.
      Anatomy of lymphatics in the upper abdominal region is complex and subject to considerable variation [
      • Brunner T.B.
      • Baum U.
      • Grabenbauer G.G.
      • Sauer R.
      • Lambrecht U.
      Large topographic variability of upper abdominal lymphatics and the consequences for radiation treatment planning.
      ]. Aside from the anatomical description [

      Terminology FCoA. Terminologia Anatomica: International Anatomical Terminology. . New York: Thieme; 1998.

      ], two clinical classifications of lymph node regions are commonly in use: the UICC classification (currently in its 8th version) [
      • Brierley J.D.
      • Gospodarowicz M.K.
      TNM classification of malignant tumors.
      ] and the Japanese classification [
      • Society JP
      Classification of pancreatic carcinoma.
      ,
      • Isaji S.
      • Murata Y.
      • Kishiwada M.
      New Japanese classification of pancreatic cancer.
      ]. For the purpose of this guideline, the expert panel agreed to use the Japanese classification (Table 1) because it is frequently used in most of the participating countries. The other classifications and a comparison of the described lymph node regions are available in the supplementary material. Contouring guidelines for the different regions of the Japanese classification are currently developed by ESTRO and will soon be published.
      Table 1Japanese classification used in this guideline and description of nodal areas.
      Japanese classificationabb.Description (simplified)
      infrapyloric6along the first branch and proximal part of the right gastroepiploic artery down to the confluent of the right gastroepiploic vein and the anterior superior pancreaticoduodenal vein
      common hepatic8located around the CHA
      celiac9located around the CA
      splenic hilar10located in the splenic hilum (along the splenic artery, distal to the pancreatic tail)
      splenic artery11located around the splenic artery (superiorly to the pancreatic body/tail)
      hepatoduodenal12located around the CBD, PV and proper hepatic artery in the hepatoduodenal ligament (upper border: branch of cystic duct)
      post. pancreatoduodenal13located dorsally of the pancreatic head
      SMA14located around the SMA
      paraaortic16located around the aorta from CA to the inferior mesenteric artery, including nodes between aorta and ICV
      ant. pancreatoduodenal17located ventrally of the pancreatic heads
      subpancreatic18located inferiorly of the pancreas
      abb.: abbreviation, CHA: common hepatic artery, CA: celiac axis, CBD: common bile duct, PV: portal vein, ICV: inferior caval vein

      Pattern of lymph node involvement

      Many patients with locoregionally confirmed pancreatic cancer suffer already from lymph node metastases. Several studies have examined the pattern of nodal metastases in surgically resected patients [
      • Kayahara M.
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      • Papadopoulos T.
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      ,
      • Cubilla A.L.
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      Lymph node involvement in carcinoma of the head of the pancreas area.
      ,

      Deki H, Sato T. An anatomic study of the peripancreatic lymphatics. Surg Radiol Anat. 1988;10(2):121-35. PubMed PMID: 3135617. Epub 1988/01/01. eng.

      ,

      Kayahara M, Nagakawa T, Ohta T, Kitagawa H, Ueno K, Tajima H, et al. Analysis of paraaortic lymph node involvement in pancreatic carcinoma: a significant indication for surgery? Cancer. 1999 Feb 1;85(3):583-90. PubMed PMID: 10091731. Epub 1999/03/26. eng.

      ,
      • Kayahara M.
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      • Kadoya N.
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      Lymphatic flow in carcinoma of the head of the pancreas.
      ,
      • Nagakawa T.
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      • Ueno K.
      • Ohta T.
      • Kayahara M.
      • Miyazaki I.
      Clinical study of lymphatic flow to the paraaortic lymph nodes in carcinoma of the head of the pancreas.
      ,

      Sun W, Leong CN, Zhang Z, Lu JJ. Proposing the lymphatic target volume for elective radiation therapy for pancreatic cancer: a pooled analysis of clinical evidence. Radiation oncology (London, England). 2010;5:28. PubMed PMID: 20398316. Pubmed Central PMCID: 2859771. Epub 2010/04/20. eng.

      ]. If elective nodal irradiation is considered, the regions with the highest risk of involvement should be considered to be included. The panel therefore made a corresponding recommendation based on the localization of the primary tumour in the target volume definition section. For detailed information regarding the results of the mentioned studies including a comparison, see supplementary section.

      Pattern of recurrence after surgery

      The distribution of local and nodal recurrences after curative resection of pancreatic cancer plays a major role in defining possible target volumes, not only for adjuvant but also for neoadjuvant strategies. Several studies have examined the region of highest risk [

      Heye T, Zausig N, Klauss M, Singer R, Werner J, Richter GM, et al. CT diagnosis of recurrence after pancreatic cancer: is there a pattern? World J Gastroenterol. 2011 Mar 7;17(9):1126-34. PubMed PMID: 21448416. Pubmed Central PMCID: 3063904.

      ,

      Dholakia AS, Kumar R, Raman SP, Moore JA, Ellsworth S, McNutt T, et al. Mapping patterns of local recurrence after pancreaticoduodenectomy for pancreatic adenocarcinoma: a new approach to adjuvant radiation field design. Int J Radiat Oncol Biol Phys. 2013 Dec 1;87(5):1007-PubMed PMID: 24267969. Pubmed Central PMCID: 3971882.

      ,

      Yu W, Hu W, Shui Y, Zhu X, Li C, Ren X, et al. Pancreatic cancer adjuvant radiotherapy target volume design: based on the postoperative local recurrence spatial location. Radiation oncology (London, England). 2016 Oct 19;11(1):138. PubMed PMID: 27756417. Pubmed Central PMCID: 5070214.

      ] and found similar results although using different descriptions. Heye et al. found the largest percentage of local recurrences in the tissue around the SMA and an area defined by the CA/SMA (medial border), PV (anterior) and ICV (lateral) [

      Heye T, Zausig N, Klauss M, Singer R, Werner J, Richter GM, et al. CT diagnosis of recurrence after pancreatic cancer: is there a pattern? World J Gastroenterol. 2011 Mar 7;17(9):1126-34. PubMed PMID: 21448416. Pubmed Central PMCID: 3063904.

      ]. Lower but also considerable rates were detected at the resection margin of the residual pancreatic parenchyma and around the common/proper hepatic artery. Lymph node recurrences were mainly observed in the mesenteric root in close proximity to the SMA and left-laterally of the aorta. Dholakia et al. described most recurrences in close proximity either to the SMA (69%) or the CA (31%) [

      Dholakia AS, Kumar R, Raman SP, Moore JA, Ellsworth S, McNutt T, et al. Mapping patterns of local recurrence after pancreaticoduodenectomy for pancreatic adenocarcinoma: a new approach to adjuvant radiation field design. Int J Radiat Oncol Biol Phys. 2013 Dec 1;87(5):1007-PubMed PMID: 24267969. Pubmed Central PMCID: 3971882.

      ]. In summary, most local recurrences occur in an area around the SMA/CA while lymph node recurrences are mainly found in the mesenteric root and the paraaortic space. Dholakia et al. and Yu et al. have reported specific recommendations how to cover these regions with a certain probability, for detailed information see supplementary material [

      Dholakia AS, Kumar R, Raman SP, Moore JA, Ellsworth S, McNutt T, et al. Mapping patterns of local recurrence after pancreaticoduodenectomy for pancreatic adenocarcinoma: a new approach to adjuvant radiation field design. Int J Radiat Oncol Biol Phys. 2013 Dec 1;87(5):1007-PubMed PMID: 24267969. Pubmed Central PMCID: 3971882.

      ,

      Yu W, Hu W, Shui Y, Zhu X, Li C, Ren X, et al. Pancreatic cancer adjuvant radiotherapy target volume design: based on the postoperative local recurrence spatial location. Radiation oncology (London, England). 2016 Oct 19;11(1):138. PubMed PMID: 27756417. Pubmed Central PMCID: 5070214.

      ].

      Diagnostic imaging

      Proper diagnostic imaging is essential for accurate treatment planning. Currently, MDCT is the primary modality for detection and staging [

      Chang J, Schomer D, Dragovich T. Anatomical, Physiological, and Molecular Imaging for Pancreatic Cancer: Current Clinical Use and Future Implications. BioMed research international. 2015;2015:269641. PubMed PMID: 26146615. Pubmed Central PMCID: 4471256.

      ]. MRI offers similar sensitivity and specificity rates for detection, assessment of vascular involvement and prediction of resectability [

      Chang J, Schomer D, Dragovich T. Anatomical, Physiological, and Molecular Imaging for Pancreatic Cancer: Current Clinical Use and Future Implications. BioMed research international. 2015;2015:269641. PubMed PMID: 26146615. Pubmed Central PMCID: 4471256.

      ,
      • Treadwell J.R.
      • Zafar H.M.
      • Mitchell M.D.
      • Tipton K.
      • Teitelbaum U.
      • Jue J.
      Imaging tests for the diagnosis and staging of pancreatic adenocarcinoma: a meta-analysis.
      ] but is the most sensitive imaging modality for the detection of liver metastases [
      • Bipat S.
      • Phoa S.S.
      • van Delden O.M.
      • Bossuyt P.M.
      • Gouma D.J.
      • Lameris J.S.
      • et al.
      Ultrasonography, computed tomography and magnetic resonance imaging for diagnosis and determining resectability of pancreatic adenocarcinoma: a meta-analysis.
      ]. FDG-PET/CT is regarded as an optional additional imaging modality in most European countries except for the UK where the NICE criteria recommend it as a standard for all non-stage IV patients prior to therapy [

      Exellence NNIfHaC. Pancreatic cancer in adults: diagnosis and management 2018 [cited 2020 11.07.2020]. Available from: https://www.nice.org.uk/guidance.

      ]. For detailed information regarding the value of different imaging modalities in diagnostic and planning see supplementary material.

      Radiotherapy techniques

      Conventionally fractionated CRT (25–30fractions), moderately hypofractionated (12–15 fractions) and Stereotactic Body Radiotherapy (SBRT) (3–12 fractions) are treatment options in the management of pancreatic cancer [

      Guckenberger M, Baus WW, Blanck O, Combs SE, Debus J, Engenhart-Cabillic R, et al. Definition and quality requirements for stereotactic radiotherapy: consensus statement from the DEGRO/DGMP Working Group Stereotactic Radiotherapy and Radiosurgery. Strahlenther Onkol. 2020 May;196(5):417-20. PubMed PMID: 32211940. Pubmed Central PMCID: 7182610.

      ]. There is no data to confirm superiority of one approach over the other and detailed review of the pros and cons of either modality is outside the scope of this guideline, which aims to focus on the technical aspects.

      Radiotherapy planning

      Immobilisation and CT simulation

      For planning purposes a dedicated contrast enhanced pancreatic CT protocol in treatment position is mandatory. Patients should be immobilized in treatment position with the immobilization device depending on the intended treatment technique (conventionally fractioned RT vs SBRT). For conventionally fractionated RT, the patient should be positioned supine on a flat table top with the arms above the head, resting on a support (for example an alpha-cradle or similar ad hoc devices). Additionally a knee and/or foot support should be used. For SBRT a dedicated immobilization device should be employed for high precision positioning which may include abdominal compression. Fasting > 2 hours before planning CT is recommended to ensure smaller variations in organ fillings. The use of oral contrast (usually consisting of water with or without a small amount of oral contrast given before CT acquisition) is recommended especially for SBRT treatments because it allows an improved differentiation between pancreas and stomach/duodenum. Planning CT should be performed in exhalation breath hold with intravenous contrast at least in the pancreatic phase as explained above to define the GTV. Additional scans in the portal venous phase may be used to allow an easier identification of vascular structures especially if elective nodal irradiation is planned. It is strongly recommended to use body weight adapted volumes of contrast agents and bolus tracking for adequate separation of phases [

      Lee ES, Lee JM. Imaging diagnosis of pancreatic cancer: a state-of-the-art review. World J Gastroenterol. 2014 Jun 28;20(24):7864-77. PubMed PMID: 24976723. Pubmed Central PMCID: 4069314.

      ]. Triple-phased protocols (arterial, pancreatic, portal-venous phase) are recommended. These will require a minimum flow of 3 ml/s and delays of roughly 25, 40 and 70 seconds from injection without bolus tracking. If used, the bolus tracking ROI should be placed in the descending aorta. Typical delays will be roughly 5, 20 and 50 seconds from the tracking signal (usually 80–100 HU) as reviewed in Lee et al. [

      Lee ES, Lee JM. Imaging diagnosis of pancreatic cancer: a state-of-the-art review. World J Gastroenterol. 2014 Jun 28;20(24):7864-77. PubMed PMID: 24976723. Pubmed Central PMCID: 4069314.

      ]. The team should liaise with the local radiology department to define the local protocol appropriate for their equipment. Reconstruction should use a slice thickness 3 mm or less.

      Motion assessment and management

      Four-dimensional CT
      Individual motion detection and consideration during treatment planning is mandatory due to large variations in pancreatic movement [

      Huguet F, Yorke ED, Davidson M, Zhang Z, Jackson A, Mageras GS, et al. Modeling pancreatic tumor motion using 4-dimensional computed tomography and surrogate markers. Int J Radiat Oncol Biol Phys. 2015;91(3):579-87. PubMed PMID: 25680600. Epub 2015/02/15. eng.

      ]. Four-dimensional CT (4D-CT) is currently the preferred method. This technique has the advantages to be easily implemented, not to require active cooperation of the patient and that the equipment is readily available for modern CT scanners. Nevertheless, there is some evidence that baseline 4D-CT may not always allow adequate prediction of pancreatic tumour motion over the course of treatment [
      • Lens E.
      • van der Horst A.
      • Kroon P.S.
      • van Hooft J.E.
      • Davila Fajardo R.
      • Fockens P.
      • et al.
      Differences in respiratory-induced pancreatic tumor motion between 4D treatment planning CT and daily cone beam CT, measured using intratumoral fiducials.
      ,
      • Ge J.
      • Santanam L.
      • Noel C.
      • Parikh P.J.
      Planning 4-dimensional computed tomography (4DCT) cannot adequately represent daily intrafractional motion of abdominal tumors.
      ]. Most centres perform 4D-CT without contrast-enhancement or directly after contrast-enhanced 3D-CT for treatment planning for practical reasons. 4D-CT phases are usually matched rigidly to 3D-CT bony landmarks for ITV-construction (if an ITV approach is chosen), while the final treatment planning is done on the 3D-planning CT. Choi et al. recently reported that a dedicated contrast-enhanced 4D-CT protocol might be beneficial compared to the former approach [

      Choi W, Xue M, Lane BF, Kang MK, Patel K, Regine WF, et al. Individually optimized contrast-enhanced 4D-CT for radiotherapy simulation in pancreatic ductal adenocarcinoma. Medical physics. 2016 Oct;43(10):5659. PubMed PMID: 27782710. Pubmed Central PMCID: 5035305.

      ].
      Cine MRI in treatment position is an alternative to 4DCT with the advantage of better soft tissue contrast and specific scanning protocols can be obtained from the respective MRI manufacturer. Such protocols are also of specific interest for centres providing of an MR-LINAC.
      Several motion management options exist for SBRT. A number of approaches are possible which are implemented in routine practice: In the absence of prospective comparisons, no recommendation can be made which method should be preferred.
      • -
        Continuous irradiation in free breathing using
        • o
          Internal target volume concept (ITV) based on CT scans in end breathing phases, 4D CT or cine MRI, time-averaged mid-position CT, or 4D PET/CT [
          • Buther F.
          • Ernst I.
          • Dawood M.
          • Kraxner P.
          • Schafers M.
          • Schober O.
          • et al.
          Detection of respiratory tumour motion using intrinsic list mode-driven gating in positron emission tomography.
          ,
          • Kavanagh B.D.
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          • Timmerman R.D.
          • et al.
          Interim analysis of a prospective phase I/II trial of SBRT for liver metastases.
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          • Kawahara D.
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          • Kawai S.
          • Ochi Y.
          • et al.
          Availability of using diaphragm matching in stereotactic body radiotherapy (SBRT) at the time in breath-holding SBRT for liver cancer.
          ,
          • Kruis M.F.
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          • Sonke J.J.
          • Jansen E.P.
          • van Herk M.
          Registration accuracy and image quality of time averaged mid-position CT scans for liver SBRT.
          ]
      • -
        Irradiation in specific breathing phases [

        Mancosu P, Castiglioni S, Reggiori G, Catalano M, Alongi F, Pellegrini C, et al. Stereotactic body radiation therapy for liver tumours using flattening filter free beam: dosimetric and technical considerations. Radiation oncology (London, England). 2012 Feb 1;7:16. PubMed PMID: 22296849. Pubmed Central PMCID: 3292972.

        ]
        • o
          Gating
        • o
          Active breathing coordinator (ABC system) [
          • Mendez Romero A.
          • Wunderink W.
          • Hussain S.M.
          • De Pooter J.A.
          • Heijmen B.J.
          • Nowak P.C.
          • et al.
          Stereotactic body radiation therapy for primary and metastatic liver tumors: A single institution phase i–ii study.
          ,
          • Park J.C.
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          ]
        • o
          Real-time tumour tracking

      Target volume delineation

      Summary
      Target volume definition requires adequate identification of the primary tumour (including possible infiltration of adjacent structures or organs), involved regional lymph nodes, possible regions of increased risk for subclinical disease (for example elective nodal regions) and information about tumour motion. Currently, contrast-enhanced multi-detector computed tomography (CE-MDCT) is the single most important imaging tool for target delineation. In general, any available information from pre-treatment imaging should be taken into account for target volume definition, although direct fusion of diagnostic images not taken in treatment planning position is not recommended. For respiratory motion assessment four-dimensional CT (4D-CT) is the most important imaging tool, however useful additional information can be obtained for example by ultrasound (US), cine mode MRI or 4D-PET/CT [

      Feng M, Balter JM, Normolle D, Adusumilli S, Cao Y, Chenevert TL, et al. Characterization of pancreatic tumor motion using cine MRI: surrogates for tumor position should be used with caution. Int J Radiat Oncol Biol Phys. 2009 Jul 1;74(3):884-91. PubMed PMID: 19395190. Pubmed Central PMCID: 2691867.

      ,
      • Omari E.A.
      • Erickson B.
      • Ehlers C.
      • Quiroz F.
      • Noid G.
      • Cooper D.T.
      • et al.
      Preliminary results on the feasibility of using ultrasound to monitor intrafractional motion during radiation therapy for pancreatic cancer.
      ,
      • Kishi T.
      • Matsuo Y.
      • Nakamura A.
      • Nakamoto Y.
      • Itasaka S.
      • Mizowaki T.
      • et al.
      Comparative evaluation of respiratory-gated and ungated FDG-PET for target volume definition in radiotherapy treatment planning for pancreatic cancer.
      ]. Image-guided RT needs to be planned prior to the planning CT. IGRT aspects need to be considered even more stringently for patients who are planned to be treated with SBRT. Fiducial marker implantation may be necessary if no other reliable structures for IGRT are available (e.g. surgical clips) or if the quality of the IGRT imaging method does not allow sufficient matching of the target region. This is the case for patients treated with CybeKnifeTM or when on board imaging provides insufficient soft tissue contrast

      Defining the gross tumour volume (GTV) (all indications except adjuvant)

      The GTV is delineated in the pancreatic phase planning CT. This is defined as the primary pancreatic tumour and radiologically enlarged lymph nodes (defined as short axis diameter ≥ 1 cm, or PET positive). All available diagnostic imaging should be taken into account (e.g. diagnostic CT, MRI or FDG-PET/CT). MRI is especially helpful for outlining of tumour, but also for the position of bowel structures that are typically very close to the tumour and for motion imaging [
      • Eccles C.L.
      • Patel R.
      • Simeonov A.K.
      • Lockwood G.
      • Haider M.
      • Dawson L.A.
      Comparison of liver tumor motion with and without abdominal compression using cine-magnetic resonance imaging.
      ]. If induction chemotherapy was performed prior to neoadjuvant RT, baseline imaging should also be reviewed, although GTV definition should be based on actual imaging.
      Large inter-observer variation is a recognized problem with pancreatic cancer RT [
      • Fokas E.
      • Clifford C.
      • Spezi E.
      • Joseph G.
      • Branagan J.
      • Hurt C.
      • et al.
      Comparison of investigator-delineated gross tumor volumes and quality assurance in pancreatic cancer: Analysis of the pretrial benchmark case for the SCALOP trial.
      ,

      Fokas E, Spezi E, Patel N, Hurt C, Nixon L, Chu KY, et al. Comparison of investigator-delineated gross tumour volumes and quality assurance in pancreatic cancer: Analysis of the on-trial cases for the SCALOP trial. Radiother Oncol. 2016 Aug;120(2):212-6. PubMed PMID: 27497804. Pubmed Central PMCID: 5013754.

      ]. For planning purposes it has recently been show that even the addition of MRI to CT and 4D-CT without image fusion improved GTV delineation and resulted in smaller interobserver variation and smaller GTV volumes [
      • Gurney-Champion O.J.
      • Versteijne E.
      • van der Horst A.
      • Lens E.
      • Rutten H.
      • Heerkens H.D.
      • et al.
      Addition of MRI for CT-based pancreatic tumor delineation: a feasibility study.
      ]. Practical recommendations for MRI based treatment planning have been recently published by Heerkens et al. [

      Heerkens HD, Hall WA, Li XA, Knechtges P, Dalah E, Paulson ES, et al. Recommendations for MRI-based contouring of gross tumor volume and organs at risk for radiation therapy of pancreatic cancer. Pract Radiat Oncol. 2017 Mar - Apr;7(2):126-36. PubMed PMID: 28089481.

      ]: Briefly, MRI (1.5–3.0 T, slice thickness ≤ 3 mm) should be performed on the same day as the planning CT with reproducible organ-filling, minimized differences in patient positioning and in the same respiration phase. GTV should be delineated on T1-weighted images with and without contrast-enhancement.

      Defining the internal target volume (ITV) (all indications except adjuvant)

      The internal target volume (ITV) is created from the available 4D-CT scan by contouring the tumour on multiple phases of respiration. A common practice is to outline the tumour on the 3D planning scan and on the maximum inhale and maximum exhale components of the 4D CT – the contours are fused to form the ITV. The ITV is then adjusted by running the 4D cine, to ensure that it encompasses the tumour on all phases of respiration. One of the problems of 4D-CT is that pancreatic tumours might not be visualized because of the dependence on the correct IV contrast phase. There are several solutions to this problem: the use of IV contrasted 4D CT [

      Choi W, Xue M, Lane BF, Kang MK, Patel K, Regine WF, et al. Individually optimized contrast-enhanced 4D-CT for radiotherapy simulation in pancreatic ductal adenocarcinoma. Medical physics. 2016 Oct;43(10):5659. PubMed PMID: 27782710. Pubmed Central PMCID: 5035305.

      ] may be helpful in improving image quality. In addition, if fiducial markers have been placed, the motion of fiducial markers at close proximity to the GTV can be measured and extrapolated for the expansion of the GTV to create an ITV. Alternatively, 4D-FDG-PET/CT can be employed. Cine-MR is another alternative, and can be used to obtain an ITV. Usually, the GTV or the ITV, if used, also defines the CTV without an additional margin. Typical SBRT PTV definition does not use additional CTV margins on top of the ITV. Abdominal compression can significantly reduce respiratory motion to ≤ 5 mm in all directions and thus the size of the ITV but abdominal compression does still require quantification of motion and usually employment of an ITV. Centres which perform gating or tracking do not require an ITV.

      Defining the clinical target volume (CTV)

      General considerations for CTV in primary tumours and pathological lymph nodes

      The CTV as defined originally by ICRU report 50 in 1993 is the volume where radiologically there is no visible tumour, where however there is a high likelihood of microscopic tumour spread. For pancreatic cancer primary tumours the discrepancy of CTV volumes with pathological volumes was analysed in two studies [

      Qiu H, Wild AT, Wang H, Fishman EK, Hruban RH, Laheru DA, et al. Comparison of conventional and 3-dimensional computed tomography against histopathologic examination in determining pancreatic adenocarcinoma tumor size: implications for radiation therapy planning. Radiother Oncol. 2012 Aug;104(2):167-72. PubMed PMID: 22883106. Pubmed Central PMCID: 4124599.

      ,

      Arvold ND, Niemierko A, Mamon HJ, Fernandez-del Castillo C, Hong TS. Pancreatic cancer tumor size on CT scan versus pathologic specimen: implications for radiation treatment planning. Int J Radiat Oncol Biol Phys. 2011 Aug 1;80(5):1383-90. PubMed PMID: 20708856. Epub 2010/08/17. eng.

      ]. Since these studies are of high relevance in the context of the topic of this report a closer look at the results is justified. Qiu and co-workers evaluated this discrepancy in 63 patients with preoperative CT from a 64 line MDCT with reconstruction at 0.75 mm slice thickness at 0.5-mm intervals and pathohistology. Radiologists measured maximum tumour dimension on dual phase IV contrast conventional CT (C-CT) scans and after 3D volume rendering (3D-CT). Tumours were staged T3 and located in the pancreatic head in two thirds, respectively, with a median pathologic size of 3 cm. Tumours < 3.0 cm were underestimated both, with C-CT maximum tumour diameter (MTD) and 3D-CT (median 6.5 mm, p = 0.003 and 2.0 mm, p = 0.023, respectively). This is relevant for radiotherapy in the neoadjuvant setting and for definitive therapy. On the other hand, tumours with pathologic MTD < 3.0 cm had a trend to be overestimated on C-CT by a median of 2.5 mm (p = 0.08) and on 3D-CT by 4.2 mm (p = 0.002) compared to pathology which is of interest for adjuvant radiotherapy. The influence of tumour location was also investigated. Tumours in the pancreatic head were underestimated by a median of 2.0 mm on C-CT compared to pathology (p = 0.015), while tumours located elsewhere in the gland were not. In a second study 97 patients also with predominantly pancreatic head/uncinate/neck tumours (71%) were scanned with C-CT, but not with 3D-CT [

      Arvold ND, Niemierko A, Mamon HJ, Fernandez-del Castillo C, Hong TS. Pancreatic cancer tumor size on CT scan versus pathologic specimen: implications for radiation treatment planning. Int J Radiat Oncol Biol Phys. 2011 Aug 1;80(5):1383-90. PubMed PMID: 20708856. Epub 2010/08/17. eng.

      ]. Median MTD was 25 mm on CT versus 34 mm pathologically (p < 0.0001). Tumour size was underestimated by a median of 7 mm on C-CT compared to pathology. The range of the discrepancy was −15 to +43 mm and as in the study by Qiu et al., larger tumours were less discrepant compared to smaller tumours [

      Qiu H, Wild AT, Wang H, Fishman EK, Hruban RH, Laheru DA, et al. Comparison of conventional and 3-dimensional computed tomography against histopathologic examination in determining pancreatic adenocarcinoma tumor size: implications for radiation therapy planning. Radiother Oncol. 2012 Aug;104(2):167-72. PubMed PMID: 22883106. Pubmed Central PMCID: 4124599.

      ]. Overall in 84% the tumour was larger on pathology as on C-CT. Duodenal infiltration at pathology was commonly missed on C-CT [

      Arvold ND, Niemierko A, Mamon HJ, Fernandez-del Castillo C, Hong TS. Pancreatic cancer tumor size on CT scan versus pathologic specimen: implications for radiation treatment planning. Int J Radiat Oncol Biol Phys. 2011 Aug 1;80(5):1383-90. PubMed PMID: 20708856. Epub 2010/08/17. eng.

      ].
      In summary, tumours larger than 3 cm appear to be safely treated without a designated CTV whereas for tumours <3 cm a GTV to CTV expansion should at least be considered, especially when located in the pancreatic head. Arvold et al. developed a formula to calculate an appropriate CTV margin to cover 97.5% of cases based on tumour diameter on CT [

      Arvold ND, Niemierko A, Mamon HJ, Fernandez-del Castillo C, Hong TS. Pancreatic cancer tumor size on CT scan versus pathologic specimen: implications for radiation treatment planning. Int J Radiat Oncol Biol Phys. 2011 Aug 1;80(5):1383-90. PubMed PMID: 20708856. Epub 2010/08/17. eng.

      ]. The formula is based on a single report including a low number of patients resulting in large confidence intervals. Furthermore, the authors addressed the problem of adequate orientation of the pathological specimen as a limitation of their study. Therefore the use of this formula especially for SBRT cases cannot be generally recommended. Free-breathing SBRT concepts using an ITV are often assumed to comprise already sufficient margins to be regarded as a surrogate for CTV despite of the lack of evidence for this practice [

      Shaib WL, Hawk N, Cassidy RJ, Chen Z, Zhang C, Brutcher E, et al. A Phase 1 Study of Stereotactic Body Radiation Therapy Dose Escalation for Borderline Resectable Pancreatic Cancer After Modified FOLFIRINOX (NCT01446458). Int J Radiat Oncol Biol Phys. 2016;96(2):296-303. PubMed PMID: 27475674. Epub 2016/08/01. eng.

      ]. For non-free breathing tumour volume definition we recommend to consider CTV margins that take into account the discrepancies described above. This applies to all clinical situations except for adjuvant treatment for radiotherapy of the primary tumour. Posterior margins between the pancreas and the aorta as well as vena cava inferior are not described well enough in the literature to be recommended [

      Shaib WL, Hawk N, Cassidy RJ, Chen Z, Zhang C, Brutcher E, et al. A Phase 1 Study of Stereotactic Body Radiation Therapy Dose Escalation for Borderline Resectable Pancreatic Cancer After Modified FOLFIRINOX (NCT01446458). Int J Radiat Oncol Biol Phys. 2016;96(2):296-303. PubMed PMID: 27475674. Epub 2016/08/01. eng.

      ,

      Nakamura A, Prichard HA, Wo JY, Wolfgang JA, Hong TS. Elective nodal irradiation with simultaneous integrated boost stereotactic body radiotherapy for pancreatic cancer: Analyses of planning feasibility and geometrically driven DVH prediction model. J Appl Clin Med Phys. 2019 Feb;20(2):71-83. PubMed PMID: 30636367. Pubmed Central PMCID: 6370996.

      ]. An exception might be locally recurrent cancer where the group from Johns Hopkins University systematically analysed high risk volume for recurrence [

      Dholakia AS, Kumar R, Raman SP, Moore JA, Ellsworth S, McNutt T, et al. Mapping patterns of local recurrence after pancreaticoduodenectomy for pancreatic adenocarcinoma: a new approach to adjuvant radiation field design. Int J Radiat Oncol Biol Phys. 2013 Dec 1;87(5):1007-PubMed PMID: 24267969. Pubmed Central PMCID: 3971882.

      ]. Nevertheless, this approach has not been systematically tested in clinical practice.
      Compared to primary tumours, even weaker evidence is available for the definition of a CTV for pathologic nodes (>1 cm in the short axis) from radiology to pathology comparisons. For lymphatic nodes the discrepancy between radiology and pathology is not so much size but rather between detection rates: Masuda and colleagues have described a detection rate of 31% at imaging (CT, MRI or EUS) compared to a rate of 59% of pN + after primary resection in 490 patients with PDAC [
      • Masuda T.
      • Dann A.M.
      • Elliott I.A.
      • Baba H.
      • Kim S.
      • Sedarat A.
      • et al.
      A comprehensive assessment of accurate lymph node staging and preoperative detection in resected pancreatic cancer.
      ]. Radiologically positive nodes contain also false negatives and vice versa. Additionally, Prenzel et al. showed that LN size in resected specimens is not an accurate predictor of pathologic involvement [
      • Prenzel K.L.
      • Holscher A.H.
      • Vallbohmer D.
      • Drebber U.
      • Gutschow C.A.
      • Monig S.P.
      • et al.
      Lymph node size and metastatic infiltration in adenocarcinoma of the pancreatic head.
      ]. In pancreatic cancer FDG-PET/CT was not found to increase the detection of positive nodes [
      • Kauhanen S.P.
      • Komar G.
      • Seppanen M.P.
      • Dean K.I.
      • Minn H.R.
      • Kajander S.A.
      • et al.
      A prospective diagnostic accuracy study of 18F-fluorodeoxyglucose positron emission tomography/computed tomography, multidetector row computed tomography, and magnetic resonance imaging in primary diagnosis and staging of pancreatic cancer.
      ]. In gastric cancer, Park et al. have expanded the nodal GTV by 1.5–2.5 cm in all directions, which is larger as CTV margins for the GTV of the primary tumour and therefore is not recommended [
      • Park S.H.
      • Sohn T.S.
      • Lee J.
      • Lim D.H.
      • Hong M.E.
      • Kim K.M.
      • et al.
      Phase III trial to compare adjuvant chemotherapy with capecitabine and cisplatin versus concurrent chemoradiotherapy in gastric cancer: final report of the adjuvant chemoradiotherapy in stomach tumors trial, including survival and subset analyses.
      ]. Treating nodal relapse in pancreatic cancer after resection with a 3 mm CTV resulted in 12 and 24 months local control rates of 84% and 62% in a small retrospective analysis [

      Zeng XL, Wang HH, Meng MB, Wu ZQ, Song YC, Zhuang HQ, et al. Stereotactic body radiation therapy for patients with recurrent pancreatic adenocarcinoma at the abdominal lymph nodes or postoperative stump including pancreatic stump and other stump. Onco Targets Ther. 2016;9:3985-92. PubMed PMID: 27418841. Pubmed Central PMCID: 4935106.

      ]. In summary, the use of a GTV to CTV expansion for lymph nodes cannot be generally recommended. If considered, small margins seem to be sufficient based on the limited data. Contouring guidelines for the different regions of the Japanese classification are currently developed by ESTRO and a manuscript is in preparation.

      Macroscopic tumour in Neo-adjuvant chemoradiotherapy

      In patients who underwent induction chemotherapy, creation of an additional CTV that consists in the ex-GTV prior to the start of induction chemotherapy may be considered. This approach is currently employed in a prospective trial of chemoradiotherapy (CONKO-007, EudraCT-Nr: 2009–014476-21) but to date there is no prospective evidence for this approach, i.e. both techniques with and without inclusion of the initial tumour volume are adequate.

      Elective nodal CTV

      Indication for elective nodal irradiation

      Inclusion of elective nodal volumes is a key element in adjuvant radiotherapy. However, in patients without resection there are two philosophies, one with and one without elective nodal irradiation (ENI). The philosophy without ENI has three main reasons: [
      • Brunner T.B.
      • Baum U.
      • Grabenbauer G.G.
      • Sauer R.
      • Lambrecht U.
      Large topographic variability of upper abdominal lymphatics and the consequences for radiation treatment planning.
      ] large volumes as a result of ENI have resulted in significant toxicities and consequently also led to reduced doses of chemotherapy [

      Chauffert B, Mornex F, Bonnetain F, Rougier P, Mariette C, Bouche O, et al. Phase III trial comparing intensive induction chemoradiotherapy (60 Gy, infusional 5-FU and intermittent cisplatin) followed by maintenance gemcitabine with gemcitabine alone for locally advanced unresectable pancreatic cancer. Definitive results of the 2000-01 FFCD/SFRO study. Ann Oncol. 2008 May 7. PubMed PMID: 18467316. Eng.

      ,

      Loehrer PJ, Sr., Feng Y, Cardenes H, Wagner L, Brell JM, Cella D, et al. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2011;29(31):4105-12. PubMed PMID: 21969502. Pubmed Central PMCID: Pmc3525836. Epub 2011/10/05. eng.

      ,

      Kim EJ, Ben-Josef E, Herman JM, Bekaii-Saab T, Dawson LA, Griffith KA, et al. A multi-institutional phase 2 study of neoadjuvant gemcitabine and oxaliplatin with radiation therapy in patients with pancreatic cancer. Cancer. 2013;119(15):2692-700. PubMed PMID: 23720019. Pubmed Central PMCID: Pmc4174603. Epub 2013/05/31. eng.

      ]. (2) the use of higher doses of radiotherapy (>EQD210 50 Gy) was shown to be safe in studies restricting volumes to GTV and margins [

      Ben-Josef E, Schipper M, Francis IR, Hadley S, Ten-Haken R, Lawrence T, et al. A phase I/II trial of intensity modulated radiation (IMRT) dose escalation with concurrent fixed-dose rate gemcitabine (FDR-G) in patients with unresectable pancreatic cancer. Int J Radiat Oncol Biol Phys. 2012;84(5):1166-71. PubMed PMID: 22543215. Pubmed Central PMCID: Pmc3421048. Epub 2012/05/01. eng.

      ,

      Crane CH, Varadhachary GR, Yordy JS, Staerkel GA, Javle MM, Safran H, et al. Phase II trial of cetuximab, gemcitabine, and oxaliplatin followed by chemoradiation with cetuximab for locally advanced (T4) pancreatic adenocarcinoma: correlation of Smad4(Dpc4) immunostaining with pattern of disease progression. J Clin Oncol. 2011 Aug 1;29(22):3037-43. PubMed PMID: 21709185. Pubmed Central PMCID: 3157965. Epub 2011/06/29. eng.

      ]. (3) Recurrences at lymph nodes are rare according to the available evidence [

      Ben-Josef E, Schipper M, Francis IR, Hadley S, Ten-Haken R, Lawrence T, et al. A phase I/II trial of intensity modulated radiation (IMRT) dose escalation with concurrent fixed-dose rate gemcitabine (FDR-G) in patients with unresectable pancreatic cancer. Int J Radiat Oncol Biol Phys. 2012;84(5):1166-71. PubMed PMID: 22543215. Pubmed Central PMCID: Pmc3421048. Epub 2012/05/01. eng.

      ,

      McGinn CJ, Zalupski MM. Radiation therapy with once-weekly gemcitabine in pancreatic cancer: current status of clinical trials. Int J Radiat Oncol Biol Phys. 2003;56(4 Suppl):10-5. PubMed PMID: 12826246. Epub 2003/06/27. eng.

      ]. Based on these reasons ENI is not recommended in patients receiving CRT or SBRT for LAPC.
      Neoadjuvant radiotherapy in its proper sense is restricted to patients with resectable pancreatic cancer and with BRPC and does exclude patients with LAPC. In this situation a part of the chemoradiotherapy studies of the last decade define the target volume as the GTV with margins (CONKO-007; EUDRACT 2009–014476-21). Other studies of the same era define specific nodal areas for inclusion into ENI [

      Golcher H, Brunner TB, Witzigmann H, Marti L, Bechstein WO, Bruns C, et al. Neoadjuvant chemoradiation therapy with gemcitabine/cisplatin and surgery versus immediate surgery in resectable pancreatic cancer: results of the first prospective randomized phase II trial. Strahlenther Onkol. 2015 Jan;191(1):7-16. PubMed PMID: 25252602. Pubmed Central PMCID: 4289008.

      ,

      Roeder F, Timke C, Saleh-Ebrahimi L, Schneider L, Hackert T, Hartwig W, et al. Clinical phase I/II trial to investigate neoadjuvant intensity-modulated short term radiation therapy (5 x 5 Gy) and intraoperative radiation therapy (15 Gy) in patients with primarily resectable pancreatic cancer - NEOPANC. BMC Cancer. 2012 Mar 23;12:112. PubMed PMID: 22443802. Pubmed Central PMCID: 3323416.

      ,

      Versteijne E, Suker M, Groothuis K, Akkermans-Vogelaar JM, Besselink MG, Bonsing BA, et al. Preoperative Chemoradiotherapy Versus Immediate Surgery for Resectable and Borderline Resectable Pancreatic Cancer: Results of the Dutch Randomized Phase III PREOPANC Trial. J Clin Oncol. 2020 Feb 27:JCO1902274. PubMed PMID: 32105518.

      ]. The rationale for ENI in this situation is similar to that in adjuvant CRT (see below). For patients with BRPC, i.e. with tumour contact to regional major arteries (CT, SMA), the recommendation of ENI is weak, whereas for patients with resectable tumours it is moderate. Vascularly defined nodal regions that are typically contained comprise the celiac trunk, the superior mesenteric artery, hepatic artery, superior mesenteric vein and portal vein [
      • Brunner T.B.
      • Merkel S.
      • Grabenbauer G.G.
      • Meyer T.
      • Baum U.
      • Papadopoulos T.
      • et al.
      Definition of elective lymphatic target volume in ductal carcinoma of the pancreatic head based upon histopathologic analysis.
      ,

      Sun W, Leong CN, Zhang Z, Lu JJ. Proposing the lymphatic target volume for elective radiation therapy for pancreatic cancer: a pooled analysis of clinical evidence. Radiation oncology (London, England). 2010;5:28. PubMed PMID: 20398316. Pubmed Central PMCID: 2859771. Epub 2010/04/20. eng.

      ,

      Dholakia AS, Kumar R, Raman SP, Moore JA, Ellsworth S, McNutt T, et al. Mapping patterns of local recurrence after pancreaticoduodenectomy for pancreatic adenocarcinoma: a new approach to adjuvant radiation field design. Int J Radiat Oncol Biol Phys. 2013 Dec 1;87(5):1007-PubMed PMID: 24267969. Pubmed Central PMCID: 3971882.

      ]. If ENI is used for target volume definition then this is recommended to be done in analogy with postoperative ENI definitions as discussed below [

      Golcher H, Brunner TB, Witzigmann H, Marti L, Bechstein WO, Bruns C, et al. Neoadjuvant chemoradiation therapy with gemcitabine/cisplatin and surgery versus immediate surgery in resectable pancreatic cancer: results of the first prospective randomized phase II trial. Strahlenther Onkol. 2015 Jan;191(1):7-16. PubMed PMID: 25252602. Pubmed Central PMCID: 4289008.

      ,

      Versteijne E, Suker M, Groothuis K, Akkermans-Vogelaar JM, Besselink MG, Bonsing BA, et al. Preoperative Chemoradiotherapy Versus Immediate Surgery for Resectable and Borderline Resectable Pancreatic Cancer: Results of the Dutch Randomized Phase III PREOPANC Trial. J Clin Oncol. 2020 Feb 27:JCO1902274. PubMed PMID: 32105518.

      ,

      Goodman KA, Regine WF, Dawson LA, Ben-Josef E, Haustermans K, Bosch WR, et al. Radiation Therapy Oncology Group consensus panel guidelines for the delineation of the clinical target volume in the postoperative treatment of pancreatic head cancer. Int J Radiat Oncol Biol Phys. 2012 Jul 1;83(3):901-8. PubMed PMID: 22483737. Epub 2012/04/10. eng.

      ].
      Due to the higher probability of local control at the primary tumour after resection, the value of regional control gains of importance in the neoadjuvant context similar to adjuvant treatment. There is also a circumscribed high frequency of local relapses after resection in defined lymphatic regions as mapped in a recent analysis in proximity to the celiac trunk and the superior mesenteric artery [

      Dholakia AS, Kumar R, Raman SP, Moore JA, Ellsworth S, McNutt T, et al. Mapping patterns of local recurrence after pancreaticoduodenectomy for pancreatic adenocarcinoma: a new approach to adjuvant radiation field design. Int J Radiat Oncol Biol Phys. 2013 Dec 1;87(5):1007-PubMed PMID: 24267969. Pubmed Central PMCID: 3971882.

      ]. Importantly, these sites of frequent relapse match well with the dorsal regions where the degree of radicality of the lymphatic dissection is limited to avoid postoperative morbidity.

      Selection of elective nodal areas and definition of the CTV

      If elective nodal volume is treated, based on patterns of nodal involvement (see above), we recommend inclusion of the following nodal regions:
      For pancreatic head tumours: common hepatic nodes, the celiac nodes, the hepatoduodenal nodes, the anterior and posterior pancreaticoduodenal nodes, the superior mesenteric nodes, the paraaortic nodes from the celiac trunk to the lower border of the left renal vein (JPS 16a2) and the superior and inferior head nodes. The respective numbers of the Japanese classification are given in Table 1.
      Body and tail tumours: common hepatic nodes, the celiac nodes, the hepatoduodenal nodes, the superior mesenteric nodes, the paraaortic nodes (JPS 16a2), the subpancreatic nodes and the splenic artery
      Generally, for contouring of elective volumes, the practical approach is to contour first the respective vessel defining the nodal area to be treated. Next, the vessel is expanded isotropically by defined value as described by several authors who have provided guidance regarding elective nodal definition in the abdomen: Kalbasi and Ben-Josef and Brunner et al., which was used in two prospective randomized neoadjuvant trials [
      • Brunner T.B.
      • Merkel S.
      • Grabenbauer G.G.
      • Meyer T.
      • Baum U.
      • Papadopoulos T.
      • et al.
      Definition of elective lymphatic target volume in ductal carcinoma of the pancreatic head based upon histopathologic analysis.
      ,
      • Kalbasi A.
      • Ben-Josef E.
      Biliary cancer: radiation therapy planning.
      ] (ISRCTN78805636 - NCT00335543; EudraCT Number 2012–003669-17). Based on the recurrence pattern after surgery (see above), independently of the primary tumour location the region around the CA/SMA should be included according to Dholakia et al. with a 2–3 cm margin right-laterally and a 1–2 cm margin in all other directions [

      Dholakia AS, Kumar R, Raman SP, Moore JA, Ellsworth S, McNutt T, et al. Mapping patterns of local recurrence after pancreaticoduodenectomy for pancreatic adenocarcinoma: a new approach to adjuvant radiation field design. Int J Radiat Oncol Biol Phys. 2013 Dec 1;87(5):1007-PubMed PMID: 24267969. Pubmed Central PMCID: 3971882.

      ]. Special attention should be paid to cover the region between CA/SMA (medially), PV (anteriorly) and ICV (laterally). Delineation of the major vessels (especially most proximal 1–2 cm of celiac trunk, most proximal 2–3 cm of the SMA, portal vein from confluence to bifurcation, the aorta from celiac trunk to renal artery) is recommended. As mentioned above a manuscript on the subject of the different regions of the Japanese classification is in preparation by ESTRO.

      Locally advanced pancreatic cancer:

      In locally advanced pancreatic cancer ENI is not recommended. Yamazaki et al. have not identified any regional lymph node failure with full dose gemcitabine with limited field RT [

      Yamazaki H, Nishiyama K, Koizumi M, Tanaka E, Ioka T, Uehara H, et al. Concurrent chemoradiotherapy for advanced pancreatic cancer: 1,000 mg/m2 gemcitabine can be administered using limited-field radiotherapy. Strahlenther Onkol. 2007 Jun;183(6):301-6. PubMed PMID: 17520183. eng.

      ]. Moreover, CRT is commonly delivered after a course of induction chemotherapy, often FOLFIRINOX or gemcitabine doublets, which may be adequate in controlling micrometastatic disease in regional nodes. Recent trials of long-course CRT in the definitive setting have omitted ENI [

      Mukherjee S, Hurt CN, Bridgewater J, Falk S, Cummins S, Wasan H, et al. Gemcitabine-based or capecitabine-based chemoradiotherapy for locally advanced pancreatic cancer (SCALOP): a multicentre, randomised, phase 2 trial. Lancet Oncol. 2013 Mar 5. PubMed PMID: 234743Epub 2013/03/12. Eng.

      ,
      • Hammel P.
      • Huguet F.
      • van Laethem J.L.
      • Goldstein D.
      • Glimelius B.
      • Artru P.
      • et al.
      Effect of chemoradiotherapy vs chemotherapy on survival in patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine with or without erlotinib: The LAP07 randomized clinical trial.
      ].
      For patients receiving SBRT, additional expansion of the ITV is not usually applied to take CTV into account. In the case of a pathological lymph node, several subgroups also do not use an expansion of the GTV to create a CTV.

      Adjuvant chemoradiotherapy:

      Contouring of the target volume starts with the creation of the regions of interest as given in Table 2a [

      Goodman KA, Regine WF, Dawson LA, Ben-Josef E, Haustermans K, Bosch WR, et al. Radiation Therapy Oncology Group consensus panel guidelines for the delineation of the clinical target volume in the postoperative treatment of pancreatic head cancer. Int J Radiat Oncol Biol Phys. 2012 Jul 1;83(3):901-8. PubMed PMID: 22483737. Epub 2012/04/10. eng.

      ]. To create the overall CTV, merge all the sub volumes of Table 2b and add this volume to exclude overlaps with normal organs. For creation of the PTV proceed as described below.
      Table 2aRegions of interest for adjuvant chemoradiotherapy (RTOG consensus).
      Region of interest (ROI)DefinitionComments
      Preoperative tumor volume
      • -
        include surgical clips for close margins
      • -
        contour preoperative GTV after image fusion
      -discuss significance of clips with surgeon
      Celiac arteryProximal 10–15 mm up to 1st branchingnone
      Superior mesenteric arteryProximal 25–30 mmnone
      Portal veinFrom confluent to hilar bifurcationnone
      PancreaticojejunostomyTo the right from pancreatic remnant to junction with jejunum.Do not include a pancreatogastrostomy
      AortaCraniocaudal: from uppermost contour of all other structures to the bottom of vertebra L2*none
      Table 2bThe above defined ROIs will then be expanded to create clinical target volumes (CTVs).
      ROIIsotropicalRight - leftVentral - dorsalCranial – caudal
      Preoperative tumor volume5–10 mmn.a.n.a.n.a.
      Celiac artery10(−15)mmn.a.n.a.n.a.
      Superior mesenteric artery10(−15)mmn.a.n.a.n.a.
      Portal vein10(−15)mmn.a.n.a.n.a.
      Pancreaticojejunostomy5–10 mmn.a.n.a.n.a.
      Aortan.a.Rt: 25–30 mm

      Lt: 10 mm
      Ant.: 20–25 mm

      Post: 2 mm
      Top contour of all others

      Bottom of vertebra L2
      Abbreviations: Ant. = anterior; Lt = left; n.a. = not applicable; Post. = posterior; Rt = right.

      Defining the planning target volume (PTV)

      The PTV is the required margin to compensate for set-up errors and therefore it is dependent on the consistency of the positioning. Each unit of radiotherapy has to quantify their set-up errors for the upper abdomen as a function of the used positioning method.

      Neo-adjuvant chemoradiotherapy

      The ITV of the primary tumour is isotropically expanded to define the PTV of the primary tumour according to the setup inaccuracy measured by the respective institute (usually 5–10 mm). If no 4D-CT and no gating/tracking is used, an expansion of at least 2 cm in the superior-inferior direction and 1.5 cm in all other directions seems advisable [

      Mukherjee S, Hurt CN, Bridgewater J, Falk S, Cummins S, Wasan H, et al. Gemcitabine-based or capecitabine-based chemoradiotherapy for locally advanced pancreatic cancer (SCALOP): a multicentre, randomised, phase 2 trial. Lancet Oncol. 2013 Mar 5. PubMed PMID: 234743Epub 2013/03/12. Eng.

      ].

      Locally advanced pancreatic cancer (LAPC) and recurrent tumours

      A PTV including the ITV with a 5–10 mm circumferential margin is recommended when 4D-CT is available. In the absence of 4D-CT, it is recommended that the PTV includes the GTV with a 1.5 cm margin in the anterior, posterior, and lateral directions and at least 2 cm margin in the cranial and caudal directions. However, 4D-CT is highly recommended to avoid gastrointestinal toxicity by restricting the volume.
      SBRT: All ITV are further expanded by institutionally measured dimensions to obtain the PTV, usually 0–5 mm [

      Herman JM, Chang DT, Goodman KA, Dholakia AS, Raman SP, Hacker-Prietz A, et al. Phase 2 multi-institutional trial evaluating gemcitabine and stereotactic body radiotherapy for patients with locally advanced unresectable pancreatic adenocarcinoma. Cancer. 2015;121(7):1128-37. PubMed PMID: 25538019. Pubmed Central PMCID: Pmc4368473. Epub 2014/12/30. eng.

      ,
      • Pollom E.L.
      • Alagappan M.
      • von Eyben R.
      • Kunz P.L.
      • Fisher G.A.
      • Ford J.A.
      • et al.
      Single- versus multifraction stereotactic body radiation therapy for pancreatic adenocarcinoma: outcomes and toxicity.
      ,

      Gurka MK, Collins SP, Slack R, Tse G, Charabaty A, Ley L, et al. Stereotactic body radiation therapy with concurrent full-dose gemcitabine for locally advanced pancreatic cancer: a pilot trial demonstrating safety. Radiat Oncol. 2013;8:44. PubMed PMID: 23452509. Pubmed Central PMCID: Pmc3607991. Epub 2013/03/05. eng.

      ].

      Adjuvant Chemoradiotherapy:

      Summary of ITV, CTV, PTV expansion in Neo-adjuvant CRT, CRT for LAPC, SBRT
      A summary of the target volume expansions is given in Table 3.
      Table 3Target volume expansions for adjuvant chemoradiotherapy.
      Neo-adjuvant CRTCRT for LAPC/recurrentSBRT
      exGTV (primary CTV)Tumour volume

      Consider CTV margin based on size and location
      Tumour volume

      Consider CTV margin based on size and location
      Tumour volume
      ITVTumour volume (or primary CTV) encompassed in all phases of respirationTumour volume (or primary CTV) encompassed in all phases of respirationTumour volume encompassed in all phases of respiration
      Elective nodal CTVOptional, if used:

      Head: (see above)

      common hepatic nodes, the celiac nodes, the hepatoduodenal nodes, the anterior and posterior pancreaticoduodenal nodes, the superior mesenteric nodes, the paraaortic nodes and the superior and inferior head nodes

      Body and tail:

      common hepatic nodes, the celiac nodes, the hepatoduodenal nodes, the superior mesenteric nodes, the paraaortic nodes, the subpancreatic nodes and the splenic artery
      No elective nodal CTVNo elective nodal CTV.
      PTV4D available:

      ITV + 0.5–1 cm

      4D not available:

      GTV (or primary CTV) and elective nodal CTV (if used) + 1.5 cm (A-P, L); ≥2cm (CC)
      4D available:

      ITV + 0.5–1 cm

      4D not available:

      GTV (or primary CTV) + 1.5 cm (A-P, L); ≥2 cm (CC)
      ITV + 0–5 mm

      Defining the organs at risk (OAR) (all indications)

      The following risk structures (OAR) should be delineated: stomach, duodenum, small bowel, spinal cord, left and right kidney separately as well as liver. Delineation of the OAR is recommended to follow the guidelines of Jabbour et al. and Goodman et al. [

      Goodman KA, Regine WF, Dawson LA, Ben-Josef E, Haustermans K, Bosch WR, et al. Radiation Therapy Oncology Group consensus panel guidelines for the delineation of the clinical target volume in the postoperative treatment of pancreatic head cancer. Int J Radiat Oncol Biol Phys. 2012 Jul 1;83(3):901-8. PubMed PMID: 22483737. Epub 2012/04/10. eng.

      ,

      Jabbour SK, Hashem SA, Bosch W, Kim TK, Finkelstein SE, Anderson BM, et al. Upper abdominal normal organ contouring guidelines and atlas: a Radiation Therapy Oncology Group consensus. Pract Radiat Oncol. 2014 Mar-Apr;4(2):82-9. PubMed PMID: 24890348. Pubmed Central PMCID: 4285338.

      ]. When 4D-CT is available, stomach and duodenum internal risk volumes (IRV) near the PTV may be delineated in analogy to the ITV of the tumour , however this not standard [
      • Kataria T.
      • Bisht S.S.
      • Gupta D.
      • Abhishek A.
      • Basu T.
      • Narang K.
      • et al.
      Quantification of coronary artery motion and internal risk volume from ECG gated radiotherapy planning scans.
      ]. Where MRI is available, GI tract is best seen on T2-weighted images but can be contoured also in T1 for registration purposes.
      Special consideration for SBRT: For SBRT the dose constraints of the stomach, duodenum and jejunum are particularly critical. It is recommended to contour the stomach and the duodenum completely whereas all other parts of the bowel should be contoured at least at the level of the PTV. Bowel volume changes due to peristalsis cannot be accurately predicted but they should be taken into account at a later step during plan analysis. Several approaches to protect bowel structures are used. One of them is to decrease the PTV at the interface of the PTV with bowel PTVs individually, and another one is to create quantifiable overlap regions between OARs and the PTV that are protected by a simultaneous integrated boost (SIP) [

      Brunner TB, Nestle U, Adebahr S, Gkika E, Wiehle R, Baltas D, et al. Simultaneous integrated protection : A new concept for high-precision radiation therapy. Strahlenther Onkol. 2016 Dec;192(12):886-94. PubMed PMID: 27757502. Pubmed Central PMCID: 5122615.

      ]. None of these techniques has prospective evidence but a prospective trial for the SIP approach is recruiting (DRKS00015816).

      Radiotherapy technique

      Intensity modulated RT (fixed fields or rotational = VMAT) is strongly recommended for chemo-radiotherapy. Even if 3D conformal RT is considered for CRT, it must be recognized that IMRT is better sparing of OARs [
      • Bittner M.I.
      • Grosu A.L.
      • Brunner T.B.
      Comparison of toxicity after IMRT and 3D-conformal radiotherapy for patients with pancreatic cancer - a systematic review.
      ,

      Lee KJ, Yoon HI, Chung MJ, Park JY, Bang S, Park SW, et al. A Comparison of Gastrointestinal Toxicities between Intensity-Modulated Radiotherapy and Three-Dimensional Conformal Radiotherapy for Pancreatic Cancer. Gut and liver. 2016 Mar;10(2):303-9. PubMed PMID: 26470767. Pubmed Central PMCID: 4780462.

      ,
      • Sujenthiran A.
      • Nossiter J.
      • Parry M.
      • Charman S.C.
      • Cathcart P.J.
      • van der Meulen J.
      • et al.
      Treatment-related toxicity in men who received Intensity-modulated versus 3D-conformal radiotherapy after radical prostatectomy: A national population-based study.
      ].

      Dose fractionation, dose constraints

      Long course CRT

      Long-course CRT is delivered in conventional fractionation or moderately hypofractionated with daily doses of 1.8 to 3.0 Gy. Duration of treatment is three to six weeks to total doses of 30–55 Gy [
      • Brunner T.B.
      • Seufferlein T.
      Pancreatic cancer chemoradiotherapy.
      ]. Dose prescription is mandatory to follow the ICRU report 83. Most common schemes are 25–30 fractions x1.8 Gy [

      Mukherjee S, Hurt CN, Bridgewater J, Falk S, Cummins S, Wasan H, et al. Gemcitabine-based or capecitabine-based chemoradiotherapy for locally advanced pancreatic cancer (SCALOP): a multicentre, randomised, phase 2 trial. Lancet Oncol. 2013 Mar 5. PubMed PMID: 234743Epub 2013/03/12. Eng.

      ,
      • Hammel P.
      • Huguet F.
      • van Laethem J.L.
      • Goldstein D.
      • Glimelius B.
      • Artru P.
      • et al.
      Effect of chemoradiotherapy vs chemotherapy on survival in patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine with or without erlotinib: The LAP07 randomized clinical trial.
      ] or 10-12x3 Gy [

      Roeder F. Neoadjuvant radiotherapeutic strategies in pancreatic cancer. World journal of gastrointestinal oncology. 2016 Feb 15;8(2):186-97. PubMed PMID: 26909133. Pubmed Central PMCID: 4753169.

      ].
      Concurrent chemotherapy consists either in oral capecitabine, continuous infusional 5-fluorouracil or weekly gemcitabine. Capecitabine is the preferred radiosensitizer based on a single prospective trial which demonstrated superiority of capecitabine over gemcitabine [

      Mukherjee S, Hurt CN, Bridgewater J, Falk S, Cummins S, Wasan H, et al. Gemcitabine-based or capecitabine-based chemoradiotherapy for locally advanced pancreatic cancer (SCALOP): a multicentre, randomised, phase 2 trial. Lancet Oncol. 2013 Mar 5. PubMed PMID: 234743Epub 2013/03/12. Eng.

      ]. All patients should be treated with proton pump inhibitors (PPI) during treatment and at least for 3 months thereafter.
      Table 4a gives an overview of dose constraints for organs at risk (conventional fractionation).
      Table 4aDose constraints for long course chemoradiotherapy (for 1.8–2 Gy/fraction). Adapted from the NCCN Clinical Practice Guidelines. *adapted from RTOG 0936 and RTOG 1102. **adapted from RTOG 0848.
      Organ at riskConstraint
      DuodenumDmax ≤ 55 Gy

      Circumferential* dose ≤ 50 Gy

      V50 ≤ 10 cc (optimal)V50 ≤ 10%, V45 ≤ 15%
      StomachDmax ≤ 55 Gy

      V45 ≤ 75 cc (optimal)

      V50 ≤ 10%, V45 ≤ 15%
      Small bowelDmax ≤ 55 Gy

      V50 ≤ 10 cc (optimal)

      V15 ≤ 120 ccm (optimal)

      V50 ≤ 10%, V45 ≤ 15%
      LiverDmean ≤ 25 Gy
      Kidney (summed right and left)Dmean ≤ 18 Gy

      V20 ≤ 32%
      Spinal cordD0.1 cc ≤ 45 Gy
      *Circumferential dose means that the dose not only at the adjacent side of the hollow organ wall next to the PTV but also at the opposite aspect of the wall, i.e. the dose is applied to the entire circumference of a segment of the hollow organ. Adapted from QUANTEC, RTOG 0848, SCALOP-2, NCCN

      SBRT

      The majority of experienced centres use a minimum of five fractions, being the typical fraction number in North America, whereas in Europe up to 12 fractions are used [

      Guckenberger M, Baus WW, Blanck O, Combs SE, Debus J, Engenhart-Cabillic R, et al. Definition and quality requirements for stereotactic radiotherapy: consensus statement from the DEGRO/DGMP Working Group Stereotactic Radiotherapy and Radiosurgery. Strahlenther Onkol. 2020 May;196(5):417-20. PubMed PMID: 32211940. Pubmed Central PMCID: 7182610.

      ] as a risk adapted fractionation strategy, i.e. the closer of the PTV is to stomach or duodenum, the higher is the number of fractions. The dose prescription should follow the ICRU 91 for SBRT prescription principles [
      • Seuntjens J.
      • Lartigau E.F.
      • Cora S.
      ICRU REPORT 91: Prescribing, Recording, and Reporting of Stereotactic Treatments with Small Photon Beams.
      ].
      Dose limiting OARs are first of all duodenum and stomach and SBRT has been reported to lead to high grade late complications in these organs. There is still some uncertainty about the dose constraints of these organs, however, a number of recent publications have provided more information. Other organs at risk are liver, kidney, spinal cord and colon. The current knowledge on SBRT constraints was recently summarized by Hanna et al. in a UK Consensus article [
      • Hanna G.G.
      • Murray L.
      • Patel R.
      • Jain S.
      • Aitken K.L.
      • Franks K.N.
      • et al.
      UK consensus on normal tissue dose constraints for stereotactic radiotherapy.
      ]. Table 4b shows an overview of important constraints for 3 and 5 fractions for the mentioned organs at risk based on this publication. To reduce the risk of severe side effects to duodenum and stomach, prophylactic gastric acid reduction with PPI at therapeutic doses is recommended. Although there is no available evidence, many centres prescribe PPIs, such as pantoprazole at 2 × 40 mg per day for the first three months during SBRT and for the following 3 months with a subsequent dose reduction to 1 × 40 mg for a further 3–6 months depending on the dose to the stomach or duodenum and on patient history. Patients with a positive history of gastric or duodenal ulcer have a higher risk of toxicities and dose constraints may have to be individually adapted.
      Table 4bDose constraints according to the UK recommendations
      • Hanna G.G.
      • Murray L.
      • Patel R.
      • Jain S.
      • Aitken K.L.
      • Franks K.N.
      • et al.
      UK consensus on normal tissue dose constraints for stereotactic radiotherapy.
      for stereotactic body radiotherapy using 3-or 5 fraction regimens.
      DescriptionConstraint3 fractions5 fractions
      OptimalMandatoryOptimalMandatory
      DuodenumDMax (0.5 cc)<22.2 Gy<35 Gy
      D1 cc<33 Gy
      D5 cc<16.5 Gy<25 Gy
      D9 cc<15 Gy
      D10 cc<11.4 Gy<25 Gy
      StomachDMax (0.5 cc)<22.2 Gy<33 Gy<35 Gy
      D5 cc<25 Gy
      D10 cc<16.5 Gy<25 Gy
      D50 cc<12 Gy
      Small bowelDMax (0.5 cc)<25.2 Gy<30 Gy<35 Gy
      D5 cc<17.7 Gy<25 Gy
      D10 cc<25 Gy
      Large bowelDMax (0.5 cc)<28.2 Gy<32 Gy
      LiverV10 Gy<70%
      mean dose<13 Gy<15.2 Gy
      D50%<15 Gy
      Dose to ≥ 700 ml<15 Gy<19.2 Gy
      Common bile ductDMax (0.5 cc)<50 Gy<50 Gy
      Kidneys (individualMean dose<10 Gy
      and combined)Dose to ≥ 200 cc<16 Gy
      Kidney (solitary)V10 Gy<10%<45%
      Great vesselsDmax (0.5 cc)<45 Gy<53 Gy
      Dmax is the near point maximum dose, defined as D0.5 cc, which is the minimum dose to the 0.5 cc volume of the organ receiving the highest doses; D1 cc, D5 cc, D9 cc, D10 cc, D50 cc are the minimum doses to the specified volume of the organ that receive the highest doses; V10 Gy is the percentage volume of the organ receiving a dose of 10 Gy or higher; dose to ≥ 700 cc and ≥ 200 cc is the maximum dose to the specified volume of the organ that receives the lowest doses (adapted from Hanna GG et al. Clin Oncol 2018
      • Hanna G.G.
      • Murray L.
      • Patel R.
      • Jain S.
      • Aitken K.L.
      • Franks K.N.
      • et al.
      UK consensus on normal tissue dose constraints for stereotactic radiotherapy.
      .

      Treatment and IGRT

      Daily pre-treatment volumetric IGRT with cone-beam technology is considered mandatory. Implanted markers are helpful to facilitate IGRT. Reproduce the fasting and oral contrast procedure as undertaken at planning. Daily oral pre-treatment contrast with a defined small volume and after at least two hours of fasting were described as techniques to increase consistency in stomach and bowel filling [

      Holyoake DL, Ward E, Grose D, McIntosh D, Sebag-Montefiore D, Radhakrishna G, et al. A phase-I trial of pre-operative, margin intensive, stereotactic body radiation therapy for pancreatic cancer: the 'SPARC' trial protocol. BMC Cancer. 2016 Sep 13;16(1):728. PubMed PMID: 27619800. Pubmed Central PMCID: 5020462.

      ,

      Gkika E, Adebahr S, Kirste S, Schimek-Jasch T, Wiehle R, Claus R, et al. Stereotactic body radiotherapy (SBRT) in recurrent or oligometastatic pancreatic cancer : A toxicity review of simultaneous integrated protection (SIP) versus conventional SBRT. Strahlenther Onkol. 2017 Jun;193(6):433-43. PubMed PMID: 28138949.

      ]. Intra-fraction patient or tumour position monitoring is not routinely required. However, if the treatment time is >15 min or non-coplanar fields are used there needs to be further imaging for SBRT.
      Quality assurance (QA) is a necessary component of pancreatic SBRT. This comprises mechanical accuracy and dosimetric accuracy of median 3% at isocentre (2–5%) in a phantom in the treatment field. Further mandatory QA measures comprise dedicated small field dosimetry detectors for commissioning, end-to-end testing in a phantom, QA of in-room IGRT systems and of the 4D-CT scanner. QA of the mechanical accuracy of the delivery system should be performed in minimum weekly intervals and quality checks of alignment of the IGRT system with the MV treatment beam should be performed daily or at least weekly. If VMAT planning is used, quality assurance must be measured individually for each patient.

      Follow-up

      All patients should be followed-up regularly. Since many patients will have subsequent treatment, follow-up ideally is organised in an interdisciplinary structure integrating clinical follow-up, laboratory and imaging measures. Special aspects include gastrointestinal late effects and re-evaluation of secondary resection in borderline resectable and LAPC patients. Since response at imaging is often underestimated due to scar tissue which cannot reliably be distinguished from tumour, multidisciplinary boards should consider surgical exploration to answer the question of resectability provided that complete re-staging shows no signs of distant metastasis and that the general condition of the patient is good. An analysis of the interval between CRT and resection in relation to pathologic response showed that patients with an interval of ≥11 weeks compared to a shorter interval were significantly more likely to experience a major response [
      • Chen K.T.
      • Devarajan K.
      • Milestone B.N.
      • Cooper H.S.
      • Denlinger C.
      • Cohen S.J.
      • et al.
      Neoadjuvant chemoradiation and duration of chemotherapy before surgical resection for pancreatic cancer: does time interval between radiotherapy and surgery matter?.
      ]. We therefore recommend reconsidering resection also after intervals of ≥3 months with the consideration of further systemic therapy after completion of radiotherapy. Re-staging may be performed as early as 5–6 weeks after completion of therapy [

      Golcher H, Brunner TB, Witzigmann H, Marti L, Bechstein WO, Bruns C, et al. Neoadjuvant chemoradiation therapy with gemcitabine/cisplatin and surgery versus immediate surgery in resectable pancreatic cancer: results of the first prospective randomized phase II trial. Strahlenther Onkol. 2015 Jan;191(1):7-16. PubMed PMID: 25252602. Pubmed Central PMCID: 4289008.

      ,

      Versteijne E, Suker M, Groothuis K, Akkermans-Vogelaar JM, Besselink MG, Bonsing BA, et al. Preoperative Chemoradiotherapy Versus Immediate Surgery for Resectable and Borderline Resectable Pancreatic Cancer: Results of the Dutch Randomized Phase III PREOPANC Trial. J Clin Oncol. 2020 Feb 27:JCO1902274. PubMed PMID: 32105518.

      ]. Lastly we would like to recommend including patients with pancreatic cancer that receive radiotherapy in clinical trials.

      Declaration of Competing Interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Acknowledgements

      MAH is supported by funding from the NIHR Biomedical Research Centre at University College.
      London Hospitals NHS Foundation Trust .

      Appendix A. Supplementary data

      The following are the Supplementary data to this article:
      The following are the Supplementary data to this article:

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