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Published in final edited form as: Pract Radiat Oncol. 2022 Jun 17;12(6):e463–e473. doi: 10.1016/j.prro.2022.06.004

Patterns of Recurrence After Primary Local Therapy for Pancreatic Ductal Adenocarcinoma − A Critical Review of Rationale and Target Delineation for (Neo)Adjuvant Radiation Therapy

Krishan R Jethwa a,*, Shane S Neibart b, Mark J Truty c, Salma K Jabbour b, Christopher L Hallemeier a
PMCID: PMC10905628  NIHMSID: NIHMS1954036  PMID: 35718073

Abstract

Purpose:

The purpose of this work was to describe pancreatic ductal adenocarcinoma (PDAC) patterns of locoregional spread and recurrence to help guide clinicians on (neo)adjuvant radiation therapy (RT) planning strategies and target volume delineation.

Methods and Materials:

A comprehensive review of clinical data was performed to describe PDAC patterns of locoregional spread, including extrapancreatic tumor extension, perineural invasion, regional lymph node involvement, and patterns of disease recurrence as influenced by (neo)adjuvant treatment strategy.

Results:

This review describes PDAC patterns of spread, disease progression, and evolving treatment techniques. Based upon this data, we advocate for inclusion of elective at-risk regions of extrapancreatic extension, perineural invasion, and lymphatic spread for patients receiving neoadjuvant RT.

Conclusions:

This review provides a nuanced description of PDAC patterns of spread and recurrence to guide clinicians on target volume delineation and planning strategies to maximize the effectiveness of neo(adjuvant) RT delivery for patients with PDAC. Further prospective studies are needed to better define the optimal RT dose, fractionation regimens, and target volumes to be used in the (neo)adjuvant setting.

Introduction

As part of the multidisciplinary management of patients with localized pancreatic ductal adenocarcinoma (PDAC), radiation therapy (RT) serves as a (neo)adjuvant treatment strategy for those with resectable or borderline resectable disease, or as definitive therapy for those with locally advanced pancreas cancer. However, considerable debate exists regarding optimal RT technique, target volumes, dose, and fractionation.

The purpose of this review is to discuss the patterns of PDAC spread, pattern of disease progression after initial therapy, the role of RT in the peri-operative treatment setting, and to provide guidance for clinicians on target volume delineation and treatment planning to improve the quality and effectiveness of RT delivery for patients with PDAC.

Mechanisms of locoregional spread

PDAC exhibits propensity for early and extensive locoregional spread (Figs. 1 and 2). For patients with localized disease amenable to upfront surgical resection, there are high incidences of extrapancreatic tumor extension with vascular or adjacent organ invasion, perineural invasion (PNI), and regional lymph node (LN) metastasis (Table E1), which are often occult on conventional preoperative imaging. Each of these patterns of spread and the potential effect on locoregional therapy will be discussed separately.

Figure 1.

Figure 1

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Pancreas cancer routes of locoregional spread.

Figure 2.

Figure 2

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Radiographic examples of pancreas cancer locoregional spread. A, Abdominal computed tomography showing cT2N1M0 adenocarcinoma of the pancreas head. There is extrapancreatic extension involving the peripancreatic soft tissues, the second portion of the duodenum, and abutment of the superior mesenteric vein. There is an enlarged peripancreatic lymph node or soft tissue deposit anterior to the tumor. B, Abdominal computed tomography showing cT4N1M0 adenocarcinoma of the pancreas body. The primary tumor is hypodense with upstream pancreatic ductal dilation. There is extensive extrapancreatic extension involving the peripancreatic soft tissues, posterior wall of the stomach, and encasement of the celiac artery and hepatic artery. There is an enlarged common hepatic artery lymph node (station 8).

Extrapancreatic extension

Typical imaging features of PDAC include a hypoattenuating, hypoenhancing mass relative to normally enhancing pancreas parenchyma on computed tomography (CT) or a T1 hypointense mass and a relative lack of arterial contrast enhancement compared with normal pancreas parenchyma on magnetic resonance imaging.1–4 In tumors located in the pancreatic head, the mass often associates with upstream pancreatic and biliary ductal dilatation, or the double duct sign. Multiple series suggest that CT, endoscopic ultrasound, and magnetic resonance imaging typically underestimate pathologic tumor size by a mean of 3 to 7 mm,1,2 5 mm,1 and 4 mm,3 respectively.

Occult extrapancreatic tumor extension, which is identified in 60% to 90% with anatomically resectable PDAC and its associated adjacent organ invasion or vascular extension, presents further challenges.5–14 Among a cohort of 97 patients who underwent upfront curativeintent surgical resection, duodenal invasion was pathologically identified in 58% of patients although only 8% were identified with preoperative imaging.1 The sensitivity of preoperative endoscopic ultrasound at determining vascular adherence or invasion is 63% and 50%, respectively.4 Prospective trials suggest that 30% to 60% have local invasion into adjacent organs and up to 40% will undergo vascular resection due to intraoperative identification of occult tumor adherence to vessels.5–14 Furthermore, 13% to 60% will undergo a margin-positive (R1) resection, most commonly at the retroperitoneal or vascular margin. These data demonstrate the locally invasive nature of PDAC and, in part, form the basis for adjunctive locoregional therapy.

Perineural invasion

Compared with other malignancies, PDAC exhibits one of the highest rates of PNI and is present in about 90% of cases.5–15 Extrapancreatic perineural invasion has the strongest prognostic implications and is associated with increased locoregional recurrence (LRR), increased distant metastasis (DM), and worse overall survival (OS), and is present in approximately 86% of patients who have retropancreatic tumor invasion.16–18

A thorough understanding of PDAC pathways of perineural and vascular spread depends on an understanding of pancreas vascular anatomy as neural plexi course alongside the pancreatic vasculature (Fig. 3). The head and neck of the pancreas and adjacent duodenum are supplied by the pancreaticoduodenal arteries (PDAs) and the associated anastomotic arcade, which forms at the periphery of the pancreas head and inner margin of the duodenum.19 The superior PDAs are branches of the gastroduodenal artery, which in turn is a branch of the common hepatic artery (CHA) and, hence, of celiac artery (CA) origin. The inferior PDAs arise from the superior mesenteric artery (SMA). The body and tail of the pancreas are supplied by the splenic artery. Venous drainage of the pancreas is to the portal venous system. The portal vein (PV) forms posteriorly to the neck of the pancreas by the confluence of the superior mesenteric vein (SMV) and splenic vein. Venous drainage of the head, uncinate, and neck of the pancreas flows from the superior pancreaticoduodenal veins into the gastroepiploic vein or PV directly, while the inferior pancreaticoduodenal veins drain into the SMV. The splenic vein courses adjacent to the posterior surface of the tail and body of the pancreas receiving direct venous drainage from those regions in addition to receiving the inferior mesenteric vein before joining the SMV in most cases.

Figure 3.

Figure 3

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Pathways of perineural extension in pancreas cancer.

Perineural spread may follow a predictable pathway15,20–24 through the celiac and/or superior mesenteric plexus to the associated ganglia, which are located anterior/lateral to the aorta between the CA and root of the SMA at approximately the T12-L1 level (Fig. 3). Tumors of the pancreas head and superior uncinate process typically spread via the pancreatic head plexus I (PLph I) by coursing along the superior PDAs adjacent to the superior uncinate process and subsequently traverse posteriorly to the PV along the gastroduodenal artery and CHA to ultimately meet the plexus origin in the right celiac ganglion. Alternatively, anteriorly located pancreas head or neck tumors may invade along the gastroduodenal artery directly (anterior pathway), extend toward the CHA and hepatoduodenal ligament, and subsequently reach the right celiac ganglion.

Tumors of the uncinate process or posterior-inferior pancreas head may spread via the pancreatic head plexus II (PLph II), by invading along the inferior PDAs to reach the SMA, superior mesenteric ganglion, and ultimately bilateral celiac ganglia. Alternatively, caudal spread along SMA (root of the mesentery pathway) is also possible. Pancreatic neck tumors may extend posteriorly along the dorsal pancreatic artery, which courses adjacent to the SMV, allowing for tumor spread in the groove between the SMV and SMA and involvement of the PLph II. Pancreas body and tail tumors typically spread along the splenic plexus, which courses with the splenic artery to the celiac plexus. However, a novel pathway originating independently from the celiac plexus and coursing adjacent to the main pancreatic duct in the pancreas body and tail has been described.22 Therefore, the intricate vasculoneural anatomy of the pancreas explains its extensive microscopic spread and highly infiltrative nature.

Regional lymph node involvement

PDAC exhibits a high propensity for regional LN spread. For example, among the available prospective trials of patients with anatomically resectable disease, 54% to 80% of patients were identified as having pathologically involved LNs. LN basins for PDAC are commonly defined according to guidelines from the Japanese Pancreas Society (Fig. 4). For pancreatic head tumors, common sites of LN metastasis include the posterior-superior pancreaticoduodenal (Japanese Pancreas Society 13a: 30%−32%), posterior-inferior pancreaticoduodenal (13b: 22%), anteriorsuperior pancreaticoduodenal (17a: 16%−20%), anteriorinferior pancreaticoduodenal (17b: 16%), proximal SMA (14p: 10%−16%), distal SMA (14d: 13%), CHA (8: 10%), and para-aortic (16: 7%−11%). Hepatoduodenal ligament (12) or celiac trunk (9) LNs are involved in 5% to 8% and 3% to 4%, respectively.25,26 For a pancreaticoduodenectomy, the extent of lymphadenectomy has been defined as D1 (removal of 8a, 8p, 13a, 13b, 17a, 17b), D2 (removal 5, 6, 12a, 12b, 12p, 14p, 14d), or D3 (removal of 1, 2, 3, 4, 7, 9, 10, 11p, 11d, 15, 16a2, 16b1, 18).

Figure 4.

Figure 4

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Commonly involved pancreas cancer regional lymph node stations per Japanese Pancreas Society classification

For pancreatic body or tail tumors, common sites of LN metastases include splenic artery (11: 36%), inferior margin of pancreas (18: 25%), para-aortic (16: 16%), CHA (8: 15%), celiac trunk (9: 10%), and SMA (14: 10%). For a distal pancreatectomy, the extent of lymphadenectomy has been defined as D1 (removal of 10, 11p, 11d, 18), D2 (removal of 7, 8a, 8p, 9, 14p, 14d), or D3 (removal of 5, 6, 12a, 12b, 12p, 13a, 13b, 15, 17a, 17b, 16a2, 16b1).25,26

In summary, there is a high incidence of spread to first echelon LN (60%−70%), which are commonly removed with a D1 lymphadenectomy, but also a significant likelihood (20%−40%) of spread to second and third echelon LN; however, D2 or D3 lymphadenectomy is not commonly performed.

LRR After “Surgery First” Approach

Pattern of recurrence after pancreatectomy

After surgery alone for PDAC, disease recurrence is common and can occur at local, regional, and distant sites (Table E2).5–8

Autopsy studies have helped characterize sites of recurrence (residual disease) after pancreatectomy, including those that are radiographically occult.27–29 Hishinuma et al27 reported on a series of 85 patients of whom 24 underwent autopsy, and 92% had disease recurrence. Of these, 75% had LRR commonly associated with cancer infiltration of the nerves, lymphatic vessels, or extrapancreatic soft tissues extending from the remnant pancreas to the retroperitoneum.27 Para-aortic LN recurrence occurred in 21% and DM occurred in 75% of patients, including liver (50%) and peritoneum (33%). Another autopsy series of 20 patients by Kayahara et al28 found that 15 (75%) patients had disease recurrence, including 14 (93%) with DM most commonly to the liver (n = 10, 67%) or peritoneum (n = 8, 53%) and 12 (80%) with LRR. IacobuzioDonahue et al29 reported an autopsy series including 22 patients. Twenty (91%) had disease recurrence, including 3 (15%) with local-only, 4 (20%) with DM only, and 13 (65%) with both local and distant. They reported that 30% of patients died with “locally destructive” phenotype and 70% died with widespread metastatic disease. Loss of DPC4 (Smad4) immunolabeling was associated with widespread DM (P = .007).

These data suggest that the rate of DM within 3 to 5 years after surgery ranges between 60% to 90%, most commonly manifesting with liver metastasis. However, a high percentage of patients (up to 60%−80%) have residual or recurrent locoregional disease after resection, with 15% to 50% experiencing a local-only pattern of first recurrence.

Radiographic features of LRR

PDAC LRR after prior pancreatectomy may be challenging to discriminate from postoperative changes. Common radiologic features of LRR include the interval development of an enlarging hypoattenuating soft tissue mass in the operative bed, which may be hypo- or hyperenhancing (Fig. 5) and may include nodular soft tissue formation adjacent to surgical clips.30 Recurrence adjacent to vasculature may manifest as a soft tissue mass at the vessel periphery or with perivascular infiltration encasing and running in parallel with the vessel and can result in deformation of venous structures as the first hint of recurrent disease. These findings may coincide with the development of new or increasing pancreatic ductal dilatation. Balaj et al reported the most frequent sites of CT-detected LRR were adjacent to surgical clips (94%) or with arterial encasement (CHA-64%, SMA-45%, CA24%). Correlation with positron emission tomography-CT and/or serum CA 19 to 9 may assist in the interpretation of CT findings. Formal tissue diagnosis may be difficult due to the anatomic changes precluding typical endoscopic or radiologic access.

Figure 5.

Figure 5

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Examples of pancreas cancer locoregional recurrence (LRR) after pancreatectomy. 1A, LRR involving the celiac artery. 1B, LRR involving the superior mesenteric artery and aortocaval space. 1C, LRR in the portocaval space. 1D, LRR of pancreas tail lesion. Abbreviations: LRR = locoregional recurrence.

Anatomic sites of LRR

A few studies mapped anatomic sites of LRR after pancreatectomy.31,32 Dholakia et al32 evaluated 202 patients who had pancreatectomy and 1 or more postoperative CTs. LRR occurred in 90 patients (45%). Recurrence was closer to the CA in 31% of patients (mean distance of 1.1–1.9 cm) and closer to the SMA in 69% of patients (mean distance of 0.5–0.8 cm) (Fig. 6). Yu et al31 similarly mapped patterns of recurrence in 305 patients. Of the 83 patients who experienced LRR, 77% of recurrences were closest to the SMA, with a mean distance of 2.0, 2.5, and 3.6 cm for patients with tumors that arose in the pancreatic head, body, and tail, respectively. In 23% of patients the recurrence was closest to the CA, with a mean distance of 1.9, 1.2, and 4.1 cm for patients with tumors that arose in the pancreatic head, body, and tail, respectively. Both studies contoured the CA and SMA as the most proximal 1 and 3 cm, respectively, from the aortic origin. Therefore, a vast majority of LRRs after pancreatectomy occur within a 2.0-cm margin from the most proximal 1 cm of CA and 3 cm of SMA.

Figure 6.

Figure 6

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Local recurrence map. A, Anterior-posterior and B, lateral views of local recurrence plots in relation to the celiac artery (yellow) and superior mesenteric artery (blue) after pancreaticoduodenectomy for patients receiving no adjuvant therapy (red), chemotherapy alone (orange), and chemoradiation (green). Reproduced with permission from Dholakia et al.32

Effect of postoperative chemotherapy on LRR

The incorporation of postoperative chemotherapy significantly improved outcomes for patients with PDAC.7–9,12–14 Both the CONKO001 (gemcitabine vs observation) and ESPAC-4 (gemcitabine plus capecitabine vs gemcitabine) trials identified improvements in OS and LRR with intensification of adjuvant therapy; however, LRR still occurred in 34% to 41% of patients.8,13 The Partenariat de Recherche en Oncologie Digestive-Actions Concertees dans les Cancers Colorectaux et Digestifs 24 and the Canadian Cancer Trials Group Pancreatic Adenocarcinoma 6-ACCORD 24/CCTG PA. 6) trial compared postoperative gemcitabine versus 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX).14 The median OS was improved with FOLFIRINOX compared with gemcitabine (54.4 vs 35.0 months, P = .003) and recurrence rates were reduced, 52% versus 72%. LRR occurred in 23% versus 35% (local only: 13% vs 18%) of patients and DM occurred in 38% versus 50%. These data suggest that postoperative combination chemotherapy may modestly reduce the rates of LRR, although LRR is still a significant issue occurring in at least 23% to 30% of patients.

Effect of postoperative RT on LRR

The goal of postoperative RT is to decrease LRR and improve OS for PDAC. Early randomized trials, including Gastrointestinal Tumor Study Group (GITSG) 9173 and European Organisation for Research and Treatment of Cancer (EORTC) 40891, compared observation versus postoperative split course chemoradiotherapy (CRT) and suggested lower rates of recurrence and possible improvement in OS for patients who received postoperative CRT; however, 50% to 80% of patients experienced DM.5,6 The European Study Group for Pancreatic Cancer (ESPAC)-1 trial suggested possible detriment of postoperative CRT compared with chemotherapy, although there are notable concerns about RT design, administration, and lack of quality assurance.7 The Radiation Therapy Oncology Group (RTOG) 9704 trial demonstrated a relatively low rate of LRR (26%) in patients treated with 5-fluorouracil or gemcitabine-based CRT (50.4 Gy in 28 fractions).10 The European Organisation for Research and Treatment of Cancer (EORTC)-40013–22012/Fédération Francophone de Cancérologie Digestive (FFCD)-9203/Groupe Cooperateur Multidisciplinaire en Oncologie (GERCOR) phase II trial identified a lower incidence of local first recurrence, 11% versus 24%, in patients treated with gemcitabine followed by gemcitabine-based CRT (50.4 Gy in 28 fractions) compared with gemcitabine alone.11 The RTOG 0848 trial was designed to provide a more definitive answer of the role of postoperative CRT following 6 cycles of gemcitabine for patients with resected pancreatic head PDAC.33 The study closed and we await the results regarding the RT randomization.

LRR After Neoadjuvant Strategies

For localized PDAC, the rationale for preoperative therapy is that it may allow for earlier systemic therapy to control occult DM, allow for an in-vivo assessment of disease biology to assist in patient selection for a potentially morbid surgical operation, improve pathologic downstaging, and increase R0 resection rate, which is strongly associated with OS. Furthermore, preoperative RT may be delivered to a smaller and more easily defined target volume and potentially reduce the toxicities associated with treatment compared with postoperative RT.

Several studies evaluated neoadjuvant chemotherapy and/or CRT in patients with anatomically resectable disease.34–37 The median OS for this approach ranges from 26 to 34 months with R0 resection rates ranging from 80% to 94%, significantly greater than those previously reported from upfront surgical series. Furthermore, LRR rates ranged from 0% to 25%, which appear favorable when compared across trials to up-front surgical series.

Neoadjuvant therapy for patients with borderline resectable PDAC can improve the rates of R0 resection. Truty et al38 reported on 194 patients with either borderline resectable (63%) or locally advanced (37%) PDAC who received FOLFIRINOX and/or gemcitabine plus nab-paclitaxel, CRT (50–50.4 Gy in 25–28 fractions) targeting the gross tumor, involved vasculature, and at-risk regional lymphatics, followed by surgical resection. R0 resection was achieved in 94% of patients and the median OS was 58.8 months. Patterns of recurrence included local (6%), peritoneal (13%), and distant (25%). The Alliance A021101 pilot study included 22 patients with borderline resectable PDAC treated with a preoperative regimen of modified FOLFIRINOX followed by CRT (50.4 Gy in 28 fractions).39 Fifteen patients proceeded to surgery, of which 93% underwent an R0 resection, 13% achieved a pathologic complete response, and only 2 experienced LRR.

Two prospective randomized trials evaluating neoadjuvant therapy for patients with localized PDAC provide additional insight. Jang et al40 reported an interim analysis of 50 patients with borderline resectable PDAC, comparing neoadjuvant gemcitabine-based CRT (54 Gy in 30 fractions) followed by surgery versus upfront surgery followed by postoperative CRT. Outcomes were improved with neoadjuvant CRT, with R0 resection rates of 82% versus 33% (P = .004) and 2-year OS of 41% versus 26% (P = .028). The Dutch Preoperative radiochemotherapy versus immediate surgery for resectable and borderline resectable pancreatic cancer (PREOPANC) trial randomized 246 patients with anatomically resectable (54%) or borderline resectable (46%) PDAC to either preoperative gemcitabine-based CRT to a dose of 36 Gy in 15 fractions or to up-front surgery.41 Preoperative CRT was associated with improved R0 resection (72% vs 43%, P < .001), disease-free survival (8.1 vs 7.7 months, P = .009), LRR-free interval (31.2 vs 13.4 months, P = .004), pathologic downstaging, and OS (15.7 vs 14.3 months, P = .025). The 5-year OS was 21% versus 7% (P = .025) favoring preoperative CRT, suggesting that despite modest gains in median OS, there may be striking advantages in long-term OS and perhaps “curability” with preoperative CRT.

Preoperative stereotactic body radiation therapy (SBRT) is a topic of continued study. Hill et al42 reported a Johns Hopkins experience of 155 patients with borderline resectable (n = 64) or locally advanced (n = 91) PDAC who received neoadjuvant FOLFIRINOX or gemcitabine and nab-paclitaxel for a median duration of 4 months followed by preoperative SBRT to a median dose of 33 Gy in 5 fractions. Among the 64 patients with borderline resectable disease, 78% underwent resection, of which 96% achieved R0 resection. Among the 91 patients with locally advanced disease, 63% underwent resection, of which 88% achieved R0 resection. Despite the high rates of R0 resection, 33% of patients experienced local recurrence as a component of first site of progression and 44% of all recurrences included local recurrence. Kharofa et al43 reported a prospective phase II study of 18 patients with resectable (17%) or borderline resectable (83%) PDAC treated with 3 cycles of FOLFIRINOX or gemcitabine plus nab-paclitaxel followed by SBRT to 33 Gy in 5 fractions with an optional 25 Gy volume targeting regional lymphatics and mesenteric vessels. Twelve (67%) patients underwent surgery with 11 (92%) R0 resections. Of those who underwent surgery, progression occurred in 83%, including DM (40%), local-only (40%), or local and distant (20%). The cumulative incidence of LRR at 12 months from resection was 50%, and all occurred outside of the planning target volume. The Alliance A021501 phase II trial compared 2 preoperative therapy approaches, either 8 cycles of FOLFIRINOX or 7 cycles of FOLFIRINOX followed by SBRT, with historical controls with the goal of identifying a reference regimen for future study.44 A total of 126 patients were enrolled. The SBRT treatment arm was closed after 56 patients were enrolled based upon a planned interim assessment of the R0 resection rate of all patients enrolled. For the chemotherapy alone versus chemotherapy plus SBRT cohorts, 58% versus 51% underwent surgical exploration, 48% versus 35% underwent pancreatectomy, 42% versus 25% underwent R0 resection, and the 18-month OS was 68% versus 47%, respectively. Among the SBRT cohort, 11% achieved a pathologic complete response compared with 0% for chemotherapy alone. Interestingly, the R0 resection rates in this trial were lower than those reported in the aforementioned Alliance A021101 and PREOPANC prospective trials. Further studies are needed to determine the potential role of SBRT in the preoperative setting.

In summary, these studies provide data supporting the oncologic efficacy of neoadjuvant therapy for patients with PDAC. Although further clarification is needed regarding the most optimal RT technique, dose, and target volume, these data suggest that multiagent chemotherapy and RT work synergistically to assist in patient selection and improve outcomes of OS, DM, and locoregional control.

Planning considerations for (neo)adjuvant RT

Ideally, patients will undergo CT simulation with patient-specific respiratory motion assessment such as 4-dimensional CT simulation. If respiratory motion results in >1 cm of gross tumor motion, respiratory motion management strategies such as breath-hold, phase-based gating, or abdominal compression should be considered. The use of intravenous contrast assists in accurately delineating the gross pancreas tumor and regional vasculature. In cases of dose-escalation or SBRT, placement of peritumoral fiducial markers for daily image guidance is recommended because bony anatomy and biliary stents may be relatively poor surrogates for the gross pancreas tumor.45

The fundamental goal of (neo)adjuvant RT is eradication of microscopic residual disease not removed with surgery to improve locoregional control and oncologic outcome. For PDAC, this involves clearance of microscopic extrapancreatic tumor extension, lymphovascular invasion, PNI (which often extends to the retroperitoneum), vascular extension, and occult regional LN dissemination. When delivered preoperatively, RT can improve the opportunity for R0 resection.

The RTOG 0848 trial provided consensus recommendations for postoperative RT target volumes, which suggest a combined final target volume encompassing the tumor bed plus approximately 1-cm margin upon: (1) PV from its bifurcation extending to the confluence of the SMV and splenic vein, (2) proximal 1.0 to 1.5 cm of the CA, (3) proximal 2.5 to 3.0 cm of the SMA, and (4) pancreaticojejunostomy.33,46 Inclusion of the aorta extending superiorly from the level of the CA and inferiorly to L2 with a margin of 2.5 to 3.0 cm to the right, 1.0 cm to the left, 2.0 to 2.5 cm anteriorly, and 0.2 cm posteriorly toward the anterior edge of the vertebral body is recommended. The American Society for Radiation Oncology Clinical Practice Guideline for pancreas cancer recommends these target volumes, and the work of Goodman et al46,47 serves as an excellent contouring guideline.

Studies that mapped sites of LRR after pancreatectomy provide valuable information to further guide RT volumes.31,32 Yu et al31 and Dholakia et al32 have reported that 90% of LRRs would be contained within a volume encompassed by a 3-cm right-lateral, 2.0- to 2.1-cm leftlateral, 1.5- to 2.0-cm anterior, 1.0- to 1.3-cm posterior, 1.0-cm superior, and 2.0-cm inferior expansion of the combined SMA and CA contours. Target volumes based upon these suggestions tend to be smaller compared with those suggested per RTOG 0848 and most notably exclude the hepatic hilum region.

In the preoperative setting, targeting of the primary gross tumor volume with up to a 1.5-cm margin would encompass approximately 97.5% of extrapancreatic primary tumor extension for most patients.1 Based upon the aforementioned patterns of spread data, elective inclusion of the PDAs, SMA, para-aortic, CHA, CA, and associated LN regions may be considered for patients with pancreatic head or uncinate process tumors as they would encompass LN regions with at least a 10% risk of involvement and anticipated pathways of vascular and perineural spread.25,26,48 For patients with tumors of the pancreas body or tail, inclusion of the splenic artery and inferior pancreatic body LN regions should be considered, while the PDA LN regions may be excluded.26,48 Figure 7 and Fig. E1 include representative cross-sectional images demonstrating high-risk lymph node regions for a patient with PDAC. In patients treated with 3-dimensional-conformal RT, when the clinical target volume includes only the primary gross tumor volume with a 1- to 2-cm margin and without specific inclusion of elective LNs, the “incidental” dose to peripancreatic LNs may approximate 80% of the prescription dose, while the “incidental” dose to the SMA, CA, and para-aortic LNs may be approximately 40% to 70% of the prescription dose.49 As such, there is some controversy regarding the inclusion of elective LN regions in the clinical target volumes. However, in the era of increasingly conformal RT techniques, we would advocate for careful consideration of elective target volume delineation to encompass at-risk sites of regional spread.

Figure 7.

Figure 7

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Representative cross-sectional images demonstrating high-risk lymph node regions for a patient with pancreatic ductal adenocarcinoma. Of note, this patient has variant celiac axis anatomy with the common hepatic artery arising directly from the abdominal aorta (for complete atlas, see Fig. E1).

Preoperative SBRT uses a target volume typically covering the gross tumor volume with a 0.2- to 0.5-cm margin +/− inclusion of involved vasculature. Multiple series have suggested that treatment of this volume with 33 Gy in 5 fractions resulted in an unacceptably high LRR rate outside of the planning target volume, thus prompting the addition of a simultaneous 25 Gy elective target volume to cover regional lymphatics.42,43 Miller et al50 have further supported this approach by demonstrating that SBRT targeting the gross tumor versus gross tumor plus regional lymphatics (per RTOG consensus33,46) is associated with a lower risk of LRR (45% vs 23%, P = .021) at 2 years.

Conclusions

RT plays an important role in the (neo)adjuvant management of patients with localized PDAC. In this review, we have provided a contemporary and nuanced description of PDAC patterns of spread, disease progression, and evolving treatment techniques to help guide clinicians on the effective utilization and planning of RT for patients with PDAC. For patients receiving neoadjuvant RT, we advocate for inclusion of elective at-risk regions of extrapancreatic extension, PNI, and lymphatic spread. Further prospective studies are needed to better define the optimal RT dose, fractionation regimens, and target volumes to be used in the (neo)adjuvant setting.

Supplementary Material

Appendix. Supplementary materials
Table 1-2

Sources of support:

This work had no specific funding.

Disclosures:

Dr Jethwa reports receiving honoraria from RadOnc-Questions.com, LLC; Dr Jabbour reports receiving grants and consulting fees from Merck & Co, consulting fees from IMX Medical, and participates on a data safety monitoring board or advisory board for Syntactx.

Footnotes

Drs Neibart, Truty, and Hallemeier have no conflicts of interest to disclose.

Supplementary materials

Supplementary material associated with this article can be found in the online version at doi:10.1016/j.prro.2022.06.004.

Data sharing statement:

Research data are not available at this time.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Appendix. Supplementary materials
NIHMS1954036-supplement-Appendix__Supplementary_materials.pptx (11.9MB, pptx)
Table 1-2
NIHMS1954036-supplement-Table_1-2.docx (16.1KB, docx)

Data Availability Statement

Research data are not available at this time.

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