Sarma G, Bora H, Medhi PP. Optimizing neoadjuvant chemoradiation in resectable and borderline resectable pancreatic cancer: Evidence-based insights. World J Clin Oncol 2025; 16(7): 106107 [DOI: 10.5306/wjco.v16.i7.106107]
Corresponding Author of This Article
Hima Bora, Researcher, Department of Radiation Oncology, Tezpur Medical College and Hospital, NH-15, Tezpur 784010, Assam, India. himabora36@gmail.com
Research Domain of This Article
Oncology
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Minireviews
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Author contributions: Sarma G intellectual content definition; Bora H performed data collection and manuscript editing, literature search, and drafted the manuscript; Sarma G and Medhi PP performed manuscript review and final approval; and all authors thoroughly reviewed and endorsed the final manuscript.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Hima Bora, Researcher, Department of Radiation Oncology, Tezpur Medical College and Hospital, NH-15, Tezpur 784010, Assam, India. himabora36@gmail.com
Received: February 17, 2025 Revised: April 16, 2025 Accepted: June 3, 2025 Published online: July 24, 2025 Processing time: 155 Days and 17.8 Hours
Abstract
Since its inception, localized pancreatic cancer has been identified as a systemic illness. Hence, to increase its survival rates, surgical resection followed by adjuvant chemotherapy is used as a treatment option. A significant barrier, though, is the high morbidity and drawn-out recovery after extensive surgical resection, which may postpone or prohibit the prompt administration of adjuvant therapy. Thereby, acknowledging the efficacy of neoadjuvant therapy in various digestive tract malignancies like rectal, gastric, and oesophagal cancers in enhancing long-term survival and the likelihood of successful resection, researchers have turned their attention to exploring its potential benefits in the context of both resectable and borderline resectable pancreatic cancer (RPC). According to recent data, neoadjuvant chemoradiation has major advantages for both resectable and borderline RPC. These advantages include increased surgical resection rates, longer survival times, decreased recurrence rates, and better overall disease control with a manageable toxicity profile. Despite its benefits, research is still being done to determine the best way to sequence and combine chemotherapy and radiation. Furthermore, studies have demonstrated the potential for customized therapy regimens based on the patient’s general health status and the tumor’s biological behavior to maximize the neoadjuvant approach. As progress continues, neoadjuvant chemoradiation is set to become a key component of treatment for both resectable and borderline RPC, providing a more efficient way to manage this deadly condition. While further development is required to fully grasp its potential in enhancing long-term patient outcomes, evidence supports its increasing usage in clinical practice.
Core Tip: Recognized from its inception as a systemic disease, localized pancreatic cancer is currently treated with adjuvant chemotherapy and surgical excision to improve survival rates. However, the main obstacle that may postpone or prevent the prompt delivery of adjuvant therapy is the high morbidity and delayed recovery that follows large surgical excision. Thus, acknowledging the potential of neoadjuvant chemoradiation in improving long-term survival and the chance of successful resection for a variety of digestive tract cancers, such as rectal, gastric, and oesophagal cancers, researchers have focused on investigating its potential benefits in the context of both resectable and borderline resectable pancreatic cancer.
Citation: Sarma G, Bora H, Medhi PP. Optimizing neoadjuvant chemoradiation in resectable and borderline resectable pancreatic cancer: Evidence-based insights. World J Clin Oncol 2025; 16(7): 106107
Considering its lethal nature, pancreatic adenocarcinoma (PAC) can be ranked as the second leading cause of cancer-related deaths by 2030[1]. Nonetheless, despite its rising prevalence, merely 20% of patients are deemed suitable for curative surgery due to the influence of factors such as the presence of distant metastasis or significant vessel involvement identified alongside diagnosis[2]. Additionally, the 5-year overall survival (OS) is lower for all stages, regardless the early stages treated with a curative intent, with a cumulative incidence of approximately 8%[3]. In addition to this, since recurrence after resection of pancreatic cancer occurs in 80% of patients in the first two years, even after complete resection[4], it is denoted as a systemic disease from its onset[5]. The standard treatment approach for localized PAC is based upon a trial named the European Study Group for Pancreatic Cancer (ESPAC)-1 trial[6], wherein a significant 13% rise in five-year survival rates is observed when surgery of the primary tumor and adjacent lymph nodes, followed by adjuvant chemotherapy is executed. However, a major obstacle arises from the high morbidity and prolonged recovery following extensive surgical resection, potentially delaying or preventing the timely administration of adjuvant therapy[7]. Following surgery, patients must recover within a 12-week window to receive adjuvant chemotherapy effectively. At the same time, as highlighted by studies like CONKO-001[8], those unable to undergo adjuvant chemotherapy have to come across a notably worse prognosis, with a median disease-free survival (DFS) of only 13.4 months. Therefore, acknowledging the efficacy of neoadjuvant therapy (NAT) in various digestive tract malignancies like rectal, gastric, and oesophageal cancers in enhancing long-term survival and the likelihood of successful resection, researchers have turned their attention to exploring its potential benefits in the context of pancreatic cancer[9,10]. Although a large number of studies have documented positive effects of NAT on survival, there is still a dearth of data from carefully designed randomized trials[11-14]. This article aims to comprehensively explore the role of neoadjuvant chemoradiation therapy (NACRT) in PAC, elucidating its rationale, clinical evidence, challenges, and potential future directions. We hope our analysis will offer valuable insights to support clinical practice and aid decision making. Imaging techniques play a significant role in potential improvement in PAC improvement to distinguish treatment response before and after NACRT[15,16]. However, the final dictum of resection and treatment intent is based on patient characterstics at presentation and post neoadjuvant treatment, including comorbidities besides radiologically available data[17].
DISEASE STAGING
There are primarily three stages of non-metastatic pancreatic cancer: Resectable pancreatic cancer (RPC), borderline RPC (BRPC), and locally advanced pancreatic cancer. In the past, BRPC was not acknowledged as a stage. The term “borderline resectable” (BR) was adopted by the National Comprehensive Cancer Network (NCCN)[18] in 2006 to describe cancers that, carry a risk of margin-positive resection, if treated with upfront surgery (UFS).
CRITERIA FOR RESECTION
The consensus on the resectability of PAC has been revised over time. Finally, the definition of possibility of resections was achieved with the collaboration of three important societies-the Society of Surgery for Alimentary Tract, the American Hepato Pancreatic Biliary Association and the Society of Surgical Oncology. However, the criteria for defining BR set forth by these four entities-MD Anderson Cancer Centre (MDSCC)[18], NCCN[19], the American Society of Clinical Oncology (ASCO)[20] and American Hepato Pancreatic Biliary Association[21]-are compared in Table 1[22]. Additionally, Table 1[22] comprises the criteria for identifying BR outlined by the International Association of Pancreatology[23] and the Japan Pancreas Society[24].
Table 1 An overview of borderline resectable pancreatic cancer definitions.
Solid-tumor contact ≤ 180° or contact > 180° without involvement of the aorta or GDA
No involvement
No involvement
No interface
No tumor contact/invasion
Tumor contact/invasion of less than 180 without showing stenosis/deformity
No tumor contact/invasion
Tumor contact of less than 180 without showing deformity/stenosis
CHA
Solid-tumor contact without extension to CA or hepatic artery bifurcation
Short-segment encasement or abutment of CHA or GDA
GDA encasement up to hepatic artery with either short-segment encasement or direct no tumor contact/invasion abutment of hepatic artery
No interface
No tumor contact/invasion
Tumor contact/invasion without showing tumor contact/invasion of the PHA and/or CA.
No tumor contact/invasion
Tumor contact without showing tumor contact of the PHA and/or CA
SMA
Solid-tumor contact ≤ 180° or solid-tumor contact with variant arterial anatomy
Tumor abutment of ≤ 180°
Tumor contact is not to exceed > 180°
No interface
No tumor contact/invasion
Tumor contact/invasion of less than 180 without showing stenosis/deformity
No tumor contact/invasion
Tumor contact of less than 180 without showing deformity/stenosis
SMV or PV
Solid-tumor contact > 180° or ≤ 180° with contour abnormality or thrombosis of the vein, provided there is a suitable proximal and distal vessel to allow venous resection and reconstruction
Short-segment occlusion with patent vessels above and below the occlusion
Tumor abutment with or without impingement and narrowing of the lumen; encasement without encasement of the nearby arteries; short-segment occlusion with the suitable proximal and distal vessel, allowing safe resection and reconstruction
No interface
Tumor contact/invasion of 180 or more/occlusion, not exceeding the inferior border of the duodenum
No tumor contact/invasion
Tumor contact 180 or greater or bilateral narrowing/occlusion, not exceeding the inferior border of the duodenum
-
The optimal imaging method for assessing resectability is multidetector contrast-enhanced computed tomography (CT) scans of the chest and abdomen using multiphase dynamic contrast and the pancreatic protocol. On cross-sectional imaging, the absence of tumor contact with the portal vein or superior mesenteric vein and the major surrounding arteries such as celiac artery, common hepatic artery, and superior mesenteric artery implies explicit resectability[25]. Several societies have developed definitions of BR disease primarily based on anatomic criteria, as depicted in Table 1. Further, while defining BR, both NCCN guidelines and the MDSCC Pancreatic Cancer Group also consider conditional factors such as patient characteristics of Eastern Cooperative Oncology Group Performance status two or higher and related comorbidities. The MDSCC Pancreatic Cancer Group also considers biological factors about extra pancreatic illnesses, including biopsy-proven lymph node metastases and an elevated carbohydrate antigen 19-9 (CA19-9) level (≥ 1000 U/mL). Despite the limited discrepancies across the entities BR definitions, NCCN standards are recommended globally[19]. Beyond the features mentioned above for RPC and BRPC, the rest are defined as locally advanced pancreatic cancer, which, when spread to non-regional lymph nodes or other organs, are considered in the metastatic stage.
NEOADJUVANT CHEMORADIATION TREATMENT RATIONALE IN RPC AND BRPC
Improved resection rates through therapeutic tumor debulking to improve the rates of margin - negative resection (i.e., R0 resection, a microscopically margin-negative resection) and early treatment of micrometastatic disease are among the postulated benefits of NACRT in PAC as a systemic disease[26,27]. In addition, NACRT helps reduce the rate of positive lymph nodes at surgery, assesses tumor chemosensitivity and tolerance to treatment, and most importantly, provides an opportunity to deliver systemic therapy to all patients. Moreover, NACRT may prevent futile surgery in patients with rapidly progressive disease. Reduction in postoperative complications rates, such as postoperative pancreatic fistula and post pancreatectomy hemorrhage, are also noted after NACRT, as detected in multiple studies[28-31]. For instance, Cheng et al[29] discovered that NACRT had a considerably decreased rate of intraabdominal abscesses (8.8% vs 21%, P = 0.019) and pancreatic leak (10% vs 43%, P < 0.001) in patients compared to UFS. Additionally, Yamada et al[30] demonstrated that NACRT’s positive aspect is linked to less than eight months.
Studies were being conducted to ascertain how NACRT operates in BR tumors. There is high probability of incomplete resection in borderline pancreatic cancers. Considering that the benefits mentioned above cited for RPC would also help BRPC, NACRT is considered in multidisciplinary tumor board meetings after investigating the performance status of the patients, which might improve OS[32,33].
DRAWBACKS OF NEOADJUVANT CHEMORADIATION TREATMENT
On the flip side, the NACRT has certain potential shortcomings. Disease progression and clinical decline in the performance status of the patients during therapy may render curative surgery unfeasible. Moreover, if patients do not respond to NACRT, they are unlikely to respond to adjuvant chemotherapy either. So, the decision to forego surgery after NACRT might be a calculated one to avoid futile procedures. Also, with a 10-year OS rate of merely 4% in patients without adjuvant chemotherapy following UFS, the prospect of a cure is exceptionally slim[34]. Chemotherapy, mostly fluorouracil with folinic acid, irinotecan, oxaliplatin (FOLFIRINOX), can lead to deterioration in a patient’s performance status and quality of life due to side effects like gastrointestinal complications, infections, fatigue, and neuropathy[35]. Although rare, these effects seldom make patients unfit for surgery, and chemotherapy-related deaths were rare in studies[36]. NACRT often requires biliary drainage before treatment in patients with obstructive jaundice. While this procedure can lead to infectious complications, UFS can sometimes bypass the need for biliary drainage[37]. However, most clinic-presenting patients become eligible for NACRT after sufficient biliary drainage.
Challenges in obtaining high-quality information include difficulty in recruiting patients for randomized trials, as some prefer UFS over NACRT. While studies have indicated the potential of NACRT to enhance the OS of patients with RPC and BRPC, their efficacy has often been constrained by methodological limitations such as small sample sizes, reliance on retrospective data, and outdated chemotherapy protocols[38-40], limiting their generalizability. Thus, researchers have focused on numerous randomized controlled trials (RCTs), systemic reviews, and meta-analyses based on intention- to- treat (ITT) analysis, which may address these issues to conclusively demonstrate superior OS outcomes to consolidate available evidence[41,42]. However, these analyses have encountered challenges, including significant heterogeneity in defining respectability and variations in chemoradiation therapy (CRT) regimens employed. Additionally, approximately 30% of patients receiving NACRT opt out of surgical interventions, depriving them of potentially curative treatments compared to those who undergo UFS[43-46]. Despite these complexities, the pursuit of refining treatment approaches for PAC persists, driven by the hope of improving outcomes for patients facing this challenging diagnosis.
KEY STUDIES INVESTIGATING NACRT EFFECTIVENESS IN RPC AND BRPC
Search strategy
Relevant studies and clinical trials identified by conducting a comprehensive literature search related to NACRT in carcinoma of pancreas. After a search using a combination of the following keywords: “pancreatic ductal adenocarcinoma”, “pancreatic cancer”, “pancreatic tumor”, “pancreatic neoplasm”, “neoadjuvant therapy”, “neoadjuvant”, “neoadjuvant chemotherapy”, “neoadjuvant chemoradiotherapy”, “preoperative therapy”, “surgery” on PubMed, Scopus and Google Scholar-prospective studies with restriction to phase 2 and phase 3 trials and publication dates from 2003 to 2024 were included. All of them were published in English language.
Upon analyzing the benefits of NACRT in patients affected by RPC and BRPC, the below-mentioned studies matched the criteria considered valuable for this crucial review (Table 2). Advantages of NACRT, especially in terms of OS and DFS benefit, resection rate, and pathologic parameters (i.e., R0 rate-more than 1 mm clearance from each margin and lymph node metastasis rate) compared to UFS were noted[47].
Table 2 Studies including neoadjuvant chemoradiation in resectable and borderline resectable pancreatic cancer.
Ref.
Period of study
Type of study
Number of patients (n)
Intervention
Resection rate
Category
R0
N0 resection
Survival (months)
Post-surgical complications
Combination of chemotherapy and radiotherapy in resectable pancreatic cancer
In comparison to UFS, the meta-analysis by Versteijne et al[26] and Pan et al[43] showed that NAT improved survival in BRPC and a sub-group of RPC patients. Another recent meta-analysis by van Dam et al[48], found that NAT survival benefits are predominantly centered in BR tumors. Lee et al[49] evaluated the effectiveness of NAT in RPC compared with UFS. They found that NAT showed survival benefits over adjuvant therapy for patients who completed treatment.
Combination of chemotherapy and radiotherapy in RPC
The first multicentre RCT on NACRT for RPC was conducted in between June 2003 and December 2009 by Golcher et al[41]. Randomization was used to assign patients to UFS (Arm A) or NACRT, followed by surgery (Arm B). Following surgery, both arms were administered adjuvant gemcitabine for six cycles. The primary outcome of this study was OS. Resectability was defined as no organ infiltration except for the duodenum and vascular abutment ≤ 180º based on high-resolution CT image[50]. It required 254 patients to accomplish the desired increase in median OS in both groups. In Arm B, patients received 30 mg/m2 of cisplatin and 300 mg/m2 of gemcitabine in addition to radiation therapy (RT): 50.4-55.8 Gray (Gy). Three-dimensional conformal treatment planning was employed. The Response Evaluation Criteria in Solid Tumors criteria was used to categorize the responses[51]. Between June 2003 and December 2009, total of 73 patients were recruited from eight university hospitals and tertiary referral centres in Germany and Switzerland. However, because of low recruitment rate, enrollment was halted. Sixty-six patients had their data analyzed subsequently. Of the 33 patients in Arm B, 29 completed CRT. In contrast to 19 out of 33 patients in Arm B, 23 out of 33 patients had tumor resection in Arm A. Resection rate was 48% vs 52% (A vs B, P = 0.81) and (y) pN0 (no pathological lymph node metastases) was 30% vs 39% (A vs B, P = 0.44). Radiologically, in Arm B, there were only four partial responses. The postoperative outcomes were comparable for both groups. However, fifteen serious adverse effects, including cholangitis requiring a stent change (n = 9), were documented during CRT and up until surgery. Arm B patients did not experience higher rates of high-grade postoperative complications. In patients A vs B, adjuvant chemotherapy was administered on 10/23 vs 7/19. The time to progression was 8.7 months compared to 8.4 months (A vs B, P = 0.95). According to intention-to-treat analysis, the median OS was 14.4 months as opposed to 17.4 months (A vs B, P = 0.96).
In May 2007, Casadei et al[52] conducted the first single-centre RCT in Italy by evaluating the eligibility of 350 patients with suspected RPC. Patients were divided into two arms: Arm A (UFS) and Arm B (NACRT and surgery) with adjuvant gemcitabine administered in both arms. The key objective was R0 resection with intention-to-treat analysis; the secondary endpoints included the number of patients who concluded the NAT, toxicity evaluation, radiographic and pathological tumor node-metastasis, OS, surgical morbidity, and death. Abdominal multiphase spiral CT assessed resectability according to Ishikawa classification at baseline in all patients and following CRT in Arm B[53]. The CRT schedule included chemotherapy with 1000mg/m2 of gemcitabine alone at baseline and concurrent gemcitabine 50 mg/m2 with conventional RT with 45 Gy and a boost of 9 Gy. While patient recruitment started in May 2007, it was discontinued in July 2014 due to the low accrual rate with 38 histologically proven RPC randomized in 1:1, total of 20 in Arm A and 18 in Arm B. NACRT was completed in 14/18 (77.8%) instances. Although tumor resection was carried in 15/20 (75%) vs 11/18(61.1%) (A vs B), R0 resection rate (25% vs 38.9%, P = 0.489) did not vary significantly amongst the groups. A complete response, partial and stable response, and disease progression were observed in 5.6%, 66.7%, and 22.2% of cases, respectively, when the radiological response to NACRT was evaluated. Of the 11 patients whose pathological reaction was evaluated, only one (5.6%) had a poor response, eight (44.5%) had moderate responses and two (11.1%) had minimal responses. There were notable differences in the pathological Tumor category between two groups (A vs B, P = 0.016). Mortality (10.0% vs 5.5%, respectively, P = 1.000), post-surgical morbidity (45% vs 55.6%, respectively, P = 0.746) and OS (P = 0.973) did not differ statistically between the two groups. In subgroup analysis, preoperative CRT enhanced survival in patients with tumor excision and began adjuvant treatment (35.2 vs 19.8 months, P = 0.029). During NACRT, all patients experienced adverse events, which were mostly grade 1 or 2 (61.1%), hardly grade 3 (33.3%), or grade 4 (5.6%).
Combination of chemotherapy and radiotherapy in both RPC and BRPC
For patients with RPC or BRPC, the Dutch Pancreatic Cancer Group launched the phase III PREOPANC trial at ASCO 2018 to examine whether NACRT offers a better OS rate than UFS. With adjuvant gemcitabine in both arms, these patients were randomized to UFS (Arm A) or NACRT, followed by resection (Arm B). OS was the primary endpoint of the ITT analysis. Resection rate, R0 resection rate, distant metastasis-free interval, locoregional failure-free interval, DFS, and the toxicity of both surgery and pre and postoperative treatment were the secondary objectives. Tumor having 90º arterial involvement and/or venous involvement between 90º and 270º without occlusion were considered borderline, whereas those without arterial involvement and 90º venous involvement were considered resectable. In Arm B, RT included 15 fractions of 2.4 Gy and 1000 mg/m2 gemcitabine. Two hundred forty-eight patients from 16 centres were randomized to Arm A (n = 127) or Arm B (n = 119) for IIT analysis following exclusion between April 2013 and July 2017. Ninety-one patients (91 of 119; 76%) began NACRT in the neoadjuvant group, but after a median follow-up of 27 months, 81 (89%) patients concluded CRT. Between Arm A and B, the median OS was similar (14 vs 16 months; P = 0.07), and the resection rate was not substantially different (72% vs 61%, P = 0.058). However, patients treated with NACRT had a greater R0 resection rate (40% vs 71%; P < 0.001),as well as superior DFS (7.7 months vs 8 months, P = 0.032)and locoregional failure-free interval (P = 0.0034).Additionally, in the NACRT group, there were also fewer patients with pathologic lymph nodes(78% vs 33%, P < 0.001).Addressing toxicity, 52 (42%) patients in the immediate surgery group and 62 (52%) patients in the preoperative CRT group had at least one major adverse effect (P = 0.096).Adjuvant chemotherapy was initiated in Arm A in 51% of cases (65 of 127 patients) and Arm B in 46% of cases (55 of 119 patient). However, in the preoperative CRT group, adherence to the prescribed chemotherapy was higher than the intended postoperative chemotherapy in the immediate surgery group (51% vs 76%). As far as we know, this is the only multicentre, randomized study comparing NACRT and UFS in patients with BRPC and RPC that did not show an OS improvement in the ITT[54]. On the contrary, at a median follow-up of 59 months, the PREOPANC-1 study showed a substantially greater OS benefit in the NACRT group than in the UFS group (P = 0.025), according to the updated version that reviewed long-term findings[55].
Combination of chemotherapy and radiotherapy in BRPC
One hundred ten BRPC patients from four tertiary referral institutions participated in a Korean phase 2/3 multicentre RCT. They were randomized to receive either gemcitabine-based NACRT followed by surgery (Arm A) or UFS followed by CRT (Arm B). Both arms received adjuvant gemcitabine. The 2-year survival rate (YSR) was the primary endpoint. R0 resection rate and 1-YSR were the secondary outcomes. Radiological confirmation of BRPC was by the NCCN standards from 2012[56]. RT included 45 Gy in 25 fractions and 9 Gy in 5 fractions using a three-dimensional conformal radiotherapy method. After surgery and chemoradiation, maintenance chemotherapy with gemcitabine was administered four to six weeks later, regardless of the treatment order in both groups. Out of the 50 patients enrolled, 27 were randomly assigned to Arm A and 23 to Arm B. Overall 2-YSR (41% vs 26%) and median survival (21 months vs 12 months; P = 0.028) were significantly greater in the NACRT group than in the UFS group, according to the study’s results with intention-to-treat purpose. While the UFS group had better resection rates [18/23 (78%) vs 17/27 (63%)], the NACRT group also had a considerably greater R0 resection rate (26.1% vs 52%, P = 0.004). Additionally, the NACRT group had considerably smaller tumor size and fewer positive lymph nodes than the UFS group (P = 0.014 and P = 0.003, respectively). Chemotherapy maintenance has been completed by (n = 8 vs n = 6) (A vs B). The two arms recurrence patterns did not differ significantly from one another (P = 1.000)[42].
In ALLIANCE A021101, Katz et al[57] carried out the first prospective, multicentre, single-arm trial of a multimodality therapy regime for BRPC patients with the collaboration of 14 member institutions. Preoperative modified FOLFIRINOX was administered to trial participants for four cycles, followed by capecitabine-based NACRT and adjuvant chemotherapy with gemcitabine for two cycles. The primary result is feasibility, which is determined by the accrual rate, the pancreatectomy rate, and the safety of the preoperative regime. According to the NCCN, resectability was defined[58,59]. External beam radiation was administered with three-dimensional conformal radiotherapy or intensity-modulated technique with a dose of 50.4 Gy at 1.8 Gy/fraction. From May 29, 2013, until February 7, 2014, 23 patients registered. The accrual rate was 2.6 patients each month, significantly higher than the anticipated rate of 2 patients per month. After completing their preoperative treatment, of the 22 patients who initiated therapy, 15 (68%) patients had resection. Of the 15 patients, 14 (93%) had an R0 resection, and 2 (13%) resected specimens showed a pathologic complete response to preoperative treatment. Following modified FOLFIRINOX, a radiologic response to preoperative therapy was noted in 6 (27%) patients, with 2 exhibiting complete responses. Of the 22 patients, 14 (64%) had at least one adverse event of grade 3 or higher adverse event that was presumed to be somewhat connected to preoperative treatment. Of the 22 patients, the median OS was 21.7 months.
A single-arm, phase 2 clinical study was carried out at Massachusetts General Hospital to demonstrate the effectiveness of the complete neoadjuvant approach for enhancing outcomes in patients with BRPC. The regime comprised neoadjuvant FOLFIRINOX-based therapy and then NACRT and surgery. A multidisciplinary team defined the radiographic resectability criteria. The primary objective was to assess the margin-negative (R0) resection rate. Prospectively enrolled BRPC patients who underwent eight cycles of neoadjuvant FOLFIRINOX and customized NACRT as part of this clinical trial supported by the National Cancer Institute were included in the study. Patients who had resolved vascular involvement after restaging following neoadjuvant FOLFIRINOX were given a short-course NACRT with capecitabine. In contrast, those with residual vascular involvement were given a long-course NACRT with capecitabine/5-fluorouracil. Short-course proton treatment was administered for two weeks utilizing 240-MeV protons produced from a cyclotron employing 3-dimensional, passively scattered protons to a dose of 25 Gy in five fractions or 30 Gy in ten fractions photons. Long-course RT was administered with a 6-MV photon at 50.4-58.8 Gy in 28 fractions using intensity-modulated radiation treatment. When intraoperative RT was employed, 10 Gy was administered if the tumor was removed and 15 Gy if not. Of the 48 eligible patients, 39 (81%) received all scheduled cycles of FOLFIRINOX between August 3, 2012 and August 31, 2016. Of the 48 patients, 44 (92%) underwent CRT: Short-course CRT (15 protons and 12 photons) was administered to 27 (56%) patients and long course CRT to 17 (35%) patients, 32/48 (67%) later had surgery following complete neoadjuvant treatment. Of all evaluable patients, 31/32 (97%) had R0 resection, translating to a 29/43 (65%) R0 resection rate. Only grade 1 and 2 toxicities were reported during CRT, but 9 out of 48 (19%) eligible patients experienced grade 3 or higher toxicity during FOLFIRINOX induction. With a postoperative rate of 37% positive lymph nodes among patients, this study did not find any complete pathologic reponses. Following a median follow-up of 18 months, the 2-year OS was 56%, and the 2-year PFS was 43%. The median OS and PFS were 38 months and 14.7 months, respectively[60]. The Alliance A021501 study, a randomized phase 2 study approved by National Cancer Institute for activation in 2016, further assessed the prospective experience with short-course RT in addition to FOLFIRINOX in the neoadjuvant setting. In this study, BRPC patients were randomly assigned to either seven cycles of modified FOLFIRINOX plus hypofractionated radiation (n = 56) or eight cycles of neoadjuvant modified FOLFIRINOX (n = 54). With 18-month OS of 66.4% vs 47.3%, resection rates of 49% vs 35%, and adverse events of grade 3 and higher of 57% vs 64%, respectively, modified FOLFIRINOX was demonstrated to be more effective than the combination of modified FOLFIRINOX with CRT[61].
Sixteen pancreatic centres participated in the multicentre open-label RCT known as the ESPAC-5F study. Patients with BRPC made up the intended population. In accordance with the US NCCN Clinical Practice Guidelines in Oncology, contrast-enhanced CT scan criteria define a resectable mass in pancreatic head[62]. Recruitment and resection rates were the two primary endpoints. The secondary outcome measures were quality of life, OS, DFS, and R0 resection margin rate. Patients were randomly assigned to one of the following groups (2:1:1:1). The options include neoadjuvant gemcitabine + capecitabine, neoadjuvant FOLFIRINOX, neoadjuvant capecitabine based chemoradiotherapy or UFS. The neoadjuvant CRT group was exposed to RT for five weeks to a total dose of 50.4 Gy divided into 28 daily fractions (1.8 Gy per fraction). Of the 86 patients in the study set, 31 were assigned to the immediate surgery group and 55 to the pooled NAT groups. Hence, the study’s overall enrollment rate of 2.16 people per month fell short of the anticipated goal of recruiting 100 patients. Out of 55 patients, 44 (80%) completed neoadjuvant treatment. After a median follow-up of 12.2 months with an intension-to-treat intent, the combined neoadjuvant group demonstrated significantly improved 1-year OS (P = 0.0028) and one year DFS (59% vs 33%, P = 0.016) compared to immediate surgery. Moreover, combined neoadjuvant therapies revealed a superior R0 resection rate (23% vs 14%, P = 0.49), but higher resection rates are observed in the UFS group (55% vs 68%, P = 0.33) although not statistically significant. Overall, these findings support the use of short-course neoadjuvant chemotherapy with either gemcitabine plus capecitabine or FOLFIRINOX to likely enhance OS in operable pancreatic cancer, but the optimal delivery method remains uncertain. Furthermore, compared to UFS group, NAT showed a lower positive lymph node (90% vs 77%). The NACRT group had the lowest two (25%) positive lymph nodes and the highest R0 resection rate (37%) of the neoadjuvant groups. At a median follow-up of 12.2 months with an intention-to-treat, the combined neoadjuvant group’s 1-year OS was significantly superior (P = 0.0028). Of the 68 patients who underwent resection, 29 (43%) experienced surgical complications: 14 (50%) of 28 in the immediate surgery group and 15 (38%) of 40 for the combination NAT (P = 0.54). Although the ideal administration strategy is yet unknown, this study’s results suggest using short-course neoadjuvant chemotherapy with either gemcitabine plus capecitabine or FOLFIRINOX to improve OS in operable pancreatic cancer[63].
Another multicentre, single arm, phase II experiment was conducted by Takahashi et al[64] to assess the benefit of neoadjuvant S-1 (a prodrug of 5-fluorouracil) based NACRT. The trial recruited 52 eligible BRPC patients. The R0 resection rate was the main outcome. Before surgery, each patient received S-1 (40 mg/m2) and concomitant RT (50.4 Gy in 28 fractions). Fifty (96%) of these patients underwent NAT, and of them, 52% had an R0 resection rate with 43% grade 75% toxicity with NACRT. The median OS duration was 30.8 months among the 41 centrally confirmed BRPC patients.
PREOPERATIVE THERAPIES FOR RESECTABLE AND BORDERLINE RESECTABLE PANCREATIC CANCER: INSIGHTS FROM DIFFERENT TRIALS
As noted in RPC, both Golcher et al[41] and Casadei et al[52] could not be completed and was stopped due to poor randomization rate; however, the planned percentage of the population in the later trial was 27.5% higher than that of Golcher et al[41]. As the recommended treatment for RPC, patients most often favored UFS over NACRT, perhaps due to their wish to have these aggressive tumors excised as rapidly as possible. Although survival is anticipated to be impacted by higher R0 resection rates following neoadjuvant treatment[65,66]. NACRT did not demonstrate any impact in these highly underpowered trials. According to Casadei et al[52], which demonstrates patient tolerance of NACRT, almost 80% of the patients finished NACRT without dose changes. In comparison, the remaining patients ended NACRT after receiving all radiation and at least 75% of the chemotherapy dose. Furthermore, less serious but controllable preoperative and postoperative problems were observed during NACRT, most likely due to fibrosis induction, which enhances the pancreatic tissue’s tolerance for anastomosis. Similar perioperative morbidity was also observed in a recent meta-analysis with or without NAT[66]. Despite being an older drug, gemcitabine continues to be recommended in a number of first-line treatment regimens. Future trials should focus on incorporating more sophisticated systemic treatments while acknowledging gemcitabine’s ongoing importance in particular clinical settings. Lastly, Golcher et al’s trial[41] was multicentre, but Casadei et al’s study[52] included only one centre, which may have contributed some bias in the later trial. The PREOPANC-1 trial, which included both RPC and BRPC, demonstrates that the biological behavior was likely more significant than the local breadth of the tumor’s responsiveness to NAT with the NACRT group here had a considerably higher R0 resection rate (40% vs 72%, P = 0.001). After a longer follow-up of 59 months, this might have resulted in a considerable survival benefit for NACRT over UFS[54,55]. Furthermore, in this trial, the clinically relevant benefit of the NACRT group in BRPC patients was noted in the predefined subgroup analysis of patients undergoing a resection and receiving adjuvant chemotherapy. While further investigation is necessary to ascertain whether preoperative treatment is more beneficial in BRPC or both groups, the recently released phase 2/3 JSAP-05 trial showed that preoperative chemotherapy (gemcitabine and S-1) was significantly more beneficial than immediate surgery for RPC, with a median OS of 36.7 months vs 26.6 months[67]. Better adherence to NACRT contrasted with postoperative adjuvant chemotherapy suggested more evidence of neoadjuvant approach’s superiority in the PREOPANC-1 study[55]. Even though NACRT was more effective than UFS for BRPC, which increased 1-YSR and 2-YSR survival, higher R0 resection, and significantly reduced tumor size and pathologic lymph node compared to UFS in Jang et al[42], it showed no difference in the recurrence patterns (88.2% vs 88.9%). Consequently, even after NAT and resection, a more efficient systemic therapy was needed to improve long-term survival by lowering metastasis and recurrence. Preoperative FOLFIRINOX was employed in two phase 2 trials by Murphy et al[60] and Katz et al[57] in a prospectively selected subgroup of BRPC patients to increase lifetime by halting the development of disease both locally and remotely. Murphy et al[60]. discovered that the 2-year median PFS and median OS were substantially improved compared to those of historical controls who received solely adjuvant chemotherapy by using this more aggressive regimen in their study[68]. Neoadjuvant FOLFIRINOX, followed by CRT, had a favorable toxicity profile, with no grade 3 toxicity exceeding 10% and no fatalities. In the most extensive evaluation of this regimen, a meta-analysis of retrospective studies in 315 patients with locally advanced disease revealed a median OS of 24.2 months and a 25% R0 resection rate[69]. A different trial design was applied by Katz et al[57], with FOLFIRINOX being restricted to four cycles due to concern that its toxicity would render the next procedure that was anticipated to be necessary for a cure unfeasible. Even though the study’s accrual rate was higher than the target rate with controllable toxicities, Katz et al[57] revealed a minor setback with a median OS of 21 months as opposed to 37.7 months in Murphy et al[60]. A primary reason for the disparity in median OS were the design variation in Katz et al[57], only 10 out of 22 patients got adjuvant gemcitabine, and there were fewer induction cycles of FOLFIRINOX administration. Hence, optimizing upfront treatment with FOLFIRINOX during the window of preoperative tolerance may impact survival due to micrometastatic propensity of pancreatic cancer. In Murphy et al[60], the postoperative rate of positive lymph nodes among patients who had resection was 37%, significantly lower than the reported rate of patients suitable for UFS (60%-80%)[70]. Katz et al’study[57] findings that there were apparent disparities between a tumor’s evident response to therapy and an alteration in its dimension and anatomic extent were inconsistent with the results of previous retrospective investigations that described significant “downstaging” of PAC as rare[31,71]. Compared to previous non-FOLFIRINOX-based studies that revealed rates of R0 resection of about 40%, the combined results of these two prospective trials point to a favorable percentage of R0 resection in BRPC[18]. Another trial with BRPC patients also examined the benefits of neoadjuvant S-1 based NACRT, which effectively raised the R0 resection rate and enhanced survival[64]. Moreover, customized RT is the main confounding factor in the interpretability of the rate of R0 resection in Murphy et al[60]. Although better LC is undoubtedly linked to RT use, it was unclear if this could transform into better OS because previous prospective experience with short-course RT was restricted to resectable cases. Further, a recent study, Alliance A021501, specific to BRPC, found that modified FOLFIRINOX was effective in contrast to the combination of modified FOLFIRINOX and hypofractionated RT[61]. Intraoperative RT was another possible confounding factor that could boost results, but since it is not frequently accessible, it may hinder generalizability in Murphy et al[60]. The ESPAC-5F data demonstrated that RT was less successful than chemotherapy in neoadjuvant BRPC therapy, supporting the basic biological feature of PAC as a systemic illness. However, the best way to provide this treatment is yet unknown. Additionally, neoadjuvant short course chemotherapy using gemcitabine plus capecitabine or FOLFIRINOX resulted in lower grade 3-4 toxicity compared to studies involving locally advanced disease, metastases or following surgery. The reason for this might be the brief follow-up period and only two months therapy duration for the patients assigned to ESPAC-5F[63].
STANDARD OF CARE-CURRENT GUIDELINES FOR RPC AND BRPC
Guidelines for neoadjuvant treatment used for pancreatic cancer treatment include the NCCN, the ASCO and the European Society for Medical Oncology. These guidelines recommendations are primarily based on systemic reviews of cohort studies due to lack of large RCTs. NCCN guidelines recommend either UFS or NAT for RPC but suggest considering NAT for BRPC and high-risk patients with equivocal or indeterminate imaging findings, markedly elevated CA19-9, large primary tumors, large regional lymph nodes, excessive weight loss and extreme pain. NCCN members prefer NAT at or coordinated through a high volume centre with positron emission tomography-CT scan used for disease assessment before and after NAT[21]. ASCO guidelines recommend primary surgical resection followed by six months of adjuvant chemotherapy in patients without radiographic evidence of metastatic disease in the absence of medical or surgical contraindications, while NAT is considered for those not meeting all criteria. NAT options include gemcitabine/nab-paclitaxel or FOLFIRINOX, perhaps with or without subsequent CRT. Adjuvant treatment typically involves modified FOLFIRINOX or gemcitacine-based therapies[2]. European Society for Medical Oncology guidelines recommend six months of adjuvant modified FOLFIRINOX for selected fit individuals with resectable tumors with gemcitabine-capecitabine as an alternative option. In medically fit BRPC individuals with no disease progression and a decline in CA19-9, induction treatment with gemcitabine or FOLFIRINOX is followed by CRT and surgery[72].
ROLE OF RT
Although there is prospective evidence that NACRT improves OS, the role of RT remains undefined[42,55]. Nevertheless, because of its locoregional effects, RT is thought to aid in survival; nonetheless, its inclusion in a NAT paradigm for PAC is debatable[61,73]. Large margins were previously employed in treatment volumes with conventional CRT, which increased coverage at the possible expense of toxicity[74,75]. Treatment volumes have been a topic of discussion when it comes to treating patients with pancreatic cancer, especially those with BR. Furthermore, much debate surrounds dose escalation for pancreatic cancer to reach an ablative radiation dose biologically effective dose (BED10 ≥ 100 Gy). The proximity to the gastrointestinal organs at risks of the stomach, small colon, and duodenum can restrict the delivery of such ablative dosages. On the other hand, modern radiation procedures have made it possible to administer ablative radiation doses more safely and promise improved outcomes in the future. These advancements, however, can lead to variable patient outcomes among trials employing different RT techniques, which could led to intense discussion over the applicability of treatment methods across different cancer facilities. The Alliance trial’s early completion and PREOPANC’s effectiveness with more significant target volumes led to a debate concerning optimal practices. Given the challenges encountered in delivering stereotactic ablative RT (SBRT) plus the subsequent complex operations across several centres, the A021501 trial illustrates how SBRT might have been implemented prematurely[61]. Moreover, issues with SBRT in this trial are identified in the post-hoc analysis, which shows that: (1) Defects in field coverage or contouring were present in over half of the cases; and (2) In one-third of the cases, the planning area or contouring was inappropriate, which may have impacted the standard of care and patient prescription. Moreover, insufficient experience with major pancreatic surgery following SBRT might have also contributed to lower resection rates. Consequently, the A021501 trial’s findings should not be interpreted as eliminating RT achievable benefits, and with the assistance of this data, physicians can conclude by contrasting different treatment approaches.
FUTURE PROSPECTIVES
The SOFT study (NCT03704662)[76] is one ongoing study in which patients are randomized to receive fractionated CRT or SBRT following neoadjuvant chemotherapy and prior to surgical resection for pancreatic cancer. The MASTERPLAN (NCT04089150) and PANDAS-PRODIGE 44 (NCT02676349), which combine RT with FOLFIRINOX, are two ongoing trials that seek to gather additional knowledge concerning the role of RT in locally advanced and potentially operable pancreatic cancer. Losartan and hypofractionated RT after induction chemotherapy are being tested in the University of Utah’s SHAPER (NCT04106856) trial for patients with upfront unresectable illness. In patients with vascular involvement, the Massachusetts General Hospital’s PACER trial (NCT03716531) assesses intraoperative electron beam radiation treatment after CRT. Thus, these innovative experiments highlight the continuous efforts to improve NAT protocols and enhance PAC patient outcomes through combination therapies and sophisticated radiation techniques.
CONCLUSION
In conclusion, the main topics of discussion are the various perspectives amongst interdisciplinary centres on respectability prediction, vascular resection goals, criteria for cancelling tumor resection during exploratory laparotomy, and adjuvant chemotherapy in both RPC and BRPC. In addition to this context, a comprehensive effort must be made to prospectively standardize the effectiveness and caliber of all therapeutic modalities, including surgical quality assurance, to serve as a framework for future regimens. We campaign for patient participation with a good performance status in the large ongoing RCTs evaluating the potential benefit of NACRT for RPC and BRPC patients. Future research should focus on choosing the appropriate multimodal treatment for RPC and BRPC based on the biological behavior of the tumor rather than locoregional staging, which is currently the main factor in treatment choices. Better knowledge of the clinic-pathological prognostic variables, such as molecular profiling and new biomarkers, is anticipated to result in more efficient approaches to combat this challenging disease[77].
Footnotes
Provenance and peer review: Invited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Oncology
Country of origin: India
Peer-review report’s classification
Scientific Quality: Grade A, Grade A
Novelty: Grade A, Grade A
Creativity or Innovation: Grade A, Grade A
Scientific Significance: Grade A, Grade A
P-Reviewer: Li JT S-Editor: Bai Y L-Editor: A P-Editor: Zhao YQ
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