Initial chemotherapy and radiation for nonmetastatic, locally advanced, unresectable and borderline resectable, exocrine pancreatic cancer

INTRODUCTION — Surgical resection offers the only chance of cure for nonmetastatic exocrine pancreatic cancer. However, only 15 to 20 percent of patients have potentially resectable disease at diagnosis; approximately 40 percent have distant metastases, and another 30 to 40 percent have locally advanced, unresectable tumors. Typically, patients with locally advanced, unresectable pancreatic cancer have tumor invasion into adjacent critical structures, particularly the celiac and superior mesenteric arteries. The optimal management of these patients is controversial, and there is no internationally embraced standard approach. Therapeutic options include radiation therapy (RT) alone, chemoradiotherapy, and chemotherapy alone. In some cases, a response to initial therapy will be sufficient to permit an attempt at subsequent resection.

Others have disease that is categorized as "borderline resectable." Although the definition is variable (and often dependent on the individual surgeon), patients with focal tumor abutment of the superior mesenteric artery, encasement of the gastroduodenal artery up to the hepatic artery, or involvement of the superior mesenteric vein/portal vein that is potentially resectable and reconstructible could all fall into this category. While these patients are potentially resectable, the high likelihood of an incomplete resection has prompted interest in strategies to "downstage" the tumor prior to surgical exploration using chemotherapy with and without RT (neoadjuvant therapy).

This topic review will focus on initial chemotherapy and RT for patients with nonmetastatic, locally advanced, unresectable or borderline resectable, exocrine pancreatic cancer. Management of patients with potentially resectable disease, systemic chemotherapy for patients with metastatic disease, and a compilation of chemotherapy regimens used for treatment of pancreatic cancer are discussed separately. (See "Treatment for potentially resectable exocrine pancreatic cancer" and "Overview of surgery in the treatment of exocrine pancreatic cancer and prognosis" and "Initial systemic chemotherapy for metastatic exocrine pancreatic cancer" and "Treatment protocols for pancreatic cancer".)

DEFINITIONS — An assessment of resectability is usually made based on a preoperative staging contrast-enhanced computed tomography scan and less commonly at the time of laparotomy/laparoscopy. A variety of other imaging modalities, including magnetic resonance imaging, endoscopic ultrasound, as well as staging laparoscopy, may be needed in some circumstances. This topic is addressed in detail separately. (See "Clinical manifestations, diagnosis, and staging of exocrine pancreatic cancer", section on 'Imaging studies'.)

Criteria for unresectability — In general, pancreatic cancers can be categorized along a continuum from resectable to unresectable according to the involvement of adjacent structures and the presence of distant metastases (figure 1) [1].

A pancreatic cancer is categorically unresectable if distant metastases are present in the liver, peritoneum, omentum, or any extra-abdominal site.

Local unresectability is usually (but not always) due to vascular invasion, particularly of the superior mesenteric artery (SMA) (figure 2). Although practice is variable across institutions, many surgeons would consider a pancreatic cancer to be locally advanced and unresectable if it is associated with encasement (more than one-half of the vessel circumference) of the SMA or celiac artery, occlusion of the superior mesenteric vein (SMV) or SMV-portal vein confluence without suitable vessels above and below the tumor to allow for reconstruction.

We follow the consensus-based guidelines from the National Comprehensive Cancer Network (NCCN) [2], which are largely based on a consensus statement from the Society of Abdominal Radiology/American Pancreatic Association [3] and define the following characteristics as indicating unresectability:

●Head of pancreas/uncinate lesions:

•Solid tumor contact with the SMA >180 degrees

•Solid tumor contact with the celiac axis >180 degrees

•Solid tumor contact with the first jejunal SMA branch

•Unreconstructable SMV or portal vein due to tumor involvement or occlusion (can be due to tumor or bland thrombus)

•Contact with the most proximal draining jejunal branch into the SMV

●Body and tail lesions:

•Solid tumor contact of >180 degrees with the SMA or celiac axis

•Solid tumor contact with the celiac axis and aortic involvement

•Unreconstructable SMV or portal vein due to tumor involvement or occlusion (can be due to tumor or bland thrombus)

●For all sites:

•Distant metastases

•Metastases to lymph nodes beyond the field of resection

Similar guidelines are available from the European Society for Medical Oncology (ESMO) [4] and others [5].

Many of these patients will be managed nonsurgically with initial chemotherapy with or without chemoradiotherapy, although there are some exceptions. Increasingly, a sufficient downstaging response will be obtained after multiagent chemotherapy so that subsequent resection can be considered. Celiac artery resection can be done and appears to be safe [6,7], but this is a novel approach and is not reflected in guidelines from any group. (See 'Locally advanced, unresectable disease' below.)

Borderline resectable — Some cases are considered "borderline" resectable, although the definition is variable [8-11] and the point at which the transition takes place along the continuum from resectable to unresectable locally advanced disease is not well defined (figure 1) [1].

Some reserve the term "borderline resectable" for cases where there is no more than focal (less than one-half of the circumference) tumor abutment of the visceral arteries or short-segment occlusion of the SMV, portal vein, or SMV/portal vein confluence [8,12,13]. Others suggest that venous narrowing without occlusion also be included in the definition of borderline resectable disease [14-16]. Still others suggest that there be no interface between the tumor and the mesenteric vasculature for a pancreatic cancer to be considered "potentially resectable" [17]. Definitions continue to evolve over time, with some groups also taking into account nonanatomic "conditional" criteria, such as performance status and patient comorbidities, which significantly increase the risk for morbidity or mortality after surgery [18,19]. However, this is not a widespread practice.

An important issue is that encasement (more than one-half of the vessel circumference) or occlusion of the SMV or the SMV-portal vein confluence (figure 2) used to be considered a criterion for unresectability. However, with increasing experience in vascular reconstruction, fewer pancreatic surgeons view such cases as unresectable. Many centers have demonstrated the feasibility of SMV reconstruction, and this is now considered by many to represent borderline resectable disease, as long as there is a suitable vessel proximal and distal to the area of involvement. (See "Surgical resection of lesions of the head of the pancreas", section on 'Vascular evaluation' and "Surgical resection of lesions of the head of the pancreas", section on 'Vein excision and reconstruction'.)

The NCCN formally defines the category of borderline resectable pancreatic cancer [2], largely based on a consensus statement from the Society of Abdominal Radiology/American Pancreatic Association [3], as follows:

●For tumors of the head or uncinate process:

•Solid tumor contact with the SMV or portal vein of >180 degrees with contour irregularity of the vein or thrombosis of the vein, but with suitable vessel proximal and distal to the site of involvement, allowing for safe and complete resection and vein reconstruction.

•Solid tumor contact with the inferior vena cava.

•Solid tumor contact with the common hepatic artery without extension to the celiac axis or hepatic artery bifurcation, allowing for safe and complete resection and reconstruction.

•Solid tumor contact with the SMA ≤180 degrees.

•Solid tumor contact with variable anatomy (eg, accessory right hepatic artery, replaced right hepatic artery, replaced common hepatic artery, and the origin of replaced or accessory artery), and the presence and degree of tumor contact should be noted if present, as it may affect surgical planning.

●For tumors of the body/tail:

•Solid tumor contact with the celiac axis of ≤180 degrees.

•Solid tumor contact with the celiac axis >180 degrees without involvement of the aorta and with an intact and uninvolved gastroduodenal artery, thereby permitting a modified Appleby procedure [20] (although some members of the consensus committee preferred this criteria to be in the unresectable category).

ESMO also recommends following the NCCN definitions for resectability [2,4]. The American Society of Clinical Oncology guidelines do not specifically address the definition of "borderline resectable pancreatic cancer," but they recommend preoperative therapy rather than initial surgery for any patient with no clinical evidence of metastatic disease who has what appears to be potentially resectable pancreatic cancer with a radiographic interface between the primary tumor and mesenteric vasculature on cross-sectional imaging [21].

Patients with borderline resectable disease differ from those with potentially resectable disease in that they are at a high risk for a positive margin of resection due to tumor artery abutment [22]; they require a more complex operation, usually involving vascular resection and reconstruction; and they may be at higher risk of harboring radiographically occult metastatic disease. At many centers, all patients who meet the definition for borderline resectable disease because of vascular involvement are referred for some form of induction (neoadjuvant) treatment to increase the likelihood of a margin-negative resection. (See 'Role of surgery' below and "Overview of surgery in the treatment of exocrine pancreatic cancer and prognosis", section on 'Vascular resection'.)

APPROACH TO THE PATIENT

Pretreatment considerations — A multiphasic computed tomography scan of the chest, abdomen, and pelvis should be performed to assess disease extent [23]. Other staging studies should be performed only as dictated by symptoms. Serum levels of the tumor marker cancer antigen 19-9 should be measured at the start of treatment and then, if elevated, every one to three months during therapy. (See "Clinical manifestations, diagnosis, and staging of exocrine pancreatic cancer", section on 'Abdominal CT' and "Clinical manifestations, diagnosis, and staging of exocrine pancreatic cancer", section on 'Carbohydrate antigen 19-9'.)

All patients should have a full assessment of symptom burden, psychologic status, and social supports as early as possible. In most cases, this will indicate a need for formal palliative care consultation and services [24]. Early initiation of palliative care services improves clinical and quality of care outcomes, and may prolong survival. (See "Benefits, services, and models of subspecialty palliative care", section on 'Rationale for palliative care'.)

All patients with locally advanced pancreatic cancer should be offered aggressive treatment of pain and other symptoms of cancer, and/or cancer-directed therapy [24]. (See "Supportive care for locally advanced or metastatic exocrine pancreatic cancer".)

Multidisciplinary collaboration to formulate treatment and care plans is preferred. Baseline performance status and a comorbidity profile should be evaluated. Goals of care, patient preferences, psychologic status, support systems, and symptoms should guide decisions for treatment [24]. (See "Discussing goals of care" and "Supportive care for locally advanced or metastatic exocrine pancreatic cancer".)

All patients should be offered information about clinical trials. Enrollment in available clinical trials is preferred, if available.

Patients undergoing neoadjuvant therapy — Management of nonmetastatic pancreatic cancer is in evolution, but increasingly, initial chemotherapy using combination regimens is favored. The rationale for neoadjuvant chemotherapy is as follows:

●Improve the selection of patients for whom resection will not offer a survival benefit (ie, those who rapidly progress to metastatic disease during preoperative therapy).

●Increase rates of margin-negative resection, which is the major goal of surgery.

●Early treatment of micrometastatic disease.

Acknowledging that few of these treatment approaches are supported by high-quality evidence, a suggested algorithmic approach to management of nonmetastatic exocrine pancreatic cancer utilizing upfront chemotherapy for both locally advanced unresectable disease and borderline resectable disease is presented below. (See 'Treatment algorithm' below.)

Important pretreatment considerations for individuals who will be treated initially with chemotherapy include the following:

●A tissue diagnosis should be established before initiation of therapy. This differs from a surgery-first strategy, in which preoperative tissue diagnosis may not be needed. (See "Clinical manifestations, diagnosis, and staging of exocrine pancreatic cancer", section on 'Diagnostic algorithm and need for preoperative biopsy'.)

●For patients who present with obstructive jaundice, delivery of neoadjuvant therapy necessitates durable biliary decompression for as many as six months. This can usually be accomplished through placement of a biliary stent. This subject, which includes a discussion of different types of stents, is provided elsewhere. (See "Surgical resection of lesions of the head of the pancreas", section on 'Preoperative biliary drainage' and "Endoscopic stenting for malignant biliary obstruction" and "Supportive care for locally advanced or metastatic exocrine pancreatic cancer", section on 'Jaundice'.)

Genomic and targeted tumor genetic testing — For patients with locally advanced pancreatic cancer, both genomic (ie, germline) testing (if not already known) and gene profiling of tumor tissue (ie, with next-generation sequencing) should be undertaken as quickly as possible after diagnosis. Pathogenic or likely pathogenic alterations in the breast cancer susceptibility (BRCA) or partner and localizer of BRCA2 (PALB2) gene are present in approximately 10 percent of pancreatic cancer specimens. Approximately one-half of these will have somatic alterations only, and one-half will be germline (ie, roughly 5 percent of patients with pancreatic cancer have a germline BRCA or BRCA-like [ie, PALB2] mutation). (See "Familial risk factors for pancreatic cancer and screening of high-risk patients", section on 'Hereditary breast cancer: BRCA and PALB2' and "Cancer risks and management of BRCA1/2 carriers without cancer", section on 'Pancreas'.)

In principle, all patients with a germline BRCA or PALB2 pathogenic or likely pathogenic variant should have that same variant detected (if looked for) in the tumor. For patients whose germline BRCA or PALB2 variant carrier status is not known, targeted tumor testing that identifies the presence of a BRCA or BRCA-like pathogenic variant might be interpreted as likely somatic or germline, but most tests cannot reliably distinguish between the two, and this may not be reported uniformly by all the different companies that provide this service. Furthermore, pathogenic germline variants (PGVs) may be missed by tumor testing alone for a variety of reasons, including technical limitations of tumor sequencing (especially small copy number deletions and large or complex insertions or deletions), variant interpretation differences between tumor and germline tests, or differences in the genes tested in the tumor and the germline. In one report, in which 2023 patients with cancer unselected for family history received germline testing and previously had tumor DNA sequencing, PGVs were found in 617 (30.5 percent), and in 41.7 percent of the 187 pancreatic cancers [25]. Potentially more importantly, 8.1 percent of the PGVs were missed by tumor sequencing. Thus, tumor testing cannot substitute for germline testing in patients for whom a PGV in a gene such as a BRCA or PALB2 might influence treatment decisions, as described below.

Influence on choice of chemotherapy agents — Cells that lack BRCA have a deficiency in the repair of DNA double-strand breaks. There is accumulating evidence of increased sensitivity to platinum agents in BRCA-associated breast and ovarian cancers. (See "Medical treatment for relapsed epithelial ovarian, fallopian tube, or peritoneal cancer: Platinum-sensitive disease", section on 'PARP inhibition in BRCA carriers' and "ER/PR negative, HER2-negative (triple-negative) breast cancer", section on 'Germline BRCA mutation'.)

In addition to BRCA and PALB2, pathogenic or likely pathogenic alterations in other genes involved in homologous recombination repair (HRR; including ATM, BAP1, BARD1, BLM, BRIP1, CHEK2, FAM175A, FANCA, FANCC, NBN, RAD50, RAD51, RAD51C, and RTEL1) are associated with a defective DNA damage response, which increases sensitivity to DNA damaging agents, such as platinum agents, and to drugs targeting the DNA damage response pathway, including poly(ADP-ribose) polymerase inhibitors. (See "Initial systemic chemotherapy for metastatic exocrine pancreatic cancer", section on 'Germline and targeted tumor genomic testing' and "Initial systemic chemotherapy for metastatic exocrine pancreatic cancer", section on 'General principles' and "Familial risk factors for pancreatic cancer and screening of high-risk patients".)

There are no prospective studies comparing platinum-containing versus non-platinum-containing chemotherapy regimens as neoadjuvant therapy in patients with locally advanced, unresectable, but not metastatic pancreatic cancer. Nevertheless, there are emerging data supporting the sensitivity of HRR deficiency-associated pancreatic cancers to platinum-based regimens in the setting of metastatic disease, and in the setting of borderline resectable disease [26]. (See "Initial systemic chemotherapy for metastatic exocrine pancreatic cancer".)

Despite the lack of prospective data utilizing a platinum-based regimen as initial therapy, updated consensus-based guidelines from the National Comprehensive Cancer Network (NCCN) suggest consideration of FOLFIRINOX (short-term infusional fluorouracil [FU] plus leucovorin, irinotecan, and oxaliplatin) or gemcitabine plus cisplatin as an alternative to other chemotherapy regimens for neoadjuvant chemotherapy of locally advanced, unresectable pancreatic cancer that harbors a known BRCA or PALB2 pathogenic or likely pathogenic variant [2]. We also consider this a reasonable approach for individuals with other alterations that are associated with HRR deficiency. Our approach to these patients is as follows:

●For patients with known pathogenic or likely pathogenic variants associated with HRR deficiency (BRCA1/2, PALB2, ATM, BAP1, BARD1, BLM, BRIP1, CHEK2, FAM175A, FANCA, FANCC, NBN, RAD50, RAD51, RAD51C, and RTEL1), either germline or somatic, we prefer FOLFIRINOX over other regimens, including gemcitabine plus nanoparticle albumin-bound paclitaxel (nabpaclitaxel) or gemcitabine plus cisplatin, as induction therapy, both in the setting of locally advanced unresectable and borderline resectable pancreatic cancer.

●For patients with unknown (or pending) mutation status, we do not recommend waiting until germline or somatic mutation status is known given the rapidity of disease progression in most patients with newly diagnosed pancreatic cancer. Therefore, FOLFIRINOX has become our standard induction regimen for most patients by default. Often, we start FOLFOX (leucovorin plus short-term infusional FU and oxaliplatin) in those patients who have a borderline performance status and then add irinotecan when we know that patients can tolerate it.

●If germline and tumoral HRR deficiency status is known and there are no pathogenic or likely pathogenic variants, gemcitabine plus nabpaclitaxel is an option, particularly for patients with an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or a comorbidity profile that is inadequate for aggressive therapy.

Treatment algorithm — The treatment of nonmetastatic, locally advanced, unresectable and borderline resectable pancreatic cancer is in evolution:

●Following the development of combination chemotherapy regimens such as FOLFIRINOX and nabpaclitaxel plus gemcitabine that, at least in the setting of metastatic disease, produced significantly higher objective response rates than were seen with gemcitabine alone (23 percent [nabpaclitaxel plus gemcitabine] and 39 percent [FOLFIRINOX] versus approximately 10 percent with gemcitabine alone), many institutions have embraced neoadjuvant combination chemotherapy for initial therapy for both categories of these patients, followed by reevaluation for surgical exploration. This is despite the paucity of evidence from prospective randomized trials that these more intensive neoadjuvant chemotherapy regimens are more effective than other regimens, and acknowledging the fact that the frequency of a complete resection and long-term survival are low for patients who have initially unresectable tumors. (See 'Combination regimens' below.)

●For patients treated initially with multiagent neoadjuvant chemotherapy, the contribution of radiation therapy (RT) to achieving a microscopically complete resection is unclear, and the use of RT in this setting is diminishing. An important area of controversy that informs this debate is the unreliability of imaging to assess resectability after modern combination chemotherapy. (See 'Is there benefit to chemoradiotherapy after initial chemotherapy?' below.)

Our general approach to these patients, which is outlined in the algorithm (algorithm 1) and described in detail in the sections below, is consistent with clinical practice guidelines for treatment of locally advanced, unresectable pancreatic cancer from the American Society of Clinical Oncology [24], as well as consensus-based guidelines from the NCCN [2] and the European Society for Medical Oncology [4].

Jaundiced patients and those with a poor performance status — The management of patients with either borderline resectable or locally advanced unresectable but nonmetastatic pancreatic cancer who have a persistently elevated total bilirubin or an ECOG performance status of 2 or higher (table 1) can be particularly challenging. An individualized decision must be made as to suitability for neoadjuvant therapy and the specific approach to be used:

●For patients who present with obstructive jaundice, delivery of neoadjuvant therapy necessitates durable biliary decompression for up to six months. This can usually be accomplished through placement of a biliary stent. (See "Surgical resection of lesions of the head of the pancreas", section on 'Preoperative biliary drainage' and "Endoscopic stenting for malignant biliary obstruction" and "Supportive care for locally advanced or metastatic exocrine pancreatic cancer", section on 'Jaundice'.)

For patients with persistently elevated bilirubin despite stenting, a decision must be made prior to initiating chemotherapy as to whether there is adequate drainage of the common bile duct (CBD). If good visualization of the CBD was not seen on endoscopic retrograde pancreatography, a repeat attempt at adequate drainage should be considered, or the possibility of transhepatic drainage should be discussed. For those patients who have persistently elevated bilirubin levels but good drainage of bile through the CBD into the small intestine or through a transhepatic catheter, consideration could be given to dose-adjusted FOLFIRINOX or gemcitabine/nabpaclitaxel with close monitoring of toxicities. In this manner, patients may have the opportunity to experience downstaging of their pancreatic cancer so that it might be resected. While single-agent gemcitabine can be used, conversion to resectable in the locally advanced setting is uncommon (<5 percent), and therefore, treatment is not considered potentially curative. (See "Supportive care for locally advanced or metastatic exocrine pancreatic cancer", section on 'Jaundice'.)

●For patients with a poor performance status (≥2, (table 2)), a similar individualized approach to the patient can be considered given that single-agent gemcitabine is generally not considered potentially curative. For instance, if the performance status is poor due to recent infection (eg, cholangitis) and the patient is recovering well after intervention, then consideration could be made for dose-adjusted combination chemotherapy. If the performance status is poor due to locally advanced disease-causing disabling pain and gastric outlet obstruction, then aggressive treatment of the pain and/or gastric outlet obstruction should be considered prior to initiation of chemotherapy. (See "Supportive care for locally advanced or metastatic exocrine pancreatic cancer", section on 'Pain' and "Supportive care for locally advanced or metastatic exocrine pancreatic cancer", section on 'Gastric outlet obstruction'.)

LOCALLY ADVANCED, UNRESECTABLE DISEASE — Patients with nonmetastatic, locally advanced, unresectable disease are not considered candidates for upfront resection; for most patients, this is due to local vascular invasion. (See 'Criteria for unresectability' above.)

Overview of our suggested approach — There is no consensus as to the best approach for patients with locally advanced, unresectable pancreatic cancer. The following represents our recommended approach, which is outlined in the algorithm (algorithm 1):

●For most patients, we prefer enrollment in a clinical trial testing new treatment strategies. If a clinical trial is unavailable or participation is not feasible, we suggest an initial period of chemotherapy rather than immediate radiation therapy (RT) or chemoradiotherapy (CRT). The optimal regimen has not been established, and enrollment of these patients in clinical trials is preferred. If trials are unavailable or participation is not feasible, we base our initial approach on candidacy for chemotherapy and the presence or absence of a pathogenic or likely pathogenic germline or somatic variant in a gene associated with homologous recombination repair (HRR) deficiency (see 'Genomic and targeted tumor genetic testing' above):

•For patients with known variants or if status is unknown or pending, and who have a good performance status and comorbidity profile and have the preference for and support systems to permit aggressive medical therapy, combination chemotherapy with modified FOLFIRINOX (short-term infusional fluorouracil [FU] plus leucovorin, irinotecan, and oxaliplatin) is preferred (table 3).

One option for patients with a borderline performance status or several comorbid conditions is to start with FOLFOX (leucovorin plus short-term infusional FU and oxaliplatin). Irinotecan could be added for later cycles if mutations are discovered in a gene associated with HRR deficiency and the patient has adequately tolerated FOLFOX.

•For patients without HRR pathway alterations in the germline or tumor, options include gemcitabine plus nanoparticle albumin-bound paclitaxel (nabpaclitaxel) or FOLFIRINOX.

•While single-agent gemcitabine can be used, conversion to resectable in the locally advanced setting is uncommon (<5 percent), and therefore, treatment is not considered potentially curative. We restrict this approach to individuals with a performances status of 2 or worse (table 2), or significant comorbidity that precludes the ability to administer more aggressive combination therapy including gemcitabine plus nabpaclitaxel, an approach that is consistent with National Comprehensive Cancer Network (NCCN) guidelines [2].

●A careful assessment of resectability should be undertaken after four to six months of neoadjuvant therapy. In the era prior to FOLFIRINOX and gemcitabine/nabpaclitaxel, it was very rare for tumors to be converted to resectable after gemcitabine or chemoradiation. More recently, multiple institutions have published results showing routine conversion of patients from unresectable to resectable after FOLFIRINOX or gemcitabine/nabpaclitaxel regimens, although the exact rate of conversion has not yet been defined in large, multi-institutional studies. (See 'Combination regimens' below and 'Role of surgery' below.)

●For patients who develop metastatic disease after initial chemotherapy we suggest continued chemotherapy rather than CRT. However, CRT is a reasonable approach to optimize local control in selected patients, such as those who can no longer tolerate further chemotherapy but who continue to have localized disease and maintain a good performance status. (See 'Is there benefit to chemoradiotherapy after initial chemotherapy?' below.)

●For patients who remain potential surgical candidates, concomitant CRT cannot be recommended as a standard approach after initial chemotherapy. However, this is a controversial issue. At some institutions, FU-based CRT or stereotactic body RT (SBRT) or additional chemotherapy would be offered if there was concern that a microscopically complete resection might not be possible following neoadjuvant chemotherapy. However, it is unknown whether RT contributes to a higher resection rate following systemic chemotherapy, particularly if FOLFIRINOX is given. Furthermore, imaging assessment of resectability may be unreliable after initial multiagent chemotherapy [27]. (See 'Is there benefit to chemoradiotherapy after initial chemotherapy?' below.)

●There is considerable debate and institutional variability regarding which patients should be taken to the operating room (OR) after neoadjuvant therapy. In the absence of distant metastases, some centers (including those of some of the authors and editors of this topic) take nearly all patients with a radiographic response to initial chemotherapy for exploration regardless of local imaging findings, while other centers rely more on imaging characteristics to guide surgical decision-making. We await the results of ongoing clinical trials to guide this debate. (See 'Role of surgery' below.)

An important point is that the ability to reliably determine resectability of a locally advanced cancer is limited after multiagent chemotherapy due to the presence of fibrosis and scar tissue. Traditional signs of unresectable disease may not apply in this setting. Because of this, in our view, in the absence of overt metastatic disease, the determination of resectability should be made intraoperatively. Specific issues regarding the accuracy of radiographic assessment after multiagent chemotherapy are discussed below. (See 'FOLFIRINOX' below.)

●For patients who are not considered candidates for surgical exploration, continued chemotherapy is our preferred approach. However, fluoropyrimidine-based CRT could be considered in selected patients, such as those who can no longer tolerate further chemotherapy but who continue to have localized disease and maintain a good performance status.

●RT as a single modality could be considered to palliate pain for a patient who is not considered a candidate for combined CRT due to medical comorbidities, and whose pain is not adequately controlled with narcotic analgesics. Another option is celiac plexus nerve block. (See "Supportive care for locally advanced or metastatic exocrine pancreatic cancer", section on 'Sympathetic neurolytic blocks'.)

Initial chemotherapy — Initial chemotherapy is an increasingly utilized treatment option for patients with locally advanced, unresectable but nonmetastatic exocrine pancreatic cancer.

Combination regimens — In the metastatic setting, many clinicians are now using FOLFIRINOX and gemcitabine combinations such as gemcitabine plus nabpaclitaxel based on the improved activity and survival when these regimens are compared with gemcitabine monotherapy. However, these regimens are also associated with enhanced toxicity, and appropriate patient selection is critically important. (See "Initial systemic chemotherapy for metastatic exocrine pancreatic cancer".)

Alterations in genes associated with HRR deficiency are also a relevant issue given the increased sensitivity to platinum agents in these cancers. (See 'Genomic and targeted tumor genetic testing' above.)

We prefer that eligible patients be enrolled in clinical trials testing novel neoadjuvant strategies. Where such trials are unavailable or patients are ineligible or choose not to participate, upfront combination chemotherapy is a reasonable option for patients with good enough performance status, as long as they understand the lack of data proving benefit for this more toxic approach as compared with single-agent gemcitabine. For most patients, especially those with alterations (germline or somatic) in genes associated with HRR deficiency (as well as those with unknown mutation status), we prefer FOLFIRINOX over gemcitabine/nabpaclitaxel. (See 'Genomic and targeted tumor genetic testing' above.)

The optimal number of courses of neoadjuvant combination chemotherapy has not been established in this setting. The contribution of CRT following initial chemotherapy is addressed below. The approach used at our institutions is outlined in the algorithm (algorithm 1). (See 'Is there benefit to chemoradiotherapy after initial chemotherapy?' below.)

FOLFIRINOX — Many institutions have embraced neoadjuvant FOLFIRINOX (short-term infusional FU plus leucovorin, irinotecan, and oxaliplatin (table 4)) for patients with locally advanced pancreatic cancer and a good performance status, especially in patients who have a germline or somatic alteration in a gene associated with HRR deficiency or if mutation status is unknown or pending. (See 'Genomic and targeted tumor genetic testing' above.)

Although it appears that objective response rates in the primary tumor are at least as good as they are in metastatic disease, there are few data on rates of resectability, perioperative morbidity, and mortality in patients who undergo surgery after receiving FOLFIRINOX for locally advanced, unresectable disease; few data on long-term outcomes; and no adequately powered robust phase III randomized trials proving benefit over less intensive chemotherapy regimens in this setting [28-41].

Nevertheless, the FOLFIRINOX regimen is being increasingly used in this setting as it is an active regimen, and some patients will have sufficient downstaging (with FOLFIRINOX alone or followed by RT/CRT) to permit a later R0 resection [33,36-38,41-44]:

●A systematic review of data from 13 studies of FOLFIRINOX for locally advanced pancreatic cancer (315 patients, most derived from retrospective analysis) concluded that the proportion of patients undergoing surgical resection ranged from 0 to 43 percent (pooled proportion 26 percent), and of those patients undergoing resection, an R0 resection was reported in 74 percent [39]. Although 64 percent of patients received RT after FOLFIRINOX, the independent contribution of RT and/or CRT to these results could not be determined.

●Additional information on the benefits of neoadjuvant FOLFIRINOX in borderline resectable pancreatic cancer is available from a retrospective analysis of data on 1835 consecutive patients presenting with localized pancreatic cancer (52 percent locally advanced, 29 percent borderline resectable, 19 percent potentially resectable) who received at least one cycle of mFOLFIRINOX chemotherapy as initial treatment in one of five referral centers in the United States and Netherlands between 2012 and 2019 [41]. The median number of chemotherapy cycles was 6 (interquartile interval 4 to 8), and subsequent treatment included radiotherapy in 49 percent, and resection in 38 percent. The margin-negative (R0) resection rates for the subgroup with locally advanced unresectable tumors was 55 percent, the median overall survival duration was 18.7 months, and the five-year overall survival rate was 9.5 percent.

At many institutions, CRT or SBRT has been given after initial chemotherapy in an attempt to increase the likelihood of a R0 resection. Unfortunately, it is unknown whether RT contributes to the R0 resection rate in patients treated with aggressive combination regiments like FOLFIRINOX. (See 'Is there benefit to chemoradiotherapy after initial chemotherapy?' below.)

Given the lack of randomized trials comparing FOLFIRINOX with any other neoadjuvant chemotherapy regimen in patients with locally advanced pancreatic cancer, the identification of which patients are most likely to benefit from an aggressive regimen like FOLFIRINOX would greatly assist in treatment decision-making. Additional research is needed in this important area. The few randomized trials that directly compare the benefits of FOLFIRINOX relative to other neoadjuvant regimens in locally advanced or borderline resectable pancreatic cancer are described below. (See 'Gemcitabine combinations versus FOLFIRINOX' below and 'Choice of regimen' below.)

An important point is that postchemotherapy imaging may be unreliable at predicting resectability in patients treated with upfront combination regimens such as FOLFIRINOX [35,45]. This was shown in a multi-institutional retrospective review of 40 patients who received neoadjuvant FOLFIRINOX as initial treatment for locally advanced/borderline resectable disease [35]. Despite the fact that post-treatment clinical staging suggested that 19 were still classified as locally advanced unresectable, and nine had persistently borderline resectable disease, 92 percent had an R0 resection. Although post-treatment imaging should be undertaken to assess the presence of distant metastatic disease, which would preclude an attempt at resection, these data suggest that the determination of resectability should be made intraoperatively.

For most patients, we prefer the modified FOLFIRINOX regimen that uses lower irinotecan doses (table 3).

Gemcitabine combinations — There are even fewer data on gemcitabine combinations especially gemcitabine plus nabpaclitaxel [46,47]. One phase II trial evaluating neoadjuvant gemcitabine plus oxaliplatin in patients with initially unresectable (n = 18) or borderline resectable (n = 15) nonmetastatic pancreatic cancer showed that 40 percent had sufficient tumor regression to undergo operative resection, which was R0 in 69 percent [46]. (See "Initial systemic chemotherapy for metastatic exocrine pancreatic cancer", section on 'Gemcitabine plus nabpaclitaxel'.)

Gemcitabine combinations versus FOLFIRINOX — Few data on the relative efficacy of gemcitabine-containing regimens versus FOLFIRINOX (short-term infusional FU plus leucovorin, irinotecan, and oxaliplatin) in locally advanced pancreatic cancer are available.

●NEOLAP trial – The multicenter, phase II NEOLAP trial initially administered two initial courses of neoadjuvant gemcitabine/nabpaclitaxel, and then randomly assigned the 130 who had neither disease progression nor unacceptable adverse effects to two additional courses of gemcitabine/nabpaclitaxel or two months of FOLFIRINOX [48]. Secondary resectability was assessed by surgical exploration in all patients achieving stable disease or an objective response to neoadjuvant chemotherapy.

In a preliminary report presented at the 2019 European Society for Medical Oncology (ESMO) Congress, sequential FOLFIRINOX was not significantly superior with regard to surgical exploration (approximately 63 percent in each group) or rate of complete macroscopic tumor resection (R0 or microscopically positive [R1] margins, 45 versus 31 percent, odds ratio 0.54, 95% CI 0.26-1.13).

●ESPAC-5F trial – FOLFIRINOX was compared with gemcitabine plus capecitabine in the small randomized phase II ESPAC-5F trial, which focused mainly on the benefits of neoadjuvant therapy over immediate surgery for those with borderline resectable pancreatic cancer [49]. Although FOLFIRINOX provided a greater 12-month overall survival compared with gemcitabine/capecitabine, the trial was not designed to compare different neoadjuvant strategies. (See 'Choice of regimen' below.)

●MD Anderson series – Additional data are available from a retrospective analysis of 485 consecutive patients with potentially resectable (n = 181), borderline resectable (n = 133), or locally advanced unresectable (n = 171) pancreatic cancer treated over an eight-year period at MD Anderson Cancer Center; 285 received FOLFIRINOX and 200 received gemcitabine plus nabpaclitaxel as the first-line regimen [50]. Patients treated with FOLFIRINOX were generally younger and had a better overall performance status, but more locally advanced tumors. After propensity score matching to control for some of these variables, many serologic and radiographic correlates of response were similar between the two groups; however, Response Evaluation Criteria In Solid Tumors partial response was more common with FOLFIRINOX (19 versus 6 percent), and pancreatectomy was subsequently performed more often in this group as well (27 versus 16 percent). Despite this, at a median follow-up of 33 months, the overall survival duration was similar (median 21 versus 20 months).

Gemcitabine alone — The data to support the use of gemcitabine in this setting come mainly from two sources: chemotherapy trials conducted in mixed populations of patients with both locally advanced and metastatic disease, and the few trials that have directly compared FU-based CRT with FU or gemcitabine chemotherapy alone in locally advanced disease. (See 'Comparative studies' below.)

As noted above, conversion to resectable in the locally advanced setting is uncommon with gemcitabine monotherapy (<5 percent), and therefore, treatment is not considered potentially curative. We restrict this approach to individuals with a performances status of 2 or worse (table 2), or significant comorbidity that precludes the ability to administer more aggressive combination therapy including gemcitabine plus nabpaclitaxel, an approach that is consistent with NCCN guidelines [2].

Initial chemoradiotherapy versus chemotherapy — For most patients, we suggest an initial period of chemotherapy rather than initial chemoradiotherapy (CRT). As has been seen in a variety of tumors arising in the gastrointestinal tract, the addition of concurrent chemotherapy to EBRT improves outcomes compared with EBRT alone in patients with locally advanced pancreatic cancer. From the standpoint of symptom palliation, cancer-related pain is diminished in a greater number of patients (35 to 65 percent), and cachexia and obstructive symptoms may also improve. However, a survival benefit from CRT relative to EBRT alone or initial chemotherapy alone has been difficult to demonstrate, and local control remains problematic, even in irradiated patients.

Furthermore, despite initial CRT, many locally advanced pancreatic cancers metastasize rapidly, which has diminished enthusiasm for choosing CRT as initial treatment. Instead, guidelines from ESMO [4] and NCCN [2] advocate induction chemotherapy rather than CRT. A separate issue, whether there is benefit from CRT after initial chemotherapy, is addressed below. (See 'Is there benefit to chemoradiotherapy after initial chemotherapy?' below.)

There are two approaches to CRT for locally advanced pancreatic cancer: fluoropyrimidine-based and gemcitabine-based. The following sections will review the available data on initial CRT.

●FU-based approaches – Most studies evaluating initial CRT for locally advanced pancreatic cancer have evaluated combined fluorouracil (FU) plus EBRT, which are synergistic in other gastrointestinal malignancies. While the majority compare CRT with EBRT alone, the control arm in a few studies was supportive care only [51] or chemotherapy alone.

A survival benefit for the addition of concomitant FU to RT has been difficult to demonstrate; two early randomized trials directly comparing EBRT with and without concomitant FU-based chemotherapy came to opposite conclusions [52-54]. A pooled analysis of both trials concluded that the length of survival with CRT was significantly increased relative to RT alone (hazard ratio [HR] for death 0.69, 95% CI 0.51-0.94) [55]. A qualitative meta-analysis of 21 studies also concluded that FU-based CRT improved overall survival when compared with RT alone or best supportive care [56]. However, CRT was not superior to chemotherapy alone.

Further support for the benefit of CRT as compared with RT alone was provided by a retrospective but large series of 1700 older adult patients with locally advanced pancreatic cancer derived from a linked Medicare/Surveillance, Epidemiology, and End Results database [57]. Forty-four percent of patients received some form of therapy, and the adjusted mean survival durations for patients undergoing CRT, RT alone, chemotherapy alone, and no therapy were 47, 29, 27, and 15 weeks, respectively. Although not derived from a randomized trial, these data support the view that CRT provides benefit over either modality alone and that treatment appears to be better than supportive care. The authors performed a sophisticated statistical analysis using propensity score methods to minimize the impact of selection bias. However, the possibility that patients who are considered good candidates for CRT may survive longer due to other unmeasurable factors can only be excluded in a randomized trial.

●Gemcitabine versus FU-based approaches – The observation that gemcitabine has potent radiation sensitizing effects in conjunction with its demonstrated clinical benefit in metastatic pancreatic cancer provided the rationale for investigating its use in patients with locally advanced disease [58]. (See "Initial systemic chemotherapy for metastatic exocrine pancreatic cancer".)

A variety of gemcitabine treatment schedules and doses have been studied, limiting the ability to compare outcomes among published studies, although many concluded that this approach was associated with unexpectedly high toxicity rates [59-66].

Three very small randomized trials have directly compared gemcitabine with FU-based CRT for locally advanced pancreatic cancer [67-70]. Although the small size of these trials limits the confidence with which conclusions can be drawn, there is little evidence to support better outcomes in patients undergoing CRT for locally advanced pancreatic cancer with concomitant gemcitabine as compared with concurrent daily infusional FU (the usual regimen) or capecitabine, and nonhematologic toxicity rates may be higher. A 2009 qualitative systematic review concluded that FU is still the reference chemotherapy for use with concurrent RT [56]. We agree with this conclusion.

Comparative studies — A few trials have directly compared initial CRT with chemotherapy alone (either FU-based or gemcitabine) for patients with locally advanced, unresectable pancreatic cancer, none of which provides a definitive answer as to which approach is better:

●In early trials comparing CRT versus FU-based chemotherapy, RT doses and chemotherapy combinations were often suboptimal [71-75]. One of the negative trials, the only one to show a worse outcome with CRT, used a very toxic and unusual regimen of 60 Gy RT with cisplatin and FU [75].

●Two separate meta-analyses of trials comparing CRT (with or without subsequent chemotherapy) versus chemotherapy alone concluded that there was no survival benefit (and greater toxicity) for CRT compared with chemotherapy alone [55,56]. However, the obvious heterogeneity in the trials in terms of chemotherapy regimen and RT dose, as well as their small size, limits the confidence in this conclusion.

Importantly, none of these trials used modern combination chemotherapy. In the absence of a survival benefit from initial CRT, and the accumulating evidence for benefit of multiagent regimens such as FOLFIRINOX, most institutions favor initial multiagent chemotherapy. (See 'Combination regimens' above.)

Is there benefit to chemoradiotherapy after initial chemotherapy? — Concomitant chemoradiotherapy (CRT) cannot be recommended as a standard approach for all patients who do not have metastatic disease after initial systemic chemotherapy and who are being considered for resection. Although RT can significantly improve local endpoints such as pathologic complete response, this benefit has not translated into an improvement in clinically meaningful endpoints such as progression-free survival (PFS) or overall survival. However, this is a very controversial area. As noted above, there are three unresolved controversies that impact the decision to pursue CRT after initial chemotherapy:

●The first controversy is whether the imaging obtained after neoadjuvant chemotherapy accurately predicts for the ability of the surgeon to obtain an R0 resection. Some centers do not rely on imaging after preoperative chemotherapy and are taking nearly all patients who appear to have a radiographic response to initial chemotherapy to the OR for an assessment of resectability while others are not, based on the results of imaging. In our view, all patients with locally advanced pancreatic cancer who have not experienced progressive disease on initial chemotherapy should be evaluated by an experienced pancreatic surgeon as emerging data does suggest that imaging may not be reliable in certain circumstances. (See 'FOLFIRINOX' above.)

●The second controversy surrounds the ability of RT to improve the rate of successful surgical resection (ie, complete or microscopically complete [R0/R1] as opposed to macroscopic residual disease [R2 resection]) in patients with locally advanced pancreatic cancer. Uncontrolled, institutional experiences suggest an improved rate of resection and long-term survival with the addition of RT, but these are subject to various biases and the findings have not been borne out by the available randomized data. There are no randomized data supporting the claim of increased resectability. In the absence of an R0/R1 resection, it is clear from the LAP07 trial (which is discussed below) that standard doses of RT are not beneficial to long term survival [71].

In the setting of potentially resectable disease, the PREOPANC study suggests that neoadjuvant CRT may improve the R0 resection rate [76]. However, this study used surgery alone and not upfront chemotherapy as the control group. (See 'Benefit of neoadjuvant therapy' below.)

●Lastly, there is controversy around whether there is any added benefit of RT to chemotherapy in the adjuvant, neoadjuvant, or perioperative setting for patients with resectable pancreatic cancer. This controversy has been extended to include those patients with locally advanced pancreatic cancer who are taken to the OR after initial chemotherapy. Unfortunately, the overall benefit of RT for patients with localized pancreatic cancer, whether initially resectable or potentially resectable, remains an unresolved issue.

Our preferred approach is to encourage patients with locally advanced pancreatic cancer to enroll in clinical trials testing the contribution of neoadjuvant RT to modern combination chemotherapy. If trials are unavailable or participation is not feasible, we suggest not treating with fluoropyrimidine-based CRT if patients are considered appropriate candidates for resection. We reserve CRT for those who are not resected with the goal of improving local control as demonstrated in LAP-07 trial and by others [71,77]. These recommendations are consistent with guidelines for treatment of locally advanced, unresectable pancreatic cancer from the American Society of Clinical Oncology (ASCO) [24] and American Society for Radiation Oncology [27]. (See 'Overview of our suggested approach' above.)

Available data — Up to one-third of patients with locally advanced pancreatic cancer develop overt metastases during the initial phase of neoadjuvant treatment [78,79]. Given the lack of proof for a survival benefit of initial CRT versus chemotherapy in patients with locally advanced unresectable disease [72,73], it was hypothesized that a period of initial disease control with chemotherapy alone might allow the selection of patients without occult micrometastatic disease who might benefit from RT in terms of both local control and survival.

This hypothesis was supported by data from at least three retrospective series [78,80,81]. However, the efficacy of this approach could not be confirmed in the international LAP07 trial, a randomized 2x2 factorial design study in which 442 patients with locally advanced pancreatic cancer and an Eastern Cooperative Oncology Group performance status of 0 to 2 (table 2) were initially randomly assigned to gemcitabine with or without erlotinib; at the end of four months, patients without progression were randomly assigned to two additional months of chemotherapy or CRT (54 Gy EBRT plus concurrent capecitabine 1600 mg/m² per day) [71]. The trial was terminated prematurely after accrual of only 442 of the 820 intended participants when interim analysis revealed that prespecified futility criteria were met. At a median follow-up of 36 months, CRT was not superior to continuing chemotherapy (median overall survival 15.2 versus 16.5 months), and the proportion of patients with a sufficient therapy response to permit later pancreatectomy after the second randomization was not significantly different (eight patients after chemotherapy alone versus four patients after chemotherapy plus CRT). Local control was significantly better in the CRT group (locoregional progression in 32 versus 46 percent with chemotherapy alone). The toxicity data did not reveal substantial differences in adverse events for individuals treated with or without CRT; however, patient-reported toxicity data were not included.

There were some issues with RT compliance; only 32 percent of patients in the CRT arm were treated per protocol, while 50 percent had minor deviations, and 18 percent had major deviations. However, these deviations did not appear to significantly impact outcomes. Median survival from the date of the first randomization for patients treated per protocol or with minor deviations did not differ significantly from that in patients who had major deviations (17 versus 13.4 months).

The issue was further addressed in the CONKO-007 trial, in which 525 patients were enrolled to undergo induction chemotherapy for three months (choice of gemcitabine alone [93 patients] or FOLFIRINOX [n = 402] by clinician choice), and those who were still alive and without overt disease progression (n = 336) were randomly assigned to three additional months of the same chemotherapy regimen, or CRT (50.4 Gy plus weekly gemcitabine 300 mg/m²) followed by one additional cycle of gemcitabine [82]. Overall survival was the planned endpoint, but this was changed to complete (R0) resection rate because of slower than anticipated accrual. In a preliminary report presented at the 2022 annual ASCO meeting, at a median follow-up of 16 months, individuals treated with CRT had more severe (grade ≥3) treatment-related toxicity, especially leucopenia and thrombocytopenia; non-hematologic toxicities were comparable. Resection was performed in 122 patients (60 after chemotherapy, 62 after CRT); in this cohort, the addition of RT improved the pathologic complete response rate (7 versus 0.6 percent) and improved the R0 resection rate (69 versus 50 percent, p = 0.04), but the R0 resection rate was not significantly better when the entire randomized cohort of 336 patients was analyzed (25 versus 18 percent, p = 0.11). These differences did not translate into better PFS (median 9 versus 8 months, HR 0.976, 95% CI 0.780-1.222), or overall survival (median 15 months in both groups, HR 0.975, 95% CI 0.756-1.211).

In our view, it is increasingly clear that the effect of RT in patients with truly unresectable pancreatic cancer is minimal. Whether RT may contribute to increasing resectability and R0 resection rates in patients who are not progressing after initial FOLFIRINOX as was seen in CONKO-007 is an intriguing idea which remains an unanswered question. (See 'FOLFIRINOX' above.)

Radiation sensitizer during RT — If CRT is chosen, fluoropyrimidines (infusional FU or daily oral capecitabine) should be used rather than gemcitabine as a radiation sensitizer.

●Continuous infusion FU – Largely based on the experience in other gastrointestinal malignancies such as rectal cancer, infusional rather than bolus FU has become the most commonly used approach for radiation sensitization. (See "Adjuvant therapy for resected rectal adenocarcinoma in patients not receiving neoadjuvant therapy", section on 'Infusional versus bolus fluorouracil' and "Neoadjuvant therapy for rectal adenocarcinoma".)

●Oral rather than IV fluoropyrimidines – Accumulating data from uncontrolled trials support the view that oral capecitabine can safely replace infusional FU as a radiation sensitizer in patients treated for locally advanced pancreatic cancer [67,83,84]. Based on the results of phase III studies comparing capecitabine versus infusional FU during CRT for rectal cancer, many investigators feel that substituting capecitabine for infusional FU as a radiation sensitizer is reasonable for other gastrointestinal malignancies and that the question is not worthy of phase III studies in each tumor type. We agree with this point of view. (See "Neoadjuvant therapy for rectal adenocarcinoma", section on 'Fluoropyrimidines'.)

S-1 is an oral fluoropyrimidine that includes three different agents: ftorafur (tegafur), gimeracil (5-chloro-2,4 dihydropyridine, a potent inhibitor of dihydropyrimidine dehydrogenase), and oteracil (potassium oxonate, which inhibits phosphorylation of intestinal 5-FU, thought responsible for treatment-related diarrhea). S-1 is approved in Japan for adjuvant therapy of gastric cancer and in Europe for treatment of advanced gastric cancer; it is not available in the United States. Although fewer data are published with S-1 than with capecitabine, S-1 also appears to be a safe and effective substitute for infusional FU, where available [85].

●Gemcitabine – We suggest not pursuing gemcitabine-based rather than fluoropyrimidine-based CRT. As noted above, there is no evidence that survival is better compared with FU-containing RT, and nonhematologic toxicity may be worse [67,70]. (See 'Initial chemoradiotherapy versus chemotherapy' above.)

Stereotactic body radiation therapy — In experienced centers, SBRT is often considered an alternative to conventional fractionation CRT following systemic multiagent chemotherapy as long as patients are informed about potential risks and general uncertainty as to benefit. However, in our view (and that of ASCO [24]), until randomized trials comparing this approach with conventional modern multiagent chemotherapy with or without fluoropyrimidine-based CRT are completed, the place of SBRT in the therapeutic armamentarium for locally advanced pancreatic cancer will remain uncertain, and it cannot be recommended as a standard approach.

SBRT is capable of precisely delivering high doses of radiation to small tumor volumes. SBRT uses a variety of motion management techniques to account for tumor and normal tissue motion, permitting higher doses than conventional RT to the tumor while minimizing the risk of injury to adjacent organs. (See "Radiation therapy techniques in cancer treatment", section on 'Stereotactic radiation therapy techniques'.)

SBRT has been explored in an increasing number of clinical studies as an alternative approach to conventionally fractionated EBRT with concurrent chemotherapy for the management of locally advanced disease. However, the benefit of SBRT remains uncertain, since it is not clear that median survival is better than would be expected with other forms of therapy, and toxicity has been worse in some studies [86-92].

The substantial local toxicity seen in these early reports was not counterbalanced by any suggestion of improved survival. More favorable outcomes have been reported by others using smaller treatment fields, more conformal techniques, and hypofractionated protocols [79,93-95].

However, benefit from SBRT has been called further into question the phase II Alliance A021501 trial, in which 126 patients with borderline resectable pancreatic cancer were randomly assigned to eight courses of preoperative modified (m) FOLFIRINOX or seven courses of mFOLFIRINOX followed by SBRT (33 to 40 Gy in five fractions) or hypofractionated image-guided RT (25 Gy in 5 fractions) [96]. The fraction undergoing surgery (58 versus 51 percent), and the number undergoing surgery who had a complete (R0) resection (88 versus 74 percent), the 18-month overall survival (66.7 versus 47.3 percent), and median overall survival (29.8 versus 17.1 months) all favored chemotherapy alone, although there were significant problems with the interpretation of this study, as outlined below. (See 'Contribution of RT' below.)

Role of surgery — In our view, in the absence of metastatic disease, all patients who have a radiographic response to therapy after initial chemotherapy, who retain an acceptable performance status and comorbidity profile, and who prefer aggressive therapy should undergo exploration. However, there is considerable debate and practice variability regarding which patients are taken to the OR for exploration after induction chemotherapy alone or chemotherapy followed by chemoradiation. Some centers, including those of several of the authors and editors of this topic review, take nearly all patients, regardless of vascular involvement on imaging, to the OR to assess for resectability, especially after receiving initial therapy with the multiagent regimen FOLFIRINOX. (See 'FOLFIRINOX' above.)

By contrast, other centers rely more on local imaging characteristics to guide surgical candidacy. We await the results of ongoing clinical trials to guide this debate.

Guidelines from ASCO [24] and the NCCN [2] both state that surgery may be considered in a patient with a dramatic response to initial chemotherapy and/or RT, but neither addresses the difficulty in assessing resectability on cross-sectional imaging after initial medical therapy. NCCN guidelines further state that patients with radiographically stable disease after neoadjuvant therapy should still be considered for surgery if there is a marked clinical improvement and/or decrease in cancer antigen 19-9 (CA 19-9). However, it is unclear what level of change in CA 19-9 constitutes a meaningful treatment response. At least some data suggest a lack of association between the magnitude of the change in CA 19-9 level and survival after multimodality treatment in this setting, unless the CA 19-9 normalizes [97]. ESMO guidelines do not address any indications for exploration [4].

In the era prior to FOLFIRINOX and gemcitabine/nabpaclitaxel, it was very rare for tumors to be converted to resectable after gemcitabine or chemoradiation [71]. More recently, multiple institutions have published results showing routine conversion of patients from unresectable to resectable after FOLFIRINOX or gemcitabine/nabpaclitaxel regimens, although the exact rate of conversion is unknown.

The median survival of patients with locally advanced, unresectable pancreatic cancer is approximately 10 to 12 months, but there is a potential for longer-term survival if disease can be resected. Two independent systematic reviews concluded that approximately one-third of initially unresectable pancreatic tumors could be rendered potentially resectable through the use of neoadjuvant therapy [98,99]. Pathologic complete responses have even been reported in 3 to 5 percent of cases [98]. However, these data must be interpreted cautiously given the heterogeneous nature of this group of patients and the treatments given to them, and the fact that at least some of them might have been considered to have potentially resectable disease by modern standards. In the prospective randomized LAP07 trial, described above, only 4 percent of study participants responded to initial treatment sufficiently (gemcitabine alone or with erlotinib, with or without subsequent CRT) to enable a subsequent pancreatectomy [71]. (See 'Is there benefit to chemoradiotherapy after initial chemotherapy?' above.)

It is possible that the use of more intensive initial combination chemotherapy (eg, FOLFIRINOX or gemcitabine/nabpaclitaxel) might have resulted in a higher frequency of downstaging [33,48,100]. The following data are available:

●Promising results are available from a single-institution retrospective analysis of 415 patients with locally advanced pancreatic cancer who were treated with a neoadjuvant approach that included combination chemotherapy in all (FOLFIRINOX in 50 percent, FOLFIRINOX plus gemcitabine in 19 percent, and gemcitabine-based chemotherapy in 31 percent); 54 percent also received RT [100]. Overall, 84 patients (20 percent) were amenable to resection, 75 of whom had a margin-negative resection. Median overall survival for the resected patients was 35 months, and for those undergoing an R0 resection, three-year overall survival was approximately 50 percent. Importantly, this was not a randomized trial, and selection bias may have accounted for these unexpectedly favorable results. (See 'Combination regimens' above.)

●As noted above, in the randomized NEOLAP trial comparing neoadjuvant therapy with gemcitabine/nabpaclitaxel versus sequential gemcitabine/nabpaclitaxel followed by FOLFIRINOX in patients with initially unresectable, locally advanced pancreatic cancer, 63 percent of both groups were subsequently resected, and rates of complete macroscopic tumor resection were 31 and 45 percent, respectively [48]. (See 'Gemcitabine combinations versus FOLFIRINOX' above.)

For patients treated with initial chemotherapy with or without RT, the optimal duration and the best way to define a response to upfront therapy [101] are unclear. While it is reasonable to evaluate responding patients for potential resectability after neoadjuvant treatment, the frequency with which this results in a dramatic response and culminates in a complete resection (even in patients treated with more effective and more toxic combination regimens such as FOLFIRINOX) is low [12,102-110]. In addition, long-term survival appears to be exceedingly rare in this circumstance, largely due to the development of metastatic disease [110,111].

Nevertheless, in our view, all such patients should be assessed for surgery after initial medical therapy. Imaging is imperfect in this setting. In particular, the ability to reliably determine resectability of a locally advanced cancer radiographically is limited after multiagent chemotherapy due to the presence of fibrosis and scar tissue. Laparoscopic or open evaluation of the abdomen may be necessary in order to determine the potential for resection, particularly in patients treated with highly active regimens, such as FOLFIRINOX or gemcitabine plus nabpaclitaxel [35,45,112]. (See 'FOLFIRINOX' above.)

Unfortunately, even tumors that appear to be resectable at open evaluation may have positive posterior margins as that margin cannot be assessed until the resection is completed.

Management of patients with disease progression — All patients who have not benefited from first-line treatment and have disease progression (increase in the size of the local tumor, new metastatic lesions on imaging, or a persistently rising serum CA 19-9) should be offered additional treatment. The choice of treatment depends on the site of progression (locoregional, distant) and what was given as initial treatment [24]:

●For patients with distant metastases who have received initial chemotherapy and who retain an adequate performance status and comorbidity profile, a switch to an alternative regimen is reasonable. (See "Initial systemic chemotherapy for metastatic exocrine pancreatic cancer".)

●For patients with locally advanced disease treated only with systemic chemotherapy who have only locoregional progression, radiation (EBRT with or without chemotherapy, SBRT) is a reasonable option to enhance local control [47,48]. (See 'Is there benefit to chemoradiotherapy after initial chemotherapy?' above and 'Stereotactic body radiation therapy' above.)

Guidelines from ASCO for treatment of locally advanced pancreatic cancer also advocate a short course of palliative RT (either conventional RT or SBRT) for patients with persistent pain or other prominent local symptoms (worsening jaundice, gastrointestinal bleeding, local infiltration into the gastrointestinal tract causing impending gastric outlet or duodenal obstruction) [24]. (See "Supportive care for locally advanced or metastatic exocrine pancreatic cancer".)

BORDERLINE RESECTABLE DISEASE — Some cases are classified as "borderline resectable," mostly based on radiographic interface between the primary tumor and the mesenteric vasculature. Although some of these patients will prove to be resectable with initial surgery, the likelihood of an incomplete resection is high. (See 'Borderline resectable' above.)

Overview of the therapeutic approach — There is no consensus as to the best approach to patients with borderline resectable pancreatic cancer. The following represents our preferred approach, which is similar to our approach for patients who have locally advanced, nonmetastatic but unresectable disease at presentation, which is outlined in the algorithm (algorithm 1), and described in detail below (see 'Locally advanced, unresectable disease' above):

●For most patients, we prefer enrollment in a clinical trial testing new treatment strategies. If a clinical trial is unavailable or participation is not feasible, we suggest the following approach in the absence of metastatic disease:

•For fit patients, we suggest an initial attempt at neoadjuvant therapy followed by restaging and surgical exploration, rather than upfront surgery. This approach is consistent with guidelines from the American Society of Clinical Oncology (ASCO) [24] and the National Comprehensive Cancer Network (NCCN) [2].

For most patients, we suggest an initial period of chemotherapy rather than immediate radiation therapy (RT) or chemoradiotherapy (CRT). This recommendation is also consistent with consensus-based guidelines from ASCO [24], the NCCN [2], and the European Society for Medical Oncology [4].

As in the setting of locally advanced unresectable tumors, we base our choice of chemotherapy regimen on the presence or absence of pathogenic or likely pathogenic variants in genes associated with homologous recombination repair (HRR) deficiency (ie, BRCA1/2, PALB2, ATM, BAP1, BARD1, BLM, BRIP1, CHEK2, FAM175A, FANCA, FANCC, NBN, RAD50, RAD51, RAD51C, and RTEL1) and candidacy for chemotherapy (algorithm 1). (See 'Overview of our suggested approach' above.)

•A careful assessment for resectability should be undertaken after four to six months of neoadjuvant chemotherapy. For patients without metastatic disease, we suggest surgical exploration. For those with metastatic disease, continued chemotherapy is a reasonable option.

Rationale and outcomes — The major goal of surgery for pancreatic cancer is an R0 resection; a margin-positive resection strongly predicts early recurrence and short survival [113-116]. The term "borderline resectable" was proposed to differentiate a group of patients with limited vascular involvement that was potentially amenable to resection and reconstruction, albeit with a high risk of a margin-positive resection [13,117-120]. These patients were considered to be good candidates for neoadjuvant therapy, with the expectation that downstaging would provide an enhanced opportunity for a complete resection and long-term survival [121,122]. (See 'Borderline resectable' above.)

The bulk of the available data consist of small single-institution series and small phase II (uncontrolled) trials that enrolled a mixture of patients with initially resectable, unresectable, and borderline resectable disease. A meta-analysis of 38 studies consisting primarily of single-arm observational studies in patients with potentially resectable or borderline resectable pancreatic cancer, found that neoadjuvant treatment had similar overall survival compared with upfront surgery (weighted mean overall survival 18.8 versus 14.8 months) [123]. The difference was larger among patients whose tumors were resected (26.1 versus 15 months). Although overall resection rates were lower with upfront surgery (66 versus 81 percent), the R0 resection rate was higher (87 versus 67 percent), and the pathologic nodal positivity rate was also lower (44 versus 65 percent).

Benefit of neoadjuvant therapy — Most of these early studies utilized older chemotherapy regimens (gemcitabine alone, gemcitabine plus cisplatin), mostly with fluorouracil (FU)-based CRT. More recently, the better outcomes that may be achieved with more intensive therapy (either multiagent neoadjuvant chemotherapy or chemotherapy plus chemoradiotherapy) can be illustrated by a prospective phase II study of 48 patients with borderline resectable pancreatic cancer; treatment consisted of eight preoperative cycles (16 weeks) of FOLFIRINOX (short-term infusional FU plus leucovorin, irinotecan, and oxaliplatin) followed by radiographic restaging [44]. Patients who had resolution of vascular involvement (n = 27) underwent short-course RT (5 Gy in five fractions with proton beam irradiation) concurrent with capecitabine (825 mg/m² twice daily Monday through Friday for two weeks), while those with persistent vascular involvement (n = 17) received long-course CRT (50.4 Gy with concomitant FU [225 mg/m² daily as continuous infusion Monday through Friday] or capecitabine [825 mg/m² twice daily Monday through Friday] during RT). Surgery was performed one to three weeks after short-course RT or four to eight weeks after long-course RT. All eight cycles of chemotherapy were completed by 34 patients (79 percent), and an R0 resection was achieved in 31 of the 48 eligible patients (65 percent). At a median follow-up of 18 months, the two-year progression-free survival rate was 43 percent, and median overall survival was 37.7 months. Among the patients who underwent resection (n = 32), the two-year progression-free and overall survival rates were 55 and 72 percent, respectively.

Several randomized trials have directly addressed whether outcomes with modern neoadjuvant therapy are better than those that can be achieved with surgery followed by adjuvant therapy; two of the largest and a meta-analyses are described below:

●Large-randomized trials

•The phase III PREOPANC trial randomly assigned 246 patients with potentially resectable or borderline resectable (approximately 50 percent each) pancreatic cancer to upfront surgery followed by six months of adjuvant gemcitabine alone, or to neoadjuvant gemcitabine plus gemcitabine-based CRT (two weekly doses of gemcitabine followed by one week of rest, gemcitabine-based CRT [36 Gy in 15 fractions with gemcitabine 1000 mg/m² on days 1, 8, and 15], and then two weekly doses of gemcitabine alone) followed by surgery and four months of adjuvant gemcitabine alone [76]. Resectable disease was strictly defined as no contact with the superior mesenteric artery (SMA), celiac trunk, or common hepatic artery, and ≤90° contact with the superior mesenteric vein (SMV). Borderline resectable disease was defined as ≤90° contact with the SMA, celiac trunk, or common hepatic artery, or 90 to 270° contact with the SMV without occlusion.

In the initial report, the R0 resection rate was significantly higher with preoperative therapy (71 versus 40 percent), and preoperative CRT was associated with significantly better disease-free survival and locoregional failure-free interval as well as with significantly lower rates of pathologic lymph nodes, perineural invasion, and venous invasion. However, the difference in median overall survival (the primary endpoint) did not reach the level of statistical significance (median 16 versus 14.3 months, hazard ratio [HR] 0.78, 95% CI 0.58-1.05). Neoadjuvant therapy was associated with slightly higher rates of serious (grade 3 or worse) adverse events (52 versus 41 percent).

However, in the latest analysis at a median follow-up of 59 months, the difference in median survival between the neoadjuvant and adjuvant therapy groups was slightly smaller (median 15.7 versus 14.3 months), but statistically significant (HR for death 0.73, 95% CI 0.56-0.96) [124]. The five-year overall survival rate with neoadjuvant therapy was 20.5 percent compared with 6.5 percent in the control group.

•The four-arm prospective multicenter phase II ESPAC-5F trial [49] directly compared immediate surgery versus four to six weeks of neoadjuvant gemcitabine plus capecitabine (GEMCAP; two months), FOLFIRINOX (two months), or CRT (50.4 Gy, with concurrent daily capecitabine) in 90 patients with borderline resectable pancreatic cancer, as defined by NCCN criteria. All patients also received adjuvant therapy after surgery. (See 'Borderline resectable' above.)

In a preliminary report at the 2020 annual ASCO meeting, there was no difference in resection rate (R0/R1, the primary endpoint) among the four arms; however, the microscopically complete (R0) resection rate was modestly higher among all individuals undergoing neoadjuvant therapy (23 versus 15 percent), and 12-month overall survival was significantly higher in those receiving any form of neoadjuvant therapy as well (77 versus 42 percent, HR 0.28, 95% CI 0.14-0.57). (See 'Choice of regimen' below.)

An important caveat is that, as noted above, there is increasing evidence that a "response" to neoadjuvant therapy in patients with borderline resectable disease is not necessarily reflected by standard radiographic indicators. In a single-center study of 122 borderline resectable cases treated using a variety of neoadjuvant strategies, 15 patients had a partial response, 84 were deemed to have stable disease, and 23 had progressive disease as determined using standard Response Evaluation Criteria In Solid Tumors response criteria (table 5) [125]. Although only one patient had disease downstaged to resectable status by imaging criteria, 85 were able to undergo pancreatectomy after neoadjuvant therapy, and 81 achieved R0 resection status. These data raise questions as to the optimal duration and end point of neoadjuvant therapy in these patients. However, they do support the view that all patients who remain surgical candidates should undergo surgical exploration after neoadjuvant treatment in the absence of documented metastatic disease. (See 'FOLFIRINOX' above.)

●Meta-analysis – A meta-analysis included these two trials and five others (totaling 938 patients) in which the comparator arm was any form of neoadjuvant therapy (including gemcitabine and gemcitabine/cisplatin-based CRT) compared with upfront surgery followed by adjuvant gemcitabine (none of the trials used adjuvant FOLFIRINOX) for potentially or borderline resectable pancreatic cancer [126]. Overall neoadjuvant therapy improved overall survival compared with upfront surgery (HR for death 0.66, 95% CI 0.52-0.85), representing an increase in median survival from 19 to 29 months. In an unplanned subgroup analysis, the overall survival benefit was limited to those patients with borderline resectable tumors (HR for death 0.61, 95% CI 0.44-0.85), and not those with potentially resectable disease upfront. However, a test for interaction was not provided. (See "Treatment for potentially resectable exocrine pancreatic cancer", section on 'Neoadjuvant therapy'.)

Contribution of RT — In our view, concomitant CRT or stereotactic body RT (SBRT) cannot be recommended as a standard approach for all patients with borderline resectable disease who have not developed metastatic disease after initial systemic chemotherapy and who are being considered for resection.

As with locally advanced unresectable pancreatic cancer, there are no randomized trials demonstrating that patients who receive radiation therapy (RT) as a component of neoadjuvant therapy have better survival than do those undergoing induction chemotherapy alone. However, this remains an open question as the available studies have used various RT doses and modalities, and randomized trials such as ALLIANCE A021501 were not adequately powered to compare chemotherapy with or without RT. As a result, the role of RT in the neoadjuvant setting has not been fully vetted [127]. (See 'Is there benefit to chemoradiotherapy after initial chemotherapy?' above and 'Stereotactic body radiation therapy' above.)

The possibility that CRT after initial FOLFIRINOX might lead to high complete (R0) resection rates in borderline resectable disease was initially suggested in a phase II trial [44]. (See 'Benefit of neoadjuvant therapy' above.)

However, subsequent analyses have been disappointing:

●ALLIANCE A021501 – Benefit for adding RT to upfront FOLFIRINOX could not be confirmed in the phase II Alliance A021501 trial, in which 126 patients with borderline resectable pancreatic cancer were randomly assigned to eight courses of preoperative modified (m) FOLFIRINOX or seven courses of mFOLFIRINOX followed by either SBRT (33 to 40 Gy in five fractions) or hypofractionated image-guided RT (25 Gy in 5 fractions) [96]. Patients in either arm without disease progression then underwent pancreatectomy, followed by four courses of postoperative FOLFOX (leucovorin plus short-term infusional FU and oxaliplatin) chemotherapy. The primary endpoint was 18 month overall survival. The trial was not powered to compare both arms, but instead to compare each with a historical reference standard of 50 percent survival at 18 months.

The fraction undergoing surgery (58 versus 51 percent), the number of enrolled patients who had a complete (R0) resection (43 versus 25 percent), the 18-month overall survival (66.7 versus 47.3 percent), and median overall survival (29.8 versus 17.1 months) all favored chemotherapy alone. The authors concluded that mFOLFIRINOX represents a reference regimen in this setting.

This trial is problematic from a number of standpoints, and in our view, does not present definitive evidence to discredit the potential for benefit of RT in this setting for the following reasons:

•As noted above, the trial was not statistically powered to compare FOLFIRINOX with or without RT.

•There were imbalances in certain prognostic features between the two groups. As an example, the median cancer antigen 19-9 (CA 19-9) was higher in the SBRT arm (260 [range 0-14,010] versus 167 [range 1-13, 221] U/mL). Furthermore, CA 19-9 levels as high as 13,000 to 14,000 U/mL suggest categorically unresectable and incurable disease (table 6). (See "Clinical manifestations, diagnosis, and staging of exocrine pancreatic cancer", section on 'Carbohydrate antigen 19-9'.)

•More patients in the SBRT arm developed metastatic disease and therefore were not eligible for attempted resection. Notably, the lower rates of pancreatectomy (35 percent with combined therapy [R0 in 74 percent] versus 49 percent after chemotherapy alone [R0 resection in 88 percent]) in this study contrast with the results of high-volume centers, which report complete (R0) resection rates of 84 to 97 percent; this relatively low rate of resection might have been attributable to the variable expertise of the enrolling centers.

•The timing of surgery was at four to eight weeks, which may not have allowed for maximal downstaging.

●Other analyses

•A meta-analyses of 15 studies (512 patients, seven prospective uncontrolled studies, the remainder retrospective series) in which patients with borderline or resectable pancreatic cancer received either FOLFIRINOX alone or with RT concluded that the addition of RT improved the complete (R0) resection rate (97.6 versus 88 percent, p = 0.045), but this did not translate into a significant difference in median overall survival (22.4 versus 21.6 months) [128].

•Similarly, a TAPS (Trans-Atlantic Pancreatic Surgery) consortium multicenter retrospective analysis of propensity score-matched individuals who received or did not receive RT after modified FOLFIRINOX for borderline resectable pancreatic cancer concluded that the use of neoadjuvant RT was associated with more node-negative disease and better pathologic response in patients who underwent resection, but no difference in overall survival [129].

Role of intraoperative radiation therapy — In the absence of randomized trials demonstrating benefit, intraoperative radiation therapy (IORT) cannot be considered a standard approach for treatment of borderline resectable pancreatic cancer, and it should be reserved for carefully selected patients who are being treated in a center with significant experience and expertise, preferably within the context of a clinical trial.

IORT permits the delivery of high-dose RT directly to areas of tumor involvement without the morbidity associated with irradiation of adjacent normal tissues, particularly the small bowel. A number of reports from both single institutions and cooperative groups have explored IORT, usually in conjunction with preoperative CRT [12,130-133]. Taken together, the available data suggest that while local control rates may be higher with IORT compared with EBRT alone, this benefit is offset by the rapid development of metastatic disease in most reports, and it is not clear that IORT contributes to higher survival rates. The benefits of IORT have been marginal or absent in other reports [12].

A systematic review of IORT for treatment of pancreatic cancer included 14 reports published between 1995 and 2007 (the majority case series, no randomized trials) involving patients with either localized resectable or locally advanced disease [134]. The authors concluded that, while the use of IORT may be associated with a slight (and statistically nonsignificant) improvement in median survival among patients with localized, potentially resectable pancreatic cancer, no benefit could be shown in the setting of locally advanced disease. No published studies addressed quality of life issues.

Choice of regimen — The best regimen to use for neoadjuvant therapy in this setting has not been established. Our approach to neoadjuvant therapy for patients with borderline resectable tumors is similar to that used for locally advanced, unresectable disease and is outlined in the algorithm (algorithm 1). For most patients who are able to tolerate it, we prefer the multiagent FOLFIRINOX regimen, especially for individuals with pathogenic variants or likely pathogenic variants in a gene associated with HRR deficiency, or if mutation status is unknown or pending, [44]. Gemcitabine plus nabpaclitaxel is an option for those without germline or somatic (tumoral) mutations. (See 'Overview of our suggested approach' above.)

The benefits of FOLFIRINOX in this setting can be illustrated by the following data:

●The four-arm prospective multicenter phase II ESPAC-5F trial [49] directly compared immediate surgery versus neoadjuvant GEMCAP (two months), FOLFIRINOX (two months), or CRT (50.4 Gy, with concurrent daily capecitabine) in 90 patients with borderline resectable pancreatic cancer, as defined by NCCN criteria. All patients received adjuvant therapy after surgery. (See 'Borderline resectable' above.)

In a preliminary report at the 2020 annual ASCO meeting, the complete (R0) resection rate was modestly higher among all individuals undergoing neoadjuvant therapy (23 versus 15 percent), but 12-month overall survival was significantly higher (77 versus 42 percent, HR 0.28, 95% CI 0.14-0.57). When the neoadjuvant therapy arms were compared, the highest 12-month survival was seen with FOLFIRINOX, followed by GEMCAP, and then CRT (84 versus 79 and 64 percent, respectively), and the differences when compared with immediate surgery were significantly higher for both FOLFIRINOX (HR 0.16, 95% CI 0.05-0.56), and GEMCAP (HR 0.32, 95% CI 0.12-0.85). From a toxicity standpoint, grade 3 or 4 serious adverse events occurred more often with FOLFIRINOX than GEMCAP (26 versus 6 percent) but were manageable.

●A patient-level meta-analysis, which focused on patients with borderline resectable pancreatic cancer (24 studies, 8 prospective and 16 retrospective, comprising 313 patients treated with FOLFIRINOX), came to the following conclusions [135]:

•Patient-level data were available for 283 patients, and at a median follow-up of 22.9 months, median overall survival was 22.2 months, and the pooled overall survival rates at one, three, and five years were 76, 36, and 21 percent, respectively.

•Few trials reported the number of planned neoadjuvant FOLFIRINOX courses, and only 11 studies reported the number of courses actually administered. Within these limitations, there was no correlation between the reported median number of cycles of FOLFIRINOX administered, and the patient-level median overall survival.

•Adverse events during treatment with FOLFIRINOX were reported from 14 studies, of which nine reported only pooled outcomes across disease stages. The most commonly reported grade 3 or 4 adverse events during FOLFIRINOX were neutropenia (pooled event rate 17.5 per 100 patients), diarrhea (pooled event rate 11.1 per 100 patients), and fatigue (pooled event rate 10.8 per 100 patients); neutropenia risk was lower in the studies that administered primary granulocyte colony stimulating factors prophylaxis.

●Additional information on the benefits of neoadjuvant FOLFIRINOX in borderline resectable pancreatic cancer is available from a retrospective analysis of data on 1835 consecutive patients presenting with localized pancreatic cancer (52 percent locally advanced, 29 percent borderline resectable, 19 percent potentially resectable) who received at least one cycle of mFOLFIRINOX chemotherapy as initial treatment in one of five referral centers in the United States and Netherlands between 2012 and 2019 [41]. The median number of chemotherapy cycles was 6 (interquartile interval 4 to 8), and subsequent treatment included radiotherapy in 49 percent, and resection in 38 percent. The margin-negative (R0) resection rates for those with borderline resectable tumors was 63 percent, the corresponding median overall survival duration was 23.2 months, and the five-year overall survival rate was 18.4 percent.

ROLE OF ADJUVANT THERAPY — For patients with pancreatic cancer who received preoperative therapy, we suggest additional adjuvant systemic therapy so that patients receive a total of six months of systemic chemotherapy, including the preoperative regimen. This recommendation, which is consistent with American Society of Clinical Oncology guidelines [21], is based on an extrapolation of data from adjuvant therapy trials conducted in patients undergoing upfront surgery for a potentially resectable pancreatic cancer.

If protocol therapy is not available or declined, for patients with an excellent performance status who are able to tolerate it, we prefer modified FOLFIRINOX (oxaliplatin plus irinotecan with leucovorin and short-term infusional fluorouracil) rather than gemcitabine alone, or gemcitabine plus capecitabine. For less fit patients, gemcitabine plus capecitabine is an option. Therapy with gemcitabine alone or, where available, S-1 alone is another reasonable option, particularly for patients with a borderline performance status or a comorbidity profile that precludes multiagent therapy.

For patients undergoing upfront resection of a potentially resectable pancreatic cancer, adjuvant therapy is routinely recommended. Randomized trials have demonstrated a significant survival benefit for the administration of six months of adjuvant chemotherapy, and it is recommended in the United States and elsewhere. By contrast, benefit of adjuvant radiation therapy is less certain, and practice is variable within and outside of the United States. (See "Treatment for potentially resectable exocrine pancreatic cancer", section on 'Adjuvant therapy'.)

None of the trials that support modern adjuvant chemotherapy after resection of pancreatic cancer enrolled patients who had received preoperative (neoadjuvant) therapy, and there are no randomized controlled trials to guide the administration of postoperative therapy in this setting. The available data from retrospective series are conflicting:

●One multi-institutional international retrospective analysis of 520 patients with resected pancreatic cancer after neoadjuvant FOLFIRINOX, 343 of whom received some form of adjuvant therapy, suggested that the benefit of adjuvant chemotherapy was limited to those with node-positive disease [136]. The majority (59 percent) received a gemcitabine-based regimen, while 20 percent received FOLFIRINOX, and the remainder received either capecitabine alone, or another combination, or the regimen was unknown. No conclusions could be drawn as to the optimal adjuvant therapy regimen.

●On the other hand, two separate analyses derived from the population-based National Cancer Database suggest benefit for other subgroups:

•In an analysis of 3897 individuals undergoing neoadjuvant therapy for pancreatic cancer and subsequent surgical resection, also using data from the National Cancer Database, concluded that the survival benefit from adjuvant chemotherapy was limited to those with low-risk pathologic features (ie, lymph node ratio <0.15, non-high-grade histology, negative surgical margins) [137].

•A later analysis of 6560 patients receiving resection for pancreatic ductal adenocarcinoma after neoadjuvant chemotherapy from 2004 to 2016 with propensity score matching concluded that use of adjuvant chemotherapy (which was given to 2111 patients [32 percent]) was associated with improved survival in the entire group (hazard ratio for death in the matched population 0.81, 95% CI 0.75 to 0.87) and was similar in all subgroups regardless of nodal status and margin status [138]. The analysis was limited to patients with survival of six months or more, primarily to account for patients who did not survival long enough to receive adjuvant therapy. However, it is possible that doing so also excluded patients who died due to adjuvant chemotherapy-related complications.

Both of these analyses are limited by the potential for selection bias.

Pathologic scoring systems to assess the response to neoadjuvant therapy in resected pancreatic cancer have been developed as an aid to prognostication and the selection of candidates for adjuvant therapy [139-141]. However, consensus on how to assess the response to preoperative therapy is lacking [142], and more information is needed on the comparative prognostic and predictive value of the various available scoring systems before this approach can be recommended.

POST-TREATMENT SURVEILLANCE — There is no consensus as to optimal post-treatment surveillance strategy after treatment of locally advanced pancreatic cancer and no evidence from randomized trials to guide practice. For patients who have completed treatment and have stable disease or no disease, we follow recommended American Society of Clinical Oncology guidelines [24]:

●A follow-up visit every three to four months that includes a physical examination and liver and renal function tests for two years, after which time intervals can be increased to every six months.

●Testing for serum tumor markers (cancer antigen 19-9 [CA 19-9], if initially elevated) and cross-sectional imaging (computed tomography [CT] scanning) at least every three to four months during the first two years, then every six months once disease stability is comfortably established.

●Routine use of positron emission tomography imaging is not recommended.

Similar guidelines are available for borderline resectable disease from the National Comprehensive Cancer Network [2]. Guidelines from the European Society for Medical Oncology emphasize the incurability of recurrent pancreatic cancer and the lack of clear advantage to earlier detection of asymptomatic recurrences, but suggest assessment of CA 19-9 (if initially elevated) every three months for two years and an abdominal CT scan every six months [4].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pancreatic cancer".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Pancreatic cancer (The Basics)")

●Beyond the Basics topic (see "Patient education: Pancreatic cancer (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Pretreatment considerations

•A multidisciplinary team should develop treatment and care plans for patients with nonmetastatic pancreatic cancer guided by radiographic disease extent, performance status, comorbidities, goals of care, patient preferences, psychosocial issues, and symptom burden, and the results of both germline and targeted tumoral (somatic) testing. (See 'Pretreatment considerations' above.)

•A tissue diagnosis is required before initiation of neoadjuvant therapy, if planned. (See "Clinical manifestations, diagnosis, and staging of exocrine pancreatic cancer", section on 'Diagnostic algorithm and need for preoperative biopsy'.)

•Durable biliary decompression necessary for neoadjuvant therapy can usually be accomplished with a biliary stent. If bilirubin levels remain elevated, pursue repeat drainage prior to initiating chemotherapy. (See 'Jaundiced patients and those with a poor performance status' above.)

●Locally advanced, unresectable disease – Our general approach, which is outlined in the algorithm (algorithm 1), is as follows:

For most patients, we suggest initial systemic chemotherapy rather than radiation therapy (RT) or chemoradiotherapy (CRT) (Grade 2C). (See 'Initial chemotherapy' above and 'Initial chemoradiotherapy versus chemotherapy' above.)

The optimal regimen is not established, and enrollment in clinical trials is preferred. If trials are unavailable or patients are ineligible, our approach is based on germline and somatic tumoral genetic testing of genes associated with homologous recombination repair (HRR) deficiency and candidacy for chemotherapy (see 'Influence on choice of chemotherapy agents' above):

•For patients with known pathogenic or likely pathogenic variants in one of the HRR deficiency genes, or if mutation status is unknown or pending, who have a good performance status and comorbidity profile, we suggest combination chemotherapy with modified FOLFIRINOX ( (table 3) short-term infusional fluorouracil [FU] plus leucovorin, irinotecan, and oxaliplatin) over other combination regimens (Grade 2C). (See 'Combination regimens' above.)

A reasonable alternative for patients with a less good performance status or comorbidity profile is to start with FOLFOX (leucovorin plus short-term infusional FU and oxaliplatin, (table 7)), and add irinotecan for later cycles if FOLFOX is adequately tolerated.

•For patients with no detectable HRR deficiency-associated pathogenic or likely pathogenic germline or somatic alterations, options include gemcitabine plus nanoparticle albumin-bound paclitaxel (nabpaclitaxel) (table 8) or modified FOLFIRINOX (table 3).

•For patients with persistently elevated bilirubin despite adequate biliary drainage, dose-adjusted FOLFIRINOX or gemcitabine/nabpaclitaxel may be offered with close monitoring of toxicities. (See 'Jaundiced patients and those with a poor performance status' above.)

•We reserve single-agent gemcitabine for patients who we feel cannot tolerate multiagent chemotherapy (performance status ≥2 (table 2), bilirubin >1.5 times the upper limit of normal, unfavorable comorbidity profile). (See 'Gemcitabine alone' above.).

For patients with locally advanced pancreatic cancer who do not progress following four to six months of chemotherapy, we assess resectability by CT scan.

•If distant metastases have developed, we suggest continued chemotherapy rather than CRT (Grade 2C). (See 'Is there benefit to chemoradiotherapy after initial chemotherapy?' above.)

•For patients who remain potential surgical candidates, use of concomitant CRT cannot be considered a standard approach. (See 'Is there benefit to chemoradiotherapy after initial chemotherapy?' above.)

Given the limitations of imaging after neoadjuvant treatment (particularly after FOLFIRINOX), we offer surgical exploration to all patients without documented metastatic disease. However, institutional practice varies, and other centers use local imaging to guide surgical candidacy. (See 'Role of surgery' above.)

●Borderline resectable – Local unresectability is usually due to vascular invasion, particularly of the superior mesenteric artery (figure 2). Some cases are considered "borderline" resectable, mostly based on vascular involvement, although the definition is variable. (See 'Borderline resectable' above.)

Management of these cases is evolving. The following represents our general approach:

•For otherwise fit patients, we suggest neoadjuvant therapy, followed by restaging and surgical exploration in responders, rather than upfront surgery (Grade 2B). (See 'Overview of the therapeutic approach' above.)

•The best form of neoadjuvant therapy to use in this setting is unclear. We encourage enrollment in clinical trials testing new approaches. If trials are unavailable or participation is not feasible, we offer systemic combination chemotherapy similar to that used for locally advanced, unresectable pancreatic cancer (algorithm 1).

•Given the limitations of imaging after neoadjuvant treatment (particularly after FOLFIRINOX), we offer subsequent surgical exploration to all patients without documented metastatic disease. (See 'Rationale and outcomes' above.)

●Adjuvant therapy – For patients who received neoadjuvant therapy, we suggest adjuvant systemic therapy to complete a total of six months of systemic chemotherapy, including the preoperative regimen (Grade 2C). (See 'Role of adjuvant therapy' above.)

For patients with an excellent performance status who are able to tolerate it, we prefer modified FOLFIRINOX (table 3). For less fit patients, gemcitabine plus capecitabine is an option. Gemcitabine alone or, where available, S-1 alone is another reasonable option, particularly for patients with a borderline performance status or a comorbidity profile that precludes multiagent therapy.

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges David P Ryan, MD, who contributed to earlier versions of this topic review.