INTRODUCTION — Approximately 60,430 people develop exocrine pancreatic cancer each year in the United States, and almost all are expected to die from the disease [1]. Information on worldwide incidence and mortality is available from the World Health Organization GLOBOCAN database. The majority of these tumors (85 percent) are adenocarcinomas arising from the ductal epithelium. (See "Pathology of exocrine pancreatic neoplasms".)

Surgical resection offers the only chance of cure for exocrine pancreatic cancer, but only 15 to 20 percent of cases are potentially resectable at presentation. Local unresectability is usually (but not always) due to vascular invasion. (See "Clinical manifestations, diagnosis, and staging of exocrine pancreatic cancer", section on 'Assessing resectability' and "Overview of surgery in the treatment of exocrine pancreatic cancer and prognosis", section on 'Candidates for resection'.)

Unfortunately, prognosis is poor, even for those undergoing microscopically complete (R0) resection. Given the high rates of both systemic (>80 percent) and local (>20 percent) recurrence after surgery alone, systemic chemotherapy, radiation therapy, and combined approaches (chemoradiotherapy) have been used both prior to and following surgical resection in an effort to improve cure rates.

Management of potentially resectable pancreatic cancer will be discussed here. Neoadjuvant strategies for locally advanced, unresectable or "borderline" resectable exocrine pancreatic cancer; surgical management of localized exocrine pancreatic cancer; and chemotherapy for advanced disease are discussed separately. (See "Overview of surgery in the treatment of exocrine pancreatic cancer and prognosis" and "Ampullary carcinoma: Epidemiology, clinical manifestations, diagnosis and staging" and "Initial chemotherapy and radiation for nonmetastatic, locally advanced, unresectable and borderline resectable, exocrine pancreatic cancer" and "Initial systemic chemotherapy for metastatic exocrine pancreatic cancer".)

OVERVIEW OF THE TREATMENT APPROACH — A suggested approach to treatment of non-metastatic pancreatic cancer is presented in the algorithm (algorithm 1).

Assessing resectability — Surgical resection is a prerequisite for cure of pancreatic cancer. Unfortunately, because of the late presentation of the disease, only 15 to 20 percent of patients are candidates for pancreatectomy. Most of the time, distant metastatic disease precludes potentially curative surgery. In the absence of distant metastases, local unresectability is usually (but not always) due to vascular invasion (figure 1).

A triple-phase staging contrast-enhanced computed tomography (CT) scan of the abdomen or pelvis, or magnetic resonance imaging (MRI) should be performed for all patients to assess the anatomic relationships of the primary tumor and to assess for the presence of intra-abdominal metastases [2]. In general, pancreatic cancers can be categorized on a continuum from resectable to unresectable according to the involvement of adjacent structures and the presence of distant metastases (figure 2) [3]. (See "Clinical manifestations, diagnosis, and staging of exocrine pancreatic cancer", section on 'Imaging studies'.)

Tumors that are limited to the pancreas are most likely to be cured by resection. Tumors with limited involvement of the major peripancreatic vessels, such as the superior mesenteric vein (SMV), portal vein, superior mesenteric artery, or hepatic artery, may be technically resectable, but the impact of more aggressive resections (particularly arterial resection) on long-term outcomes is controversial. (See "Overview of surgery in the treatment of exocrine pancreatic cancer and prognosis", section on 'Vascular resection' and "Surgical resection of lesions of the head of the pancreas", section on 'Vascular evaluation'.)

Some of these cases are considered "borderline" resectable, although the definition is variable (see "Clinical manifestations, diagnosis, and staging of exocrine pancreatic cancer", section on 'Definitions of unresectable and borderline resectable disease' and "Overview of surgery in the treatment of exocrine pancreatic cancer and prognosis", section on 'Vascular resection'):

●Some reserve this term for cases where there is focal (less than one-half of the circumference) tumor abutment of the visceral arteries or short-segment occlusion of the SMV or SMV/portal vein confluence.

●Others suggest that venous narrowing without occlusion should be included in the definition of borderline resectable disease.

●Encasement (more than one-half of the vein circumference) or occlusion of the SMV or the SMV/portal vein confluence was previously considered unresectable. However, many centers have demonstrated the feasibility of SMV reconstruction, and provided that venous reconstruction is possible, this is now considered by many to represent borderline resectable disease.

Although some of these patients will prove to be resectable with initial surgery, the likelihood of an incomplete resection is high. A preferred approach is attempted downstaging with neoadjuvant therapy (algorithm 1). (See "Initial chemotherapy and radiation for nonmetastatic, locally advanced, unresectable and borderline resectable, exocrine pancreatic cancer", section on 'Borderline resectable disease'.)

Absolute contraindications to resection include the presence of metastases in the liver, peritoneum, omentum, or any extra-abdominal site. Other indications of local unresectability include encasement (more than one-half of the vessel circumference) or occlusion/thrombus of the superior mesenteric artery, unreconstructable SMV or SMV/portal vein confluence occlusion, or direct involvement of the inferior vena cava, aorta, or celiac axis, as defined by the absence of a fat plane between the low-density tumor and these structures on CT scan or endoscopic ultrasound (EUS). Management of these patients usually entails initial chemotherapy and not surgical exploration (algorithm 1). (See "Clinical manifestations, diagnosis, and staging of exocrine pancreatic cancer", section on 'Definitions of unresectable and borderline resectable disease' and "Initial chemotherapy and radiation for nonmetastatic, locally advanced, unresectable and borderline resectable, exocrine pancreatic cancer" and "Initial systemic chemotherapy for metastatic exocrine pancreatic cancer".)

Whether and how to use preoperative levels of the serum tumor marker carbohydrate antigen 19-9 (CA 19-9; also called cancer antigen 19-9) to select the initial therapeutic strategy is controversial. Elevated levels of CA 19-9 can help to predict the presence of radiographically occult metastatic disease, the likelihood of a microscopically complete (R0) resection, and long-term outcomes in patients with potentially resectable pancreatic cancer [4]. However, while high levels of CA 19-9 may help surgeons to better select patients who need staging laparoscopy, the use of CA 19-9 alone as an indicator of operability is not advised [2]. Furthermore, while a year 2016 clinical practice guideline on management of potentially curable pancreatic cancer from the American Society of Clinical Oncology (ASCO) suggested that chemotherapy could be used before surgery for patients who had potentially anatomically resectable but high-risk tumors (as judged by elevated preoperative levels of CA 19-9), there was no recommendation for a specific cutoff value of CA 19-9 to select patients for neoadjuvant therapy [2]. In our view, serum CA 19-9 levels should not be used to direct the initial treatment strategy. This subject is discussed in detail elsewhere. (See "Clinical manifestations, diagnosis, and staging of exocrine pancreatic cancer", section on 'Carbohydrate antigen 19-9'.)

Suitability for resection and symptom burden — In addition to the extent of tumor involvement, the baseline performance status, comorbidity profile, and goals of care should be evaluated and established. Primary surgical resection should only be offered to patients who have a performance status and comorbidity profile that are appropriate for a major abdominal operation [2]. All patients with newly diagnosed pancreatic cancer should have a full assessment of symptom burden, psychological status, and social supports as early as possible. In some instances, this may indicate the need for a formal palliative care consult. (See "Benefits, services, and models of subspecialty palliative care", section on 'Rationale for palliative care'.)

Patients with potentially curable pancreatic cancer may experience various distressing symptoms and concerns that require ongoing supportive care, including pain, anorexia and weight loss, depression and anxiety, biliary obstruction, pancreatic insufficiency, and venous thromboembolism. These topics are all discussed in detail elsewhere. (See "Cancer pain management with opioids: Optimizing analgesia" and "Management of psychiatric disorders in patients with cancer" and "Management of cancer anorexia/cachexia" and "Overview of surgery in the treatment of exocrine pancreatic cancer and prognosis", section on 'Role of preoperative biliary drainage' and "Risk and prevention of venous thromboembolism in adults with cancer" and "Anticoagulation therapy for venous thromboembolism (lower extremity venous thrombosis and pulmonary embolism) in adult patients with malignancy" and "Supportive care of the patient with locally advanced or metastatic exocrine pancreatic cancer", section on 'Pancreatic exocrine insufficiency'.)

Upfront pancreatectomy — Primary surgical resection is appropriate for patients with no distant metastatic disease, a performance status and comorbidity profile that are appropriate for major abdominal surgery, and no radiographic interface between the primary tumor and the mesenteric vasculature. An overview of surgical treatment for pancreatic cancer is provided elsewhere. (See "Overview of surgery in the treatment of exocrine pancreatic cancer and prognosis".)

For those patients who have potentially resectable tumors, and a performance status or comorbidity profile that is not appropriate for a major abdominal operation but is potentially reversible, we suggest initial chemotherapy as is used for borderline resectable pancreatic cancers. Surgery could then be reconsidered at a later time if appropriate. (See "Initial chemotherapy and radiation for nonmetastatic, locally advanced, unresectable and borderline resectable, exocrine pancreatic cancer", section on 'Borderline resectable disease'.)

Adjuvant therapy

Indications — We recommend adjuvant chemotherapy for all patients with resected pancreatic ductal adenocarcinoma who did not receive neoadjuvant therapy, including those with resected T1N0 disease (table 1). This recommendation is consistent with guidelines from ASCO [2,5], the National Comprehensive Cancer Network (NCCN) [6], and the European Society for Medical Oncology (ESMO) [7].

Acinar cell histology — Acinar cell carcinomas (ACCs) are rare malignant neoplasms that constitute approximately 1 percent of all malignant nonendocrine pancreatic tumors. Histologically, there is clear evidence of acinar cell differentiation, which can be identified immunohistochemically by staining for trypsin, chymotrypsin, elastase, or lipase or can be ultrastructurally identified by the presence of zymogen granules, although variant histologic patterns reflect different degrees of differentiation (picture 1). (See "Pathology of exocrine pancreatic neoplasms", section on 'Acinar cell carcinoma'.)

Some ACCs give rise to a clinical syndrome related to lipase hypersecretion with distant manifestations, subcutaneous fat necrosis (termed "pancreatic panniculitis"), and eosinophilia and polyarthralgia (the so-called "Schmidt's triad"). This syndrome is associated with poor prognosis [8,9]. (See "Cutaneous manifestations of internal malignancy".)

The overall prognosis for patients with ACC is better than that for patients with ductal adenocarcinoma [10-13]. Patients with ACC tend to present at a younger age than do those with pancreatic ductal adenocarcinoma; they are more likely to have localized disease (15 versus 8 percent) and are more likely to undergo resection (39 versus 11 percent) [11]. Five-year survival rates among patients with resected disease range from 44 to 72 percent [11,12,14,15]; in one large series, the stage-stratified five-year survival rates for ACC versus pancreatic ductal adenocarcinoma were as follows [12]:

●Stage I – 52 versus 28 percent

●Stage II – 40 versus 10 percent

●Stage III – 23 versus 7 percent

The role of adjuvant therapy for ACC is undefined. However, despite the better overall survival compared with ductal adenocarcinoma, the available evidence suggests high recurrence rates, even after complete surgical resection [13,16,17]. We treat these patients the same as those with pancreatic ductal adenocarcinoma, offering adjuvant chemotherapy to most patients with resected disease, with the possible exception of those with well-differentiated T1 tumors with negative resection margins, who have a relatively favorable prognosis [12]. (See 'Choice of therapy' below.)

We would also consider these patients to be appropriate candidates for neoadjuvant therapy, just as we do for those with pancreatic ductal adenocarcinoma. (See 'Neoadjuvant therapy' below.)

Timing and duration — For all patients who undergo initial resection without neoadjuvant therapy, including those with pathologic T1N0 disease (table 1), we recommend six months of adjuvant chemotherapy. Adjuvant treatment should be started within eight weeks of surgery, if possible. Prior to beginning adjuvant therapy, all patients should undergo formal restaging with CT scans and a serum level of the tumor marker CA 19-9.

The optimal timing and duration of adjuvant therapy are not established. A focused guideline update on potentially curable pancreatic cancer from ASCO recommends adjuvant systemic chemotherapy for six months starting within eight weeks of surgery, assuming adequate recovery from surgery [5]. Modern adjuvant chemotherapy trials have utilized six months as the standard duration of postresection chemotherapy, and they permitted enrollment up to 12 weeks postoperatively [18]. However, there are no randomized trials addressing the impact of delayed initiation of adjuvant therapy on outcomes or addressing the effect of a longer duration of therapy.

The following data are available to address the optimal timing of adjuvant therapy:

●In an analysis of data on patients with resected stage I to III pancreatic cancer who were enrolled in the phase III ESPAC-3 trial, time to start of chemotherapy (within eight weeks of resection versus beyond) did not influence overall survival rates (hazard ratio 0.985; 95% CI 0.956-1.015) [19]. (See 'ESPAC-3 trial' below.)

●An analysis of approximately 10,000 patients with resected stage I to III pancreatic cancer derived from the National Cancer Database (NCDB) found a similar proportional benefit for adjuvant chemotherapy initiated within 12 weeks or beyond 12 weeks postresection, compared with surgery alone [20].

●On the other hand, in a separate analysis derived from the NCDB, patients with stage I or II pancreatic cancer who commenced adjuvant therapy between 28 and 59 days after primary surgical resection had better survival outcomes than did those initiating adjuvant therapy before 28 or beyond 59 days [21]. However, even patients who initiated adjuvant systemic therapy more than 12 weeks postresection had improved overall survival relative to those undergoing surgery alone.

Prior to beginning adjuvant therapy, all patients should undergo formal restaging with CT scans and a serum level of the tumor marker CA 19-9. Persistent postoperative elevations of serum tumor marker CA 19-9 are associated with a poor long-term prognosis. However, CA 19-9 levels are prognostic and not necessarily predictive of benefit from adjuvant therapy.

While some suggest withholding adjuvant therapy from such patients or treating them as if they have advanced metastatic disease [22], and some adjuvant therapy protocols (such as Radiation Therapy Oncology Group [RTOG] 0848) only allow enrollment if the post-treatment CA 19-9 level is ≤180 units/mL, we (and others [23]) suggest not using postoperative CA 19-9 levels to determine whether or not to give postoperative adjuvant therapy outside of the context of a clinical trial. (See "Clinical manifestations, diagnosis, and staging of exocrine pancreatic cancer", section on 'Carbohydrate antigen 19-9' and "Overview of surgery in the treatment of exocrine pancreatic cancer and prognosis", section on 'Prognosis and prognostic factors'.)

Choice of therapy

Chemotherapy — If protocol therapy is not available or declined, for patients with an excellent performance status who are able to tolerate it, we suggest modified FOLFIRINOX (oxaliplatin plus irinotecan with leucovorin [LV] and short-term infusional fluorouracil) rather than gemcitabine alone, and we also prefer it over 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. (See 'Gemcitabine plus capecitabine' below and 'Gemcitabine versus S-1' below and 'Modified FOLFIRINOX' below.)

Chemotherapy for BRCA and PALB2 mutation carriers — The optimal chemotherapy regimen to use for BRCA1/BRCA2 or partner and localizer of BRCA2 (PALB2) mutation carriers with pancreatic adenocarcinoma is not established. Until further information becomes available, we suggest using the same chemotherapy regimens in the adjuvant setting as are used for non-mutation carriers.

Hereditary breast and ovarian cancers are characterized by the presence of germline mutations in one of two cancer susceptibility genes, BRCA1 and BRCA2. The risk of pancreatic cancer is elevated in those with BRCA2 mutations, and it may also be elevated in BRCA1 mutation carriers, although the risk is not as well established as it is with BRCA2 gene mutations. In addition, the PALB2 gene is a breast cancer susceptibility gene that encodes a BRCA2-interacting protein; patients with inherited germline PALB2 mutations are also at a higher risk for pancreatic cancer. (See "Cancer risks and management of BRCA1/2 carriers without cancer", section on 'Pancreas' and "Familial risk factors for pancreatic cancer and screening of high-risk patients", section on 'Hereditary breast cancer: BRCA and PALB2' and "Overview of hereditary breast and ovarian cancer syndromes associated with genes other than BRCA1/2", section on 'PALB2'.)

Cells that lack functioning BRCA1 or BRCA2 have a deficiency in the repair of DNA double-strand breaks. There is accumulating evidence of increased sensitivity to platinums and poly (ADP-ribose) polymerase (PARP) inhibitors 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'.)

Whether these findings apply to pancreatic cancers that arise in the setting of a BRCA or PALB2 mutation is unclear. At least some retrospective data support the view that exposure to a platinum-based perioperative chemotherapy regimen (cisplatin, oxaliplatin, or carboplatin) might confer a survival benefit for patients with resected pancreatic ductal adenocarcinoma and a pathogenic BRCA or PALB2 mutation over the use of non-platinum-containing chemotherapy [24,25]. However, these results are, at best, hypothesis generating, and the optimal chemotherapy combination to use in these patients is not yet established.

Updated consensus-based guidelines from the NCCN suggest consideration of a platinum-based regimen for advanced-stage pancreatic cancer that arises in the setting of a BRCA mutation and in the neoadjuvant setting [6], but there are no guidelines for the adjuvant setting. Nevertheless, FOLFIRINOX is the reference standard for adjuvant therapy and represents a reasonable choice for BRCA mutant patients who are able to tolerate it.

Chemoradiotherapy — For most patients who received either gemcitabine alone or gemcitabine plus capecitabine for adjuvant therapy, we also suggest the addition of chemoradiotherapy to chemotherapy. The tolerability and benefit of adjuvant chemoradiotherapy in patients who undergo adjuvant FOLFIRINOX chemotherapy are unclear. Until further information is available, we do not offer adjuvant radiation therapy (RT) to all individuals who have had a six-month adjuvant course of FOLFIRINOX, but instead, we reserve this approach for selected patients who desire aggressive therapy and retain an excellent performance status after surgery and chemotherapy. Our approach is consistent with guidelines from ASCO, which suggest adding postoperative chemoradiotherapy to six months of adjuvant gemcitabine-based chemotherapy for patients with node-positive or margin-positive disease [2]. Updated 2019 guidelines from the NCCN suggest chemotherapy alone (gemcitabine plus capecitabine, FOLFIRINOX) as the preferred regimen for adjuvant therapy, but they include induction chemotherapy followed by chemoradiotherapy as an acceptable option for adjuvant therapy [6].

However, the benefit of adjuvant RT in the adjuvant setting, especially in patients who receive adjuvant FOLFIRINOX, is controversial, and the approach differs outside of the United States. (See 'Does chemoradiotherapy add benefit to chemotherapy' below.)

Most European clinicians advocate chemotherapy alone, emphasizing the survival benefit of chemotherapy in the German CONKO-001 trial, the lack of a significant survival benefit with chemoradiotherapy in a European Organisation for Research and Treatment of Cancer (EORTC) trial, and the detrimental impact of chemoradiotherapy on survival seen in the ESPAC-1 trial. The most recent (2015) guidelines for treatment of pancreatic adenocarcinoma suggest that chemoradiotherapy in the adjuvant setting should only be undertaken within the context of a randomized controlled trial [7]. (See 'ESPAC-1 trial' below and 'EORTC study' below.)

Similarly, the Japanese approach also includes chemotherapy alone. However, for Japanese patients, oral therapy with S-1, where available, represents a preferred alternative to gemcitabine monotherapy, given the results of a randomized trial demonstrating therapeutic noninferiority and better tolerability for S-1. (See 'Gemcitabine versus S-1' below.)

On the other hand, the American approach, which more often includes chemoradiotherapy in addition to adjuvant chemotherapy, emphasizes the following points (see 'GITSG study' below and 'ESPAC-1 trial' below and 'EORTC study' below):

●The high risk of local failure after resection of pancreatic cancer and the potential for benefit from chemoradiotherapy.

●The high rate of positive retroperitoneal margins and the adverse impact of this finding on survival.

●The survival benefit from chemoradiotherapy in the Gastrointestinal Tumor Study Group (GITSG) study.

●The trend toward improved survival seen with chemoradiotherapy in the underpowered EORTC study.

●The serious design flaws of the ESPAC-1 trial and the inherent difficulty in drawing definitive conclusions from this study.

Neoadjuvant therapy — The role of neoadjuvant therapy in patients with potentially resectable pancreatic cancer is evolving, and guidelines from expert groups are conflicting. (See 'Neoadjuvant therapy' below.)

Nevertheless, use of upfront chemotherapy prior to resection of early stage pancreatic cancer is increasing [26], and some centers have taken the view that nearly all patients who appear to have "potentially resectable" pancreatic cancer should be considered to have "borderline resectable" disease given the inaccuracy of imaging and the very high rates of a positive margin with initial surgery, which is associated with poor overall survival. Although limited, at least some data from prospective trials support some benefits from neoadjuvant therapy in patients with potentially resectable pancreatic cancer, described in detail below. (See 'Chemotherapy plus chemoradiotherapy' below and 'Induction chemotherapy alone' below.)

In general, we prefer that eligible patients be enrolled in trials testing neoadjuvant strategies. If a clinical trial is not available or participation is not feasible, we consider neoadjuvant therapy to be a reasonable alternative to upfront surgery followed by adjuvant therapy in patients who appear to have potentially resectable tumors, as long as performance status and comorbidity are sufficient to tolerate treatment. However, for the rare patient with a <2 cm, apparently node-negative tumor (as determined by pretreatment imaging), neoadjuvant therapy is probably not warranted.

If it is chosen, the best regimen for neoadjuvant therapy is not currently defined. For most patients who are able to tolerate it, we prefer the multiagent modified FOLFIRINOX regimen, followed by chemoradiotherapy in the absence of distant metastases [27]. The data supporting benefit from specific neoadjuvant strategies are presented below. (See 'Neoadjuvant therapy' below.)

ADJUVANT STRATEGIES — The following sections provide the data on which the therapeutic approach to adjuvant therapy is based.

Chemotherapy alone — Although the benefit of adjuvant chemotherapy for resected, subcentimeter, stage IA pancreatic cancer has been questioned [28], we recommend six months of adjuvant chemotherapy for all patients with resected pancreatic cancer who did not receive neoadjuvant therapy, including those with resected T1N0 disease (table 1). Off protocol, for patients with an excellent performance status who are able to tolerate it, we suggest modified FOLFIRINOX (oxaliplatin plus irinotecan with leucovorin [LV] and short-term infusional fluorouracil [FU]) rather than gemcitabine alone, and we also prefer this regimen over gemcitabine plus capecitabine. For less fit patients, gemcitabine plus capecitabine is an option, as has been recommended in a focused guideline update for potentially curable pancreatic cancer from the American Society of Clinical Oncology (ASCO) [5]. 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. (See 'Gemcitabine plus capecitabine' below and 'Gemcitabine versus S-1' below and 'Modified FOLFIRINOX' below.)

Early trials demonstrating the benefit of chemotherapy

ESPAC-1 trial — An ambitious trial sponsored by European investigators, the ESPAC-1 trial, initially set out to randomize patients to a two-by-two factorial design in which the relative benefits of adjuvant chemotherapy, chemoradiotherapy, or chemoradiotherapy followed by chemotherapy would be compared with observation alone. However, fear of poor accrual led the investigators to permit the clinician to choose from this or two other randomization schemes (described below). The final results were presented in two separate publications: one that pooled the results from the three parallel randomized trials [29], and a later report that focused on the 289 patients randomized to the four-arm study [30].

The pooled analysis included 541 patients (including those with positive margins) who were randomly assigned to postoperative treatment following resection of exocrine pancreatic cancer in the following three parallel studies [29]:

●Chemoradiotherapy versus no chemoradiotherapy – Sixty-eight patients enrolled; chemoradiotherapy consisted of 20 Gy of external beam radiation therapy (RT) plus three days of concomitant FU, repeated after a planned break of two weeks.

●Adjuvant chemotherapy versus no chemotherapy – One hundred and eighty-eight patients enrolled; adjuvant chemotherapy consisted of bolus LV-modulated FU (LV 20 mg/m², FU 425 mg/m²) administered daily for five days every 28 days for six months.

●A two-by-two factorial design trial with four groups – Chemoradiotherapy (n = 73), chemotherapy (n = 75), both (n = 72), or observation (n = 69) [30]; the chemoradiotherapy and chemotherapy treatments were as described above.

In the initial report of the pooled analysis, there was a significant survival benefit for adjuvant chemotherapy alone when the 238 patients who received it were compared with the 235 who did not receive it (median survival 19.7 versus 14 months, respectively), but there was no survival difference when the 175 patients who received postoperative chemoradiotherapy were compared with the 178 who did not receive it (median overall survival 15.5 versus 16.1 months, respectively) [29-31].

This analysis was criticized for the following reasons:

●Patients and clinicians were allowed to select which trial to enter, raising concerns as to generalizability and the appropriateness of combining results.

●Clinicians were allowed, according to their own preferences, to deliver "background" chemoradiotherapy or chemotherapy.

●Comparisons of treatment groups that were pooled together by treatment actually received, rather than "intent-to-treat" analysis, resulted in nearly one-third of the "no chemotherapy" and "chemotherapy alone" patients receiving chemoradiotherapy.

●The chemoradiotherapy group received RT in a split-course fashion, and the final dose (ranging from 40 to 60 Gy) was left to the judgment of the treating clinician.

●The chemoradiotherapy group did not include post-RT adjuvant chemotherapy.

Some (but not all) of these concerns were addressed in a subsequent report that included only the 289 patients randomized to the four-arm study [30]. In an intent-to-treat analysis, both the two-year (40 versus 30 percent) and five-year (21 versus 8 percent) survival rates were significantly greater among patients randomized to postoperative chemotherapy alone compared with those who did not receive it, despite the fact that 33 percent of those assigned to adjuvant chemotherapy did not complete all six courses and 17 percent received no chemotherapy at all.

By contrast, there was no significant benefit for chemoradiotherapy in the two groups that received it, and in fact, the data suggested a trend toward worse survival for this group (two- and five-year survival rates 29 versus 41 and 10 versus 20 percent for the chemoradiotherapy and no chemoradiotherapy groups, respectively). (See 'ESPAC-1 trial' below.)

CONKO-001 trial — A survival benefit from adjuvant gemcitabine monotherapy was shown in the multinational European CONKO-001 trial of 368 patients with a grossly complete (microscopically complete [R0] or macroscopically complete [R1]) surgical resection and a preoperative carbohydrate antigen 19-9 (CA 19-9) level <2.5 times the upper limit of normal [32]. The patients were randomly assigned to gemcitabine (1000 mg/m² on days 1, 8, and 15 every four weeks for six months) or no treatment after surgery. Patients were stratified by resection margins (which were positive in approximately 17 percent of patients), and tumor (T) and nodal (N) status; the primary endpoint was disease-free survival (DFS). In the most recent update, there was also a modest but significant improvement in overall survival that favored gemcitabine and persisted long term (five-year overall survival 21 versus 10 percent; 10-year overall survival 12.2 versus 7.7 percent) [33]. These results established gemcitabine monotherapy as a standard adjuvant treatment for resected pancreatic cancer.

Choice of regimen — Off protocol, for patients with an excellent performance status who are able to tolerate it, we suggest modified FOLFIRINOX rather than gemcitabine alone, and we also prefer FOLFIRINOX over gemcitabine plus capecitabine. For less fit patients, gemcitabine plus capecitabine is an appropriate option. Therapy with gemcitabine alone or, where available, S-1 alone is another reasonable option for patients with a borderline performance status or a comorbidity profile that precludes multiagent therapy. These recommendations are consistent with updated ASCO guidelines [34], as well as National Comprehensive Cancer Network (NCCN) guidelines, which consider either gemcitabine plus capecitabine or FOLFIRINOX to be the preferred regimen for adjuvant therapy, with FOLFIRINOX restricted to those with a European Cooperative Oncology Group (ECOG) performance status of 0 to 1 (table 2) [6]. (See 'Modified FOLFIRINOX' below.)

ESPAC-3 trial — The multicenter ESPAC-3 trial randomly assigned 1088 patients with resected exocrine pancreatic cancer to six months of postoperative adjuvant treatment with either gemcitabine (1000 mg/m² weekly for three of every four weeks) or LV-modulated FU (LV 20 mg/m² followed by intravenous bolus FU 425 mg/m² on days 1 through 5 every 28 days) [35]. At a median follow-up of 34 months, median survival was similar (23.6 versus 23 months with gemcitabine and fluoropyrimidine therapy, respectively). However, the patients assigned to FU/LV had more grade 3 to 4 treatment-related toxicity, including stomatitis (10 versus 0 percent), diarrhea (13 versus 2 percent), and more treatment-related hospitalizations. Otherwise, progression-free survival and global quality of life scores were similar between the two groups.

Some information on timing and duration of adjuvant chemotherapy is available from an analysis of the 985 patients who received adjuvant gemcitabine or FU after resection of pancreatic cancer in the ESPAC-3 trial [19] (see 'Timing and duration' above):

●Overall survival favored patients who completed the full six months of therapy over those who did not (median survival 28 versus 15 months, hazard ratio [HR] for death 0.51, 95% CI 0.44-0.60).

●Time to start of chemotherapy (within eight weeks of surgery versus later) was an important survival factor only for the subgroup of patients who did not complete all six months of therapy (and in this group, survival inexplicably favored later initiation of therapy). There seemed to be no difference in outcomes if chemotherapy was delayed for up to 12 weeks.

While these data support the view that delaying the initiation of adjuvant therapy to allow full recovery from surgery does not compromise the benefit of adjuvant therapy, the subset analysis must be viewed cautiously. There are several confounding reasons as to why patients who receive less than six months of adjuvant therapy might do worse.

RTOG 9704 study — A slightly different question, the relative value of adjuvant gemcitabine monotherapy both before and after concomitant FU-based chemoradiotherapy versus all-FU therapy in which FU is given before, during, and after RT, was addressed in a United States intergroup study (Radiation Therapy Oncology Group [RTOG] 9704) [36]. Patients who had undergone gross total resections for T1-4N0-1 (according to the 2010 tumor, node, metastasis [TNM] classification (table 3)) exocrine pancreatic cancer and who were taking in at least 1500 calories daily postoperatively were randomly assigned to one of the following two treatment arms:

●FU arm – Three weeks of continuous-infusion FU (250 mg/m² daily) followed by chemoradiotherapy (50.4 Gy in 1.8 Gy daily fractions for 5.5 weeks with concurrent infusional FU 250 mg/m² daily) and, starting three to five weeks later, two four-week courses of continuous-infusion FU (250 mg/m² daily with a two-week rest in between courses)

●Gemcitabine arm – Three weekly doses of gemcitabine alone (1000 mg/m² per week) followed by the same chemoradiotherapy protocol as for the conventional chemoradiotherapy arm and, starting three to five weeks later, three months of single-agent gemcitabine (1000 mg/m² weekly for three of every four weeks)

In the latest update, there were no significant differences in five-year overall survival or DFS between the two groups [37]. The study was sufficiently powered to separately analyze results according to the primary site (head versus body/tail). Among patients with pancreatic head tumors (n = 388), there was a trend toward better median (20.5 versus 17.1 months) and five-year survival (22 versus 18 percent, p = 0.08) with gemcitabine-based adjuvant therapy, although neither difference was statistically significant.

There were no differences between the two treatments in patients with body/tail tumors (n = 63). Compared with the all-FU treatment, the gemcitabine group had similar rates of nonhematologic grade 3 or 4 toxicity and febrile neutropenia, despite significantly more grade 4 hematologic toxicity (14 versus 1 percent) [36].

Gemcitabine versus S-1 — 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 [DPD]), and oteracil (potassium oxonate; which inhibits phosphorylation of intestinal FU, thought to be responsible for treatment-related diarrhea). It is approved in Japan for adjuvant treatment of gastric cancer and in Europe for treatment of advanced gastric cancer; it is not available in the United States.

S-1 (40 to 60 mg twice daily for four weeks and repeated every six weeks for four courses) was directly compared with gemcitabine (1000 mg/m² on days 1, 8, and 15 and repeated every four weeks for six courses) in a multicenter trial of 385 Japanese patients with completely resected stage I, II, or III pancreatic cancer [38]. S-1 was found to be noninferior to gemcitabine, and patients treated with S-1 actually had a lower mortality rate (HR for death 0.57, 95% CI 0.44-0.72; five-year survival 44 versus 24 percent). Although both treatments were associated with similarly low rates of grade 3 or 4 anorexia, thrombocytopenia, and anemia, gemcitabine was associated with more leukopenia (39 versus 9 percent) and transaminitis (5 versus 1 percent). Whether these results can be extrapolated to other populations is unclear.

Gemcitabine plus capecitabine — The benefit of a two-drug regimen, rather than gemcitabine alone, was tested in the ESPAC-4 trial, which randomly assigned 730 patients with R0 or R1 resected pancreatic adenocarcinoma to six months of gemcitabine alone (1000 mg/m² on days 1, 8, and 15 of each 28-day cycle) or to the same dose of gemcitabine plus capecitabine (1660 mg/m² per day on days 1 through 21 of each 28-day cycle) (table 4) [18]. The following outcomes were reported:

●The majority of patients in both arms had R1 resection margins (60 percent) and positive lymph nodes (80 percent).

●Of the grade 3 or 4 adverse effects, diarrhea (5 versus 2 percent), hand-foot syndrome (7 versus 0 percent), and neutropenia (38 versus 24 percent) were significantly more common with combined therapy, although there were no significant differences in the rates of treatment-related serious adverse events.

●In the latest analysis, at a median follow-up of 43 months, combination therapy was associated with a significant survival benefit (median overall survival 30.2 versus 27.9 months, HR for death 0.81, 95% CI 0.68-0.98, and five-year overall survival was 28 versus 17 percent [39]).

Modified FOLFIRINOX — Better outcomes may be achieved using multiagent chemotherapy combinations, such as FOLFIRINOX (oxaliplatin plus irinotecan with LV and short-term infusional FU), which have been shown to be more effective than gemcitabine alone in the setting of metastatic disease. (See "Initial systemic chemotherapy for metastatic exocrine pancreatic cancer".)

The benefits of modified FOLFIRINOX over gemcitabine alone were shown in the multicenter PRODIGE-24 trial, which randomly assigned 493 patients with histologically proven pancreatic ductal adenocarcinomas 21 to 84 days after R0 or R1 resection, a performance status of 0 or 1, adequate hematologic and renal function, and no cardiac ischemia to six months of gemcitabine alone (28-day cycles of gemcitabine 1000 mg/m² on days 1, 8, and 15) or modified FOLFIRINOX (table 5) [40]. At a median follow-up of 34 months, median DFS (the primary endpoint) was significantly better with modified FOLFIRINOX (21.6 versus 12.8 months, HR 0.58, 95% CI 0.46-0.73), as was median overall survival (54.4 versus 35 months, HR 0.64, 95% CI 0.48-0.86). Grade 3 to 4 adverse events that were more frequent with modified FOLFIRINOX included diarrhea (19 versus 4 percent), sensory neuropathy (9 versus 0 percent), fatigue (11 versus 5 percent), and vomiting (5 versus 1 percent).

There are no trials directly comparing adjuvant FOLFIRINOX with gemcitabine plus capecitabine.

Based on these results, off protocol, for patients with an excellent performance status who are able to tolerate it, we suggest modified FOLFIRINOX rather than gemcitabine alone for adjuvant therapy, and we also prefer this regimen over gemcitabine plus capecitabine in patients with a good performance status (ECOG 0 to 1 (table 2)).

Gemcitabine plus nabpaclitaxel — Gemcitabine plus nanoparticle albumin-bound paclitaxel (nabpaclitaxel) is a highly active regimen in metastatic pancreatic cancer. The benefit of this combination over gemcitabine alone was tested in the multicenter international APACT trial, which randomly assigned 866 patients with R0 or R1 resected pancreatic cancer to six months of gemcitabine (1000 mg/m² on days 1, 8, and 15 of every 28-day cycle) alone or with nabpaclitaxel (125 mg/m² on days 1, 8, and 15 of every 28-day cycle) [41]. In a preliminary report presented at the 2019 annual ASCO meeting, DFS as assessed by independent review was not significantly better with combination therapy (median 19.4 versus 18.8 months, HR 0.88, 95% CI 0.729-1.083), but investigator-assessed DFS and median overall survival seemed to favor combined therapy. In the latest preliminary analysis presented at the 2021 European Society for Medical Oncology (ESMO) World Congress on Gastrointestinal malignancies, overall survival was significantly improved with combined therapy (median 41.8 versus 37.7 months, HR 0.80, 95% CI 0.68-0.95, five-year overall survival 38 versus 31 percent) [42].

We await final publication of the trial results in a peer-reviewed journal before concluding that adjuvant gemcitabine plus nabpaclitaxel is preferred over gemcitabine plus capecitabine. For patients who are ineligible for FOLFIRINOX, acceptable options for adjuvant therapy include gemcitabine plus nabpaclitaxel or gemcitabine plus capecitabine.

Chemotherapy dosing in obese patients — For cancer patients with a large body surface area, chemotherapy drug doses are often reduced because of concern for excess toxicity. However, there is no evidence that fully dosed obese patients experience greater toxicity from chemotherapy for pancreatic cancer. Guidelines from ASCO recommend that full weight-based cytotoxic chemotherapy doses be used to treat obese patients with cancer, particularly when the goal of treatment is cure [43]. (See "Dosing of anticancer agents in adults", section on 'Overweight/obese patients'.)

Chemoradiotherapy — For most patients who received either gemcitabine alone or gemcitabine plus capecitabine for adjuvant therapy, we also suggest the addition of chemoradiotherapy to chemotherapy. The tolerability and benefit of adjuvant chemoradiotherapy in patients who undergo adjuvant FOLFIRINOX chemotherapy are unclear. Until further information is available, we do not offer adjuvant RT to all individuals who have had a six-month adjuvant course of FOLFIRINOX, but instead, we reserve this approach for selected patients who desire aggressive therapy and retain an excellent performance status after surgery and chemotherapy. Our approach is consistent with guidelines from ASCO, which suggest adding postoperative chemoradiotherapy to six months of adjuvant gemcitabine-based chemotherapy for patients with node-positive or margin-positive disease [2], and the American Society for Radiation Oncology (ASTRO), which provide a strong recommendation for chemoradiotherapy following four to six months of systemic chemotherapy after resection [44]. Updated 2019 guidelines from the NCCN suggest chemotherapy alone (gemcitabine plus capecitabine, FOLFIRINOX) as the preferred regimen for adjuvant therapy, but they include induction chemotherapy followed by chemoradiotherapy as an acceptable option for adjuvant therapy [6]. The ESMO suggests chemotherapy alone in this setting [7].

Rationale — The American approach to adjuvant therapy, which more often includes chemoradiotherapy in addition to adjuvant chemotherapy, emphasizes the following points (see 'GITSG study' below and 'ESPAC-1 trial' below and 'EORTC study' below):

●The high risk of local failure after resection of pancreatic cancer and the potential for benefit from chemoradiotherapy.

●The high rate of positive retroperitoneal margins and the adverse impact of this finding on survival.

●The survival benefit from chemoradiotherapy in the Gastrointestinal Tumor Study Group (GITSG) study.

●The trend toward improved survival seen with chemoradiotherapy in the underpowered European Organisation for Research and Treatment of Cancer (EORTC) study.

●The serious design flaws of the ESPAC-1 trial and the inherent difficulty in drawing definitive conclusions from this study.

Failure patterns following surgical resection alone were addressed in an autopsy series of 76 patients who had been treated for pancreatic cancer; 15 percent of those who had surgery alone for stage I or II disease had a local recurrence in the pancreatic bed alone, while 65 percent had both locally recurrent and metastatic disease [45].

The local control benefit of adding RT can be best illustrated by data from the Groupe Coopérateur Multidisciplinaire en Oncologie (GERCOR) trial of postoperative gemcitabine versus gemcitabine-based chemoradiotherapy [46]. The rate of local recurrence alone at first progression in the chemoradiotherapy group was notably lower (11 versus 24 percent), as was the rate of simultaneous local and distant progression (13 versus 20 percent). (See 'Does chemoradiotherapy add benefit to chemotherapy' below.)

However, not all studies have demonstrated improvements in local control with the use of combined modality therapy [30,47]. Furthermore, randomized trials and meta-analyses [48] have failed to confirm a survival benefit from RT. As a result, the benefit of RT has become controversial, even within the United States. (See 'Meta-analysis' below.)

Fluorouracil-based approaches

GITSG study — In a study conducted in the late 1970s and early 1980s by the Gastrointestinal Tumor Study Group (GITSG), patients with resected pancreatic cancer were randomly assigned to either observation or external beam RT (40 Gy) plus concurrent bolus FU (500 mg/m² per day on the first three and last three days of RT) followed by maintenance chemotherapy (FU 500 mg/m² per day for three days monthly) for two years or until disease progression [49]. The study was terminated after eight years due to poor patient accrual. As a result, only 43 patients were available for analysis.

Despite the relatively low RT dose, the small number of patients, and the fact that 25 percent of the patients on the treatment arm did not begin postoperative treatment until more than 10 weeks following resection, patients receiving postoperative chemoradiotherapy had significantly longer median overall survival (20 versus 11 months) and a doubling of the two-year survival rate (20 versus 10 percent). Following closure of the study, an additional 32 patients were registered on the combined modality arm, and a subsequent report that included these and the original 43 patients confirmed the initial survival benefit [50].

EORTC study — In an effort to reproduce these findings, a study sponsored by the European Organisation for Research and Treatment of Cancer (EORTC) randomly assigned 114 patients with resected pancreatic cancer to postoperative concurrent FU (25 mg/kg per day by continuous infusion) plus external beam RT (40 Gy in split courses) or to observation [47]. In contrast to the GITSG findings, there was only a trend toward improved survival for chemoradiotherapy (at two years, 26 versus 34 percent, p = 0.099). No reduction in locoregional recurrence was seen with combined modality therapy.

However, like the GITSG trial, this study was also criticized for several reasons: RT was delivered in a split-course manner (potentially allowing for tumor repopulation between courses), the dose was suboptimal, and there was no prospective assessment of the completeness of surgical margins. Furthermore, 20 percent of patients randomized to treatment never received it. However, since the trial did show a trend toward benefit of adjuvant therapy and was considered underpowered, some investigators viewed this study as supporting the conclusions of the GITSG trial.

ESPAC-1 trial — As noted above, the ambitious ESPAC-1 trial initially set out to randomize patients to a two-by-two factorial design in which the relative benefits of adjuvant chemotherapy, chemoradiotherapy, or chemoradiotherapy followed by chemotherapy would be compared with observation alone. However, fear of poor accrual led the investigators to permit the clinician to choose from this or two other randomization schemes. (See 'ESPAC-1 trial' above.)

As discussed above, the final results were presented in two separate publications:

●In an initial pooled analysis of the three parallel randomized trials [29], there was no survival difference when the 175 patients who received postoperative chemoradiotherapy were compared with the 178 who did not receive it (median overall survival 15.5 versus 16.1 months, respectively).

●However, in a subsequent intent-to-treat analysis of the 289 patients randomized in the four-arm study, there was a trend toward worse survival for the group receiving chemoradiotherapy (two- and five-year survival rates 29 versus 41 and 10 versus 20 percent for the chemoradiotherapy and no chemoradiotherapy groups, respectively) [30].

Many European clinicians cite these data as a main reason for not recommending concomitant chemoradiotherapy after resection of pancreatic cancer, while others, especially American clinicians, consider the study's flaws (including the fact that it is the only study showing worse outcomes with chemoradiotherapy, whereas all others show either equivalence or an advantage to RT) to preclude any ability to draw firm conclusions regarding the benefit of chemoradiotherapy.

Uncontrolled series — Other investigators have reported retrospective analyses that suggest benefit for postoperative FU-based chemoradiotherapy in pancreatic cancer [51-54].

The largest series included 11,526 patients undergoing resection of pancreatic adenocarcinoma from 1998 to 2002 and reported to the National Cancer Database, of whom 1029 (9 percent) had chemotherapy only, 5292 (46 percent) had chemoradiotherapy, and 5205 (45 percent) received no adjuvant therapy [52]. Propensity scores were developed for each treatment arm and were used to produce matched samples for analysis to minimize selection bias. Twenty-five percent had surgically positive margins, and 57 percent had node-positive disease. In a multivariate analysis conducted in a subset of 7288 patients with sufficient data, the use of chemoradiotherapy was associated with a significant survival benefit over no adjuvant therapy (HR 0.784, 95% CI 0.74-0.83), but adjuvant chemotherapy alone was not (HR for death 1.08, p = 0.108). In a second analysis stratified by propensity score matched groups (n = 1650 patients, 550 in each treatment group), the survival benefit for chemoradiotherapy was greater when compared with no adjuvant treatment (HR 0.70, 95% CI 0.61-0.80), but there was still no survival impact from chemotherapy alone (HR 1.04, p = 0.77).

Gemcitabine-based approaches — For patients undergoing concurrent chemoradiotherapy as a component of adjuvant therapy, we prefer infusional FU rather than gemcitabine as a radiation sensitizer.

Preliminary data support the tolerability and favorable short-term outcomes of regimens that use gemcitabine as a radiation sensitizer [46,55-57]; but no trials have compared this approach with chemoradiotherapy using FU as the radiation sensitizer, at least in the postoperative setting. Thus, we consider FU-based chemoradiotherapy to represent a standard approach. A randomized phase II trial comparing gemcitabine-based chemoradiotherapy with gemcitabine alone is discussed below. (See 'Does chemoradiotherapy add benefit to chemotherapy' below.)

Oral fluoropyrimidines as a substitute for infusional FU — The substitution of capecitabine (or where available, S-1) for infusional fluorouracil (FU) is reasonable in patients for whom ambulatory infusional FU therapy using a pump is not considered feasible.

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, although there are no data from the adjuvant setting. However, extrapolating from these and other data from phase III studies comparing capecitabine with infusional FU during neoadjuvant chemoradiotherapy 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 chemoradiotherapy, radiotherapy, and chemotherapy for rectal adenocarcinoma", section on 'Fluoropyrimidines' and "Initial chemotherapy and radiation for nonmetastatic, locally advanced, unresectable and borderline resectable, exocrine pancreatic cancer", section on 'Radiation sensitizer during RT'.)

Does chemoradiotherapy add benefit to chemotherapy — There is much debate as to the benefit of radiotherapy as an adjunct to surgery for pancreatic cancer [58]. Few trials have directly compared chemotherapy with and without chemoradiotherapy as an adjuvant strategy. Besides the ESPAC-1 trial (discussed above), the only other trial to compare the relative benefits of adding chemoradiotherapy to systemic therapy versus systemic therapy alone was the EORTC 40013/Fédération Francophone de Cancérologie Digestive (FFCD) 9203/GERCOR phase II study [46]. Ninety patients with resected pancreatic cancer (70 percent node positive, 97 percent R0 resected) were randomly assigned to gemcitabine-based chemoradiotherapy (two cycles of weekly gemcitabine alone [1000 mg/m² weekly, three weeks on, one week off] followed by RT [50.4 Gy in 28 daily 1.8 Gy fractions] with concurrent gemcitabine [300 mg/m² once weekly, four hours before RT, for five to six weeks]) or a control group. Initially, the control group was observation alone (n = 4), but the protocol was amended, and the remainder of the control group (n = 41) received four cycles of gemcitabine alone (1000 mg/m² for three consecutive weeks followed by a one-week rest). Treatment started within eight weeks of surgery.

In contrast to the results of the ESPAC-1 analysis, chemoradiotherapy was not deleterious; median DFS was 12 versus 11 months in the control group, and median overall survival was 24 months in both arms. Furthermore, the rate of local recurrence alone at first progression in the chemoradiotherapy group was notably lower (11 versus 24 percent), as was the rate of simultaneous local and distant progression (13 versus 20 percent). By contrast, the rates of distant progression were similar (40 versus 42 percent). (See 'ESPAC-1 trial' above.)

Meta-analysis — The benefits of chemoradiotherapy with and without chemotherapy were addressed in a 2013 network meta-analysis of nine randomized trials comparing six different adjuvant strategies (observation alone, FU alone, gemcitabine alone, chemoradiotherapy alone, chemoradiotherapy followed by FU, and chemoradiotherapy followed by gemcitabine) [48]. To optimize data extrapolation, the authors used Bayesian network meta-analysis to compare treatments indirectly when no direct comparator trial existed. The following results were noted:

●A statistically significant survival benefit for chemoradiotherapy could not be shown. Compared with observation alone, the HRs for death were 0.91 (95% CI 0.55-1.46) for chemoradiotherapy alone, 0.54 (95% CI 0.15-1.80) for chemoradiotherapy plus FU, and 0.44 (95% CI 0.10-1.81) for chemoradiotherapy plus gemcitabine. However, the very wide confidence intervals reflect a lack of precision for these estimates.

●When chemoradiotherapy plus chemotherapy (FU or gemcitabine) was compared with chemotherapy alone (FU or gemcitabine), the point estimates of the HRs for survival all favored the chemoradiotherapy arms; however, the confidence intervals were all wide, reflecting a lack of precision. As an example, in the comparison of chemoradiotherapy plus gemcitabine versus gemcitabine alone, the HR for survival was 0.65 (95% CI 0.14-2.70). These results include the possibility of an 86 percent reduction and a 2.7-fold increase in the risk of death with the addition of chemoradiotherapy. It is difficult to draw any meaningful conclusions from these data.

NEOADJUVANT THERAPY — The role of neoadjuvant therapy in patients with potentially resectable pancreatic cancer is evolving, and guidelines from expert groups are conflicting:

●Guidelines from the American Society of Clinical Oncology (ASCO) [2] suggest not administering neoadjuvant chemotherapy or chemoradiotherapy to patients with potentially resectable tumors in the absence of radiographic interface with the mesenteric vessels, unless in the context of a clinical trial.

●On the other hand, updated guidelines from the National Comprehensive Cancer Network (NCCN) suggest that this approach could be considered in high-risk potentially resectable tumors (ie, those with concerning imaging findings, very elevated CA 19-9 levels, large primary tumors, or large regional lymph nodes, and in patients with excessive weight loss and extreme pain).

●The European Society for Medical Oncology (ESMO) guidelines do not address the benefit of neoadjuvant therapy for potentially resectable pancreatic cancer [7].

However, some centers have taken the view that nearly all patients who appear to have "potentially resectable" pancreatic cancer should be considered to have "borderline resectable" disease given the inaccuracy of imaging and the very high rates of a positive margin with initial surgery, which is associated with poor overall survival. Although limited, at least some data from prospective trials support benefit for neoadjuvant therapy in patients with potentially resectable pancreatic cancer [27,59-62]. If a clinical trial is not available or the patient is not eligible, we consider neoadjuvant therapy to be a reasonable alternative to upfront surgery followed by adjuvant therapy in patients who appear to have potentially resectable tumors, as long as performance status and comorbidity are sufficient to tolerate treatment. However, for the rare patient with a <2 cm, apparently node-negative tumor (as determined by pretreatment imaging), neoadjuvant therapy is probably not warranted.

The best regimen for neoadjuvant therapy is not currently defined. For most patients who are able to tolerate it, we prefer initiating therapy with the multiagent modified FOLFIRINOX (oxaliplatin plus irinotecan with leucovorin [LV] and short-term infusional fluorouracil [FU]) regimen, followed by chemoradiotherapy in the absence of distant metastases. (See 'FOLFIRINOX plus chemoradiotherapy' below.)

The data supporting benefit from specific neoadjuvant strategies are presented below.

Rationale — The low rate of margin-negative resections, the poor long-term outcomes following pancreaticoduodenectomy with adjuvant therapy, and the fact that prolonged recovery prevents the delivery of postoperative adjuvant chemotherapy in approximately one-fourth of patients [63] have led to the investigation of neoadjuvant therapy in patients with potentially resectable exocrine pancreatic cancer. There appears to be a trend toward more frequent use of neoadjuvant therapy in cases of tumors that appear borderline in their resectability because of data suggesting that neoadjuvant therapy downstages some patients with initially unresectable tumors to the point where they then become surgical candidates. This subject is discussed in detail elsewhere. (See "Initial chemotherapy and radiation for nonmetastatic, locally advanced, unresectable and borderline resectable, exocrine pancreatic cancer".)

Few randomized trials of neoadjuvant therapy have been conducted in the setting of potentially resectable pancreatic cancer; three small randomized phase II trials failed to demonstrate a meaningful survival benefit using chemotherapy with or without chemoradiotherapy [60,61,64]. However, a meta-analysis of these three trials plus 35 other studies (comprising a mix of single-arm phase II trials and prospective as well as retrospective reports conducted in patients with potentially resectable or borderline resectable pancreatic cancer) concluded that neoadjuvant treatment appears to improve overall survival when analyzed by intention to treat (weighted mean overall survival 18.8 versus 14.8 months) [65]. 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 microscopically complete (R0) resection rate was higher (87 versus 67 percent), and the pathologic nodal positivity rate was also lower (44 versus 65 percent).

Most of these studies utilized older chemotherapy regimens (gemcitabine alone, gemcitabine plus cisplatin), mostly with FU-based chemoradiotherapy.

More recently, the better outcomes that may be achieved with more intensive neoadjuvant therapy can be illustrated by a study that compared the outcomes of patients who were considered to have borderline resectable or locally advanced pancreatic cancer and were treated with neoadjuvant chemotherapy (using the four-drug combination FOLFIRINOX) and chemoradiotherapy followed by surgical resection with those in patients who were taken directly to surgery because they had the presence of what was believed to be a clearly resectable lesion [66]. Despite having a higher stage of disease at presentation, patients who had neoadjuvant therapy had improved operative morbidity, smaller tumors, lower rates of lymphovascular and perineural invasion, fewer positive lymph nodes (35 versus 79 percent), and better overall survival compared with patients taken directly to surgery. The R0 resection rates were similar (92 versus 86 percent of those receiving no neoadjuvant therapy). A subsequent prospective trial from this institution utilizing this treatment sequence is discussed in detail below [27]. (See 'FOLFIRINOX plus chemoradiotherapy' below.)

NCDB analysis — The possibility of better outcomes with neoadjuvant therapy as compared with upfront surgery was also suggested by a retrospective analysis of data on 15,237 patients who underwent a potentially curative resection for early-stage (clinical stage I or II according to the 2010 [seventh edition] tumor, node, metastasis [TNM] classification (table 3)) pancreatic cancer, were identified in the National Cancer Database (NCDB) from 2006 to 2012, and were subjected to a propensity score matched analysis [67]. The conditional probability of receiving neoadjuvant therapy (the propensity score) was estimated based on age, gender, race, ethnicity, year of diagnosis, income, insurance type, area of residence, comorbidity, facility type, clinical stage, and type of surgery. From the group receiving neoadjuvant therapy (47 percent multiagent, 43 percent single agent, 10 percent unspecified), 2005 patients were propensity score matched to 6015 patients who had upfront resection. Patients undergoing neoadjuvant therapy had a lower likelihood of positive lymph nodes (48 versus 73 percent) and lower rates of pathologic T3/4 stage disease (73 versus 86 percent). The group receiving neoadjuvant therapy had significantly better median survival (median 26 versus 21 months), and rates of three- and five-year survival were also modestly higher (35 and 21 versus 29 and 18 percent, respectively, in the upfront surgery group). This difference was smaller when patients receiving neoadjuvant therapy were compared with the subset of patients undergoing upfront surgery who also received adjuvant therapy (67 percent of the total; median 26 versus 23 months; three- and five-year survival rates 35 and 21 versus 31 and 18 percent, respectively). In addition to the inherent limitations of retrospective analyses of data from large databases, another major limitation of these data is that the patients in the neoadjuvant therapy group represented only those who tolerated neoadjuvant therapy and underwent resection; the number of patients who embarked on neoadjuvant therapy for management of what was presumed to be resectable disease but who never proceeded to surgery could not be determined. However, the authors postulated that in addition to its potential for downstaging to enhance resectability, another benefit of neoadjuvant therapy is the avoidance of a Whipple procedure in patients who manifest rapid progression of disease while receiving preoperative therapy, for whom surgical intervention would not be beneficial.

A similar improvement in overall survival was seen with neoadjuvant as compared with adjuvant therapy in a separate retrospective analysis of 593 patients with clinical stage III pancreatic cancer, also derived from the NCDB [68].

Specific neoadjuvant strategies — Most of the reported studies of neoadjuvant therapy have utilized chemoradiotherapy alone or chemotherapy plus chemoradiotherapy [59,61,69-85]. Experience is more limited with neoadjuvant chemotherapy alone (without radiation therapy [RT]) [60,64,86,87].

Chemotherapy plus chemoradiotherapy — Although early reports of preoperative RT with or without concurrent FU demonstrated that this approach did not worsen perioperative morbidity and mortality, there was no obvious improvement in either resectability or overall survival [61,69-73]. A possible limitation of these initial studies is that most used single-agent bolus FU. Subsequent studies have focused on improving the treatment regimen by optimizing chemotherapy.

Two specific approaches are FOLFIRINOX plus FU-based chemoradiotherapy, and gemcitabine-based chemoradiotherapy.

FOLFIRINOX plus chemoradiotherapy — At least in the setting of borderline resectable pancreatic cancer, neoadjuvant therapy using FOLFIRINOX (oxaliplatin plus irinotecan with LV and short-term infusional FU) in conjunction with chemoradiotherapy results in a high rate of R0 resection and prolonged median progression-free and overall survival. In a phase II trial, 48 patients with locally advanced, borderline resectable pancreatic cancer received four months of FOLFIRINOX with growth factor support (table 6) [27]. Upon restaging, patients with resolution of vascular involvement received short-course chemoradiotherapy (5 Gy in five fractions using proton beam irradiation) concurrent with capecitabine (825 mg/m² twice daily, Monday through Friday, for two weeks), while those with persistent vascular involvement had long-course chemoradiotherapy (50.4 Gy with FU [225 mg/m² daily by continuous infusion Monday through Friday] or capecitabine [825 mg/m² 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. Overall, 79 percent of the patients planned to receive a full four months of chemotherapy were able to complete all cycles. 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.

The lack of a control group limits the assessment of whether these results are better than those that could be achieved using upfront resection followed by adjuvant chemotherapy. However, rates of R0 resection have historically been much lower with initial surgery for borderline resectable disease [88]. Management of borderline resectable pancreatic cancer is discussed in detail elsewhere. (See "Initial chemotherapy and radiation for nonmetastatic, locally advanced, unresectable and borderline resectable, exocrine pancreatic cancer", section on 'Borderline resectable'.)

As noted above, some centers, including ours, have taken the view that nearly all patients who appear to have "potentially resectable" pancreatic cancer should be considered to have "borderline resectable" disease given the inaccuracy of imaging and the very high rates of a positive margin with initial surgery, which is associated with poor overall survival. In our view, these results are applicable to patients with potentially resectable disease.

Gemcitabine-based chemoradiotherapy — Gemcitabine-based chemoradiotherapy may provide an enhanced local effect, although with the potential for more toxicity than FU-based regimens [82-85].

PREOPANC trial — The only trial to assess whether outcomes with neoadjuvant therapy are better than those that can be achieved with surgery followed by adjuvant therapy (the phase III PREOPANC trial) randomly assigned 248 patients with potentially resectable or borderline resectable (approximately 50 percent each) pancreatic cancer to upfront surgery followed by six months of adjuvant gemcitabine or to gemcitabine-based chemoradiotherapy (two weekly doses of gemcitabine followed by one week of rest, gemcitabine-based chemoradiotherapy [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 gemcitabine alone [59]. Resectable disease was strictly defined as no contact with the superior mesenteric artery, 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 superior mesenteric artery, celiac trunk, or common hepatic artery, or 90° to 270° contact with the SMV without occlusion.

The R0 resection rate was significantly higher with preoperative therapy (71 versus 40 percent), and preoperative chemoradiotherapy 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).

Induction chemotherapy alone — Two randomized trials have addressed the benefit of neoadjuvant chemotherapy without chemoradiotherapy in potentially resectable pancreatic cancer:

●A randomized phase II trial assigned 93 patients to receive surgery followed by six months of single-agent adjuvant gemcitabine (group A); surgery followed by six months of adjuvant cisplatin, epirubicin, gemcitabine, and capecitabine (PEGX; group B); or three cycles of PEGX before and after surgery (group C) [86]. Five patients treated at one institution were excluded from the study because of protocol noncompliance, leaving 88 patients for the analysis. The main endpoint was the proportion of patients who were event free at one year (defined as freedom from progression, relapse, new tumor occurrence, distant metastasis, or death). Following treatment, patients were closely monitored with cross-sectional imaging every three months during the first year, every four months during the second year, and every six months from the third year onward.

At a median follow-up of 55 months, the event-free survival in group A was 23 percent (95% CI 7-39 percent); in group B, it was 50 percent (95% CI 32-68 percent); and in group C, it was 66 percent (95% CI 49-83 percent). The corresponding values for three-year survival were 35, 43, and 55 percent, respectively. The R0 resection rates were 27 and 37 percent in both the adjuvant therapy groups, while it was 63 percent in group C.

The trial was initially conceived as a combined phase II/III trial, but the authors decided not to continue with the phase III component for two reasons: because the standard of care for adjuvant therapy had changed and because of the existence of newer chemotherapy regimens for which the evidence supporting benefit, at least in the setting of metastatic disease, was stronger than that for the PEGX regimen.

●Additional support for neoadjuvant chemotherapy over upfront surgery is provided by the multicenter Japanese Prep-02/JSAP-05 trial, which randomly assigned 364 patients with potentially resectable pancreatic cancer to two preoperative courses of gemcitabine (1000 mg/m² on day 1 and 8) plus S-1 (40 mg/m² twice daily on days 1 to 14) versus upfront surgery; patients in both groups who were completely resected and fully recovered by 10 weeks postoperation also received six months of therapy with S-1 alone [89]. In a preliminary report presented at the 2019 ASCO Gastrointestinal Cancers Symposium, despite no improvement in overall and R0 resection rates, patients receiving neoadjuvant chemotherapy had significantly longer median overall survival (36.7 versus 26.6 months).

Is there an optimal regimen? — SWOG S1505 directly compared perioperative (12 weeks preoperative and 12 weeks postoperative) treatment with FOLFIRINOX versus gemcitabine plus nabpaclitaxel (gem/nab) in 102 patients with potentially resectable pancreatic cancer [90]. Resectability rates were high with both regimens (73 versus 70 percent), although more patients receiving gem/nab had a complete or major pathologic response (42 versus 25 percent). Two-year overall survival, the primary endpoint, was 47 percent with FOLFIRINOX, and 48 percent with gem/nab, and neither arm met the prespecified endpoint (58 percent two-year survival). Interpretation of these results is limited by the high rate of ineligibility after central radiologic review (44 of the 147 enrolled patients). This trial raises the obvious need for biomarkers to determine which regimen is best for patients with pancreatic cancer as the two regimens have different mechanisms of action.

These trials provide further support for the growing shift toward preoperative therapy in potentially resectable pancreatic cancer, but adequately powered randomized studies are still required to determine the exact benefit. Eligible patients should be encouraged to enroll in available clinical trials.

Role of adjuvant 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 RT is less certain, and practice is variable within and outside of the United States. (See 'Chemotherapy alone' above.)

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, suggests that the benefit of adjuvant chemotherapy is limited to those with node-positive disease [91]. 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, a comprehensive analysis of patients treated with neoadjuvant therapy or upfront surgery for clinical stage I or II pancreatic cancer derived from the NCDB concluded that receipt of adjuvant therapy (which was higher in the upfront resected group, 67 versus 31 percent) remained associated with improved survival after adjustment for treatment and tumor characteristics, including the use of neoadjuvant chemotherapy (HR for death 0.62, 95% CI 0.58-0.66) [67].

We agree with guidelines from ASCO, which recommend a total of six months of systemic chemotherapy in patients with resected pancreatic cancer, to include the duration of the preoperative regimen, based on an extrapolation of data from adjuvant therapy trials [2]. (See 'Chemotherapy alone' above.)

If protocol therapy is not available or declined, for patients with an excellent performance status who are able to tolerate it, we suggest modified FOLFIRINOX (oxaliplatin plus irinotecan with leucovorin and short-term infusional FU) rather than gemcitabine alone, and we also prefer it over 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.

POST-TREATMENT MANAGEMENT — Patients who have completed treatment for potentially resectable pancreatic cancer should be monitored for recovery of treatment-related toxicities and disease recurrence [2].

Supportive care — Patients who have undergone potentially curative treatment for pancreatic cancer should continue to receive ongoing supportive care for symptom burden that may result from treatment, including pain, anorexia and weight loss, depression and anxiety, biliary obstruction, pancreatic insufficiency, and venous thromboembolism [2]. (See "Supportive care of the patient with locally advanced or metastatic exocrine pancreatic cancer" and "Cancer pain management with opioids: Optimizing analgesia" and "Supportive care of the patient with locally advanced or metastatic exocrine pancreatic cancer", section on 'Anorexia, cachexia, and weight loss' and "Management of psychiatric disorders in patients with cancer".)

Surveillance strategy — There is no evidence to guide the post-treatment surveillance strategy in patients with pancreatic cancer, and clinical practice is variable, particularly with regard to computed tomography (CT) scanning [92,93].

We suggest a periodic history and physical examination every three to six months for at least two years. If carbohydrate antigen 19-9 (CA 19-9) levels were initially elevated, we follow them every three to six months for at least two years and, if elevated, perform a CT scan. An elevated post-treatment CA 19-9 increases the risk for recurrence, with the highest risks in those with persistent elevations from diagnosis through follow-up [94]. An important point is that mild elevations in CA 19-9 can occur with biliary tract dysfunction, which often occurs in patients after a pancreaticoduodenectomy. Thus, noncancerous causes can lead to abnormal results in these patients.

Given that there is no known curative treatment for patients with recurrent pancreatic adenocarcinoma, we do not routinely obtain CT scans in the follow-up of patients following resection of a pancreatic cancer. Patients with metastatic pancreatic cancer inevitably develop symptoms and will present for treatment discussions. Additionally, it is not clear that early initiation of therapy in asymptomatic individuals is associated with a survival benefit, thereby calling into question any surveillance technique. As a result, many clinicians, including some of the authors of this topic review, do not routinely obtain CT scans in the follow-up of patients after pancreaticoduodenectomy, unless indicated by symptoms or a rising CA 19-9 level. This approach is consistent with guidelines from the American Society of Clinical Oncology (ASCO) [2]. However, others disagree with this recommendation and follow the consensus-based guidelines of the National Comprehensive Cancer Network (NCCN) and the European Society for Medical Oncology (ESMO), which recommend periodic radiographic surveillance. (See 'Guidelines from expert groups' below.)

The majority of recurrences after potentially curative treatment of exocrine pancreatic cancer occur within two years, and they can be locoregional or at distant sites, most often the liver, lung, and peritoneal cavity [95]. In one autopsy series of patients with known pancreatic cancer, approximately 30 percent died with locally destructive disease without evidence of metastasis, while 70 percent died with widespread metastatic disease [45].

The primary goal of surveillance after curative treatment for any cancer is to detect local or distant recurrence when available interventions can prolong survival. However, for pancreatic cancer, the vast majority of recurrences are not amenable to potentially curative therapy, and the evidence that early identification of recurrent or metastatic disease in asymptomatic patients improves long-term survival is limited:

●In a study of 216 patients with pancreatic cancer who developed a postoperative recurrence during the course of a surveillance regimen that consisted of physical examination, CA 19-9 assay, chest radiograph, and abdominal CT every three to four months for the first two years after surgery, then every six months until five years, and then annually, the surveillance regimen was able to detect an asymptomatic recurrence in 55 percent of patients [96]. Although the median time to recurrence was not different between patients with a symptomatic recurrence and patients with an asymptomatic recurrence, median survival was significantly less in symptomatic patients (5.1 versus 13 months). Asymptomatic patients were much more likely to receive treatment after a recurrence was identified.

●On the other hand, analysis of a large national database demonstrated no significant survival benefit for annual radiographic surveillance among patients with curatively resected pancreatic cancer [97].

Despite the lack of a consistent survival benefit, secondary benefits for detection of metastatic disease at an asymptomatic stage include early introduction of palliative chemotherapy or radiation therapy to slow disease progression and, for patients who can tolerate an aggressive regimen such as FOLFIRINOX (oxaliplatin plus irinotecan with leucovorin [LV] and short-term infusional fluorouracil [FU]), improve survival.

Guidelines from expert groups — Recommendations for post-treatment surveillance are available from several expert groups, and not surprisingly, they differ:

●ASCO guidelines for management of potentially resectable pancreatic cancer suggest visits at three- to six-month intervals to monitor for recovery of treatment-related toxicities and recurrence, with tapering of visits after two years [2]. If elevated preoperatively, serum CA 19-9 levels can be measured every three to six months as well. The benefit of surveillance imaging is less clear, and at best, it seems to result in greater detection of asymptomatic recurrence. The timing of imaging should be determined after discussion with the individual patient, taking into account their preferences, level of emotional stress, and concern regarding financial burden.

●Consensus-based guidelines from the NCCN recommend a history and physical examination for symptom assessment, and CA 19-9 determinations and follow-up CT scans every three to six months for two years, then every 6 to 12 months, with a low level of evidence but uniform consensus [6].

●Consensus-based guidelines from ESMO state that there is no evidence that regular follow-up after initial therapy with curative intent has any impact on outcome [7]. They suggest that follow-up visits concentrate on symptoms, nutrition, and psychosocial support.

SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC — The COVID-19 pandemic has increased the complexity of cancer care. Important issues in areas where viral transmission rates are persistently high include balancing the risk from delaying cancer treatment versus harm from COVID-19, minimizing the number of clinic and hospital visits to reduce exposure whenever possible, mitigating the negative impacts of social distancing on delivery of care, and appropriately and fairly allocating limited health care resources. Specific guidance for decision-making in pancreatic cancer is available from several groups, including the European Society of Medical Oncology, which has outlined high priorities in cancer care that should not be delayed, versus middle and lower priority care, which is reasonable to delay. These and other general recommendations for cancer care during active phases of the COVID-19 pandemic are discussed separately. (See "COVID-19: Considerations in patients with cancer".)

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

●Assessing suitability for resection

•Surgical resection is a prerequisite for cure of pancreatic cancer. Primary surgical resection is only recommended for patients who have no metastases, appropriate performance status and comorbidity profiles, and no radiographic interface between the primary tumor and the mesenteric vasculature on initial multiphasic computed tomography (CT) or magnetic resonance imaging (MRI). (See 'Assessing resectability' above.)

•Performance status, comorbidity, symptom burden, and goals of care should be evaluated and established. Distressing symptoms and concerns that may require ongoing supportive care, including pain, anorexia and weight loss, depression and anxiety, biliary obstruction, pancreatic insufficiency, and venous thromboembolism, should be managed aggressively. Early referral to palliative care should be initiated for those with a high symptom burden. (See 'Suitability for resection and symptom burden' above.)

●Initial resection

•Primary surgical resection is appropriate for patients with no distant metastatic disease, a performance status and comorbidity profile that are appropriate for major abdominal surgery, and no radiographic interface between the primary tumor and the mesenteric vasculature.

•For all patients who undergo initial resection without neoadjuvant therapy, including those with pathologic T1N0 disease (table 1), we recommend six months of adjuvant chemotherapy (Grade 1A). (See 'Indications' above and 'Chemotherapy alone' above.)

Adjuvant treatment should be started within eight weeks of surgery, if possible, and preceded by restaging with CT scans and a serum level of the tumor marker carbohydrate 19-9 (CA 19-9; also called cancer antigen 19-9) (see 'Timing and duration' above). All patients should be offered information about clinical trials. Off protocol, we suggest the following approach:

-For patients with an excellent performance status who are able to tolerate it, we suggest modified FOLFIRINOX (oxaliplatin plus irinotecan with leucovorin [LV] and short-term infusional fluorouracil [FU] (table 5)) rather than gemcitabine alone (Grade 2B), and we also prefer this regimen over gemcitabine plus capecitabine.

-For less fit patients, gemcitabine plus capecitabine (table 4) is a reasonable alternative. Therapy with gemcitabine alone (table 7) is another reasonable option, particularly for patients with a borderline performance status or a comorbidity profile that precludes multiagent therapy.

-For Japanese patients, S-1, where available, represents a preferred alternative to gemcitabine monotherapy because of its oral bioavailability and better tolerability. There is not enough evidence to know whether S-1 is as beneficial in non-Japanese patients. (See 'Modified FOLFIRINOX' above and 'Gemcitabine plus capecitabine' above and 'Gemcitabine versus S-1' above.)

•For most patients who have received a gemcitabine-based adjuvant chemotherapy regimen, we also suggest the addition of concurrent chemoradiotherapy to chemotherapy (Grade 2C). During the concurrent chemoradiotherapy portion, we prefer infusional FU, capecitabine or S-1 (where available) over either gemcitabine or bolus FU (see 'Fluorouracil-based approaches' above).

We do not offer adjuvant RT to all individuals who have had a six-month adjuvant course of FOLFIRINOX, but instead, we reserve this approach for selected patients who desire highly aggressive therapy and retain an excellent performance status after surgery and chemotherapy.

The approach differs outside of the United States. Most European and Japanese clinicians advocate chemotherapy alone, regardless of the adjuvant chemotherapy regimen that is used, emphasizing the lack of a consistent survival benefit from postoperative RT. (See 'ESPAC-1 trial' above and 'EORTC study' above and 'Gemcitabine versus S-1' above.)

●Neoadjuvant therapy

•Neoadjuvant therapy is a reasonable alternative to upfront surgery followed by adjuvant therapy in patients who appear to have potentially resectable tumors, as long as performance status and comorbidity are sufficient to tolerate treatment (algorithm 1). However, for the rare patient with a <2 cm, apparently node-negative tumor (as determined by pretreatment imaging), neoadjuvant therapy is probably not warranted. (See 'Neoadjuvant therapy' above.)

The best regimen for neoadjuvant therapy is not currently defined. For most patients who are able to tolerate it, we suggest the multiagent modified FOLFIRINOX regimen rather than a different chemotherapy regimen, followed by chemoradiotherapy in the absence of distant metastases (Grade 2C). (See 'FOLFIRINOX plus chemoradiotherapy' above and 'Neoadjuvant therapy' above.)

•For patients with pancreatic cancer who received preoperative therapy, we suggest a total of six months of systemic therapy for patients with resected pancreatic cancer, to include the preoperative regimen, based on an extrapolation of data from adjuvant therapy trials (Grade 2C). (See 'Role of adjuvant therapy' above.)

•For patients with an excellent performance status who are able to tolerate it, we suggest modified FOLFIRINOX rather than gemcitabine alone, and we also prefer it over 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. (See 'Role of adjuvant therapy' above.)

●Post-treatment surveillance – The optimal post-treatment surveillance strategy is unknown, and there is no consensus on the best approach:

•We perform a history and physical examination for symptom assessment every six months for two years, then annually, and check CA 19-9 level (if initially elevated) at each of the visits. Many clinicians, including some of the authors of this topic review, do not routinely obtain CT scans in the follow-up of patients after pancreaticoduodenectomy, unless indicated by symptoms or a rising CA 19-9 level. (See 'Guidelines from expert groups' above.)

•Others disagree, and follow the consensus-based guidelines of the National Comprehensive Cancer Network, which suggest follow-up CT scans every three to six months for at least two years, then every 6 to 12 months. (See 'Post-treatment management' above.)