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Treatment for potentially resectable exocrine pancreatic cancer
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Treatment for potentially resectable exocrine pancreatic cancer
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Nov 2016. | This topic last updated: Oct 03, 2016.

INTRODUCTION — Approximately 53,070 people develop exocrine pancreatic cancer each year in the United States, and almost all are expected to die from the disease [1]. 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 complete (R0) resection. Given the high rates of both systemic (>80 percent) and local (>20 percent) recurrence after surgery alone, systemic chemotherapy, radiation therapy (RT), and combined approaches (chemoradiotherapy) have been used both prior to and following surgical resection in an effort to improve cure rates. Although adjuvant (postoperative) chemotherapy has been shown to improve overall survival, the benefits of postoperative RT, and neoadjuvant (preoperative) chemotherapy and RT remain controversial.

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 "Chemotherapy for advanced exocrine pancreatic cancer".)

OVERVIEW OF THE TREATMENT APPROACH — An algorithmic approach to nonmetastatic 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 for the presence of intraabdominal 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 and peripancreatic nodes (stage I-IIB disease (table 1) [4]) are most likely to be cured by resection. Tumors with limited involvement of the major peripancreatic vessels, such as the superior mesenteric vein, 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 superior mesenteric vein (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 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 extraabdominal 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 "Chemotherapy for advanced 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 complete (R0) resection, and long-term outcomes in patients with potentially resectable pancreatic cancer [5]. However, while high levels of CA 19-9 may help surgeons to better select patients who need staging laparoscopy, an expert panel convened by the American Society of Clinical Oncology (ASCO) recommended against the use of CA 19-9 alone as an indicator of operability [6]. Furthermore, while a year 2016 Clinical Practice Guideline on management of potentially curable pancreatic cancer from 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 'CA 19-9'.)

Suitability for resection and symptom burden — In addition to the extent of tumor involvement, 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 sone 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 "Pharmacologic 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 "Treatment of venous thromboembolism in patients with malignancy" and "Supportive care of the patient with locally advanced or metastatic exocrine pancreatic cancer", section on 'Pancreatic exocrine insufficiency'.)

Pancreatectomy — Primary surgical resection is appropriate only 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 cancer, including those with resected T1N0 disease (table 1). This recommendation is consistent with guidelines from ASCO [2], the National Comprehensive Cancer Network (NCCN), and the European Society for Medical Oncology (ESMO) [7].

Timing and duration — The optimal timing and duration of adjuvant therapy is not established. Typically, it is started within four to six weeks of surgery and continued for a total of six months. There are no randomized trials addressing the impact of delayed initiation of adjuvant therapy on outcomes or the effect of a longer duration of therapy. However, at least some data support the view that delaying treatment initiation for up to 12 weeks to allow full recovery from surgery does not compromise the survival benefit [8], and modern adjuvant chemotherapy trials have permitted enrollment up to 12 weeks postoperatively [9]. (See 'ESPAC-3 trial' below and 'Gemcitabine plus capecitabine' below.)

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 the serum tumor marker CA 19-9 are associated with poor long-term prognosis. However, CA 19-9 levels are prognostic and not 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 [10], and some adjuvant therapy protocols, such as Radiation Therapy Oncology Group (RTOG) 0848, only allow enrollment if the posttreatment CA 19-9 level is ≤180 units/mL, we (and others [11]) 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 'CA 19-9' and "Overview of surgery in the treatment of exocrine pancreatic cancer and prognosis", section on 'Prognosis and prognostic factors'.)

Choice of therapy — All patients should be offered information about clinical trials. Enrollment in available clinical trials is preferred, if available. One such ongoing study, RTOG 0848, is attempting to assess the independent contributions of chemotherapy and chemoradiotherapy in patients with resected tumors of the head of the pancreas.

If protocol therapy is not available or declined, we suggest six months of combination chemotherapy with gemcitabine plus capecitabine rather than gemcitabine monotherapy for most patients. However, therapy with gemcitabine alone or, where available, S-1 alone is a reasonable option, particularly for patients with a borderline performance status or a comorbidity profile that precludes intensive therapy. (See 'Gemcitabine plus capecitabine' below and 'Gemcitabine versus S-1' below and 'CONKO-001' below.)

For most patients, we also suggest the addition of chemoradiotherapy to chemotherapy. However, the benefit of adjuvant radiation therapy remains 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 Charité Onkologie (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 European Study for Pancreatic Cancer (ESPAC)-1 trial. The most recent (2012) guidelines for treatment of pancreatic adenocarcinoma from ESMO 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 and 'Gemcitabine' 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 result 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 the and 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

In keeping with this approach, NCCN guidelines suggest that either fluorouracil-based chemoradiotherapy plus systemic gemcitabine or chemotherapy alone is an acceptable option for adjuvant therapy, and guidelines from ASCO suggest adding postoperative chemoradiotherapy to six months of adjuvant chemotherapy for patients with node-positive or margin-positive disease [2].

Neoadjuvant therapy — All patients should be offered information about clinical trials. Enrollment in available clinical trials is preferred, if available (eg, SWOG S1505 or ESPAC-5).

Outside of a clinical protocol, we suggest not administering neoadjuvant chemotherapy or chemoradiotherapy to patients with potentially resectable tumors in the absence of radiographic interface with the mesenteric vessels, which is consistent with guidelines from NCCN, ESMO [7], and ASCO [2]. Neoadjuvant therapy for patients with tumors that interface the mesenteric vasculature (ie, so-called "borderline resectable" tumors) is addressed in detail elsewhere. (See "Initial chemotherapy and radiation for nonmetastatic locally advanced unresectable and borderline resectable exocrine pancreatic cancer", section on 'Borderline resectable disease'.)

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

Chemotherapy alone — Multiple randomized controlled clinical trials and meta-analyses suggest a significant overall survival benefit from chemotherapy alone, without radiation therapy (RT), following resection of a pancreatic cancer [12-21].

Fluoropyrimidine-based regimens

ESPAC-1 — An ambitious trial sponsored by European investigators, the European Study for Pancreatic Cancer (ESPAC)-1 trial, initially set out to randomize patients to a 2x2 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 [14] and a later report that focused on the 289 patients randomized to the four-arm study [15].

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 [14]:

Chemoradiotherapy versus no chemoradiotherapy – 68 patients enrolled; chemoradiotherapy consisted of 20 Gy external beam RT (EBRT) plus three days of concomitant fluorouracil (FU), repeated after a planned break of two weeks.

Adjuvant chemotherapy versus no chemotherapy – 188 patients enrolled; adjuvant chemotherapy consisted of bolus leucovorin-modulated FU (leucovorin 20 mg/m2, FU 425 mg/m2) administered daily for five days, every 28 days, for six months.

A 2x2 factorial design trial with four groups: chemoradiotherapy (n = 73), chemotherapy (n = 75), both (n = 72), or observation (n = 69) [15]; 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 no survival difference when the 175 patients receiving postoperative chemoradiotherapy were compared with the 178 who did not receive it (median overall survival 15.5 versus 16.1 months, respectively) [14,15,17].

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" chemoradiation 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 postradiotherapy 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 [15]. 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.

In 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 were 29 versus 41 percent and 10 versus 20 percent for the chemoradiotherapy and no chemoradiotherapy groups, respectively). There were no significant imbalances for known prognostic factors (nodal positivity, resection margin status, histologic grade) in the two arms that could have contributed to these results. Local recurrence rates were similar in both groups, but there were more recurrences overall (84 versus 74) in the chemoradiotherapy group and a shorter recurrence-free interval (10.7 versus 15.2 months, respectively).

The authors postulated that the delay in administration of chemotherapy in patients undergoing chemoradiotherapy might explain the inferior outcomes seen in this group. Although the trial was underpowered to perform statistical comparisons of the four individual treatment groups, patients in both chemoradiotherapy groups had an inferior median overall survival (13.9 and 14.2 months for chemoradiotherapy alone or chemoradiotherapy plus chemotherapy) as compared with those undergoing observation alone (16.9 months). These median survival durations are markedly lower than those seen in other contemporary series of patients treated with adjuvant chemoradiotherapy (21 to 25 months in several reports [22,23]) and suggest that treatment-related toxicity might have accounted for some of the differences.

Norwegian trial — Comparable results were noted in a Norwegian trial that randomly assigned 61 patients with curatively resected pancreatic cancer to six cycles of FU, doxorubicin, plus mitomycin (FAM) or observation [13]. As was seen in the ESPAC-1 trial, chemotherapy was associated with a significantly longer median survival (23 versus 11 months). However, long-term survival was similar at both three (30 versus 27 percent) and five years (8 versus 4 percent).

Gemcitabine

CONKO-001 — A survival benefit from adjuvant gemcitabine monotherapy was shown in the multi-national European Charité Onkologie (CONKO)-001 trial of 368 patients with grossly complete (R0 or R1) surgical resection and a preoperative carbohydrate antigen 19-9 (CA 19-9) level <2.5 times the upper limit of normal [12]. The patients were randomly assigned to gemcitabine (1000 mg/m2 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 12.2 versus 7.7 percent) [18].

Japanese trial — A smaller phase III Japanese trial (JSAP-02) of surgery alone or followed by a shorter duration of gemcitabine (1000 mg/m2 days 1, 8, and 15 for three months only) in 119 patients also found a significant improvement in DFS that favored gemcitabine (median 11.4 versus 5 months), but the difference in overall survival (22 versus 18 months) was not statistically significant [20].

Gemcitabine versus a fluoropyrimidine — Gemcitabine is the preferred agent for adjuvant chemotherapy when compared with monthly bolus (Mayo Clinic) of FU plus leucovorin, given its greater tolerability. Whether similar efficacy results and a more tolerable safety profile are possible with a weekly or infusional fluoropyrimidine schedule is unknown. For Japanese patients, S-1, where available, represents a preferred alternative to gemcitabine because of its oral bioavailability and better tolerability.

ESPAC-3 trial — The multicenter European Study for Pancreatic Cancer (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 leucovorin-modulated FU (leucovorin 20 mg/m2 followed by FU 425 mg/m2 intravenous [IV] bolus days 1 through 5 every 28 days) [24]. 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/leucovorin 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 ESPAC-3 [8] (see 'Timing and duration' above):

Overall survival favored patients who completed the full six months of therapy versus those who did not (median survival 28 versus 15 months, hazard ratio [HR] for death 0.61, 95% CI 0.44-0.60).

The time to start 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 — A slightly different question, the relative value of adjuvant gemcitabine monotherapy both before and after concomitant FU-based chemoradiotherapy versus all FU-based therapy in which FU was given before, during, and after RT, was addressed in a United States Intergroup study (Radiation Therapy Oncology Group [RTOG] 9704) [25]. Patients who had undergone gross total resections for T1-4, N0-1 (table 1) 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 [26]. 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) [25].

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 [27]. 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.

Meta-analyses — Further support for the benefit of adjuvant chemotherapy alone in resected pancreatic cancer comes from two meta-analyses, both of which support a statistically significant survival benefit from adjuvant chemotherapy (mostly gemcitabine alone) [19,21].

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 macroscopically resected (R0 or R1) pancreatic adenocarcinoma to six months of gemcitabine alone (1000 mg/m2 on days 1, 8, and 15 of each 28-day cycle) or the same dose of gemcitabine plus capecitabine (1660 mg/m2 per day on days 1 through 21 of each 28-day cycle) [9]. In a preliminary report presented at the 2016 annual meeting of the American Society of Clinical Oncology (ASCO), the following outcomes were reported:

The majority of patients in both arms had microscopically positive (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.

At a median follow-up of 43 months, combination therapy was associated with a significant survival benefit (median overall survival 28 versus 25.5 months, HR for death 0.82, 95% CI 0.68-0.98). At five years, twice as many patients remained alive in the combination therapy group (19 versus 9).

More intensive combination regimens — Whether better outcomes could be achieved using chemotherapy combinations that have been shown to be more effective than gemcitabine alone in the setting of metastatic disease is unclear. While it is hoped that the benefits of newer, more effective combination regimens, such as short-term infusional FU plus leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX (table 2)) and gemcitabine plus nanoparticle albumin-bound paclitaxel (nabpaclitaxel), might extend to the adjuvant setting, there are no published randomized trials comparing either regimen to gemcitabine monotherapy alone in patients with resected disease. Given the greater toxicity of these regimens, their use in the adjuvant setting should be restricted to clinical trials. Two such trials are ongoing, the APACT (gemcitabine with and without nabpaclitaxel) and PRODIGE (gemcitabine versus FOLFIRINOX) trials, and eligible patients should be encouraged to enroll. (See "Chemotherapy for advanced exocrine pancreatic cancer".)

Chemotherapy dosing in obese patients — For cancer patients with a large body surface area (BSA), 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 [28]. (See "Dosing of anticancer agents in adults", section on 'Overweight/obese patients'.)

Chemoradiotherapy — For most patients, we suggest the addition of concurrent chemoradiotherapy to adjuvant chemotherapy. However, others disagree, arguing that a survival benefit from chemoradiotherapy has not been conclusively shown, particularly in patients receiving adjuvant chemotherapy. Ideally, patients should be encouraged to enroll in clinical trials testing the benefit of chemoradiotherapy when given in conjunction with systemic chemotherapy. In the United States, such a trial, RTOG 0848, is open for enrollment.

Rationale — A rationale for combined modality therapy is provided by the failure pattern following surgical resection alone. 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 [29]. The local control benefit of adding RT can be best illustrated by data from the Groupe Cooperateur Multidisciplinaire en Oncologie (GERCOR) trial of postoperative gemcitabine versus gemcitabine-based chemoradiotherapy [30]. 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 [15,31]. Furthermore, randomized trials and meta-analyses [19] have failed to confirm a survival benefit from radiotherapy. (See 'Meta-analysis' below.)

FU-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 EBRT (40 Gy) plus concurrent bolus fluorouracil (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 [32]. 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, small number of patients, and 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 [33].

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 EBRT (40 Gy in split courses) or observation [31]. 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 towards 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 European Study for Pancreatic Cancer (ESPAC)-1 trial initially set out to randomize patients to a 2x2 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' above.)

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

In an initial pooled analysis of the three parallel randomized trials [14], there was no survival difference when the 175 patients receiving 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 were 29 versus 41 percent and 10 versus 20 percent for the chemoradiotherapy and no chemoradiotherapy groups, respectively) [15].

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 that 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) 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 [22,34-36].

The largest series included 11,526 patients undergoing resection of pancreatic adenocarcinoma from 1998 to 2002 and reported to the National Cancer Data Base, of whom 1029 (9 percent) had chemotherapy only, 5292 (46 percent) had chemoradiotherapy, and 5205 (45 percent) received no adjuvant therapy [34]. Propensity scores were developed for each treatment arm and 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 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 that of 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 [30,37-39]; but no trials have compared this approach with chemoradiotherapy using FU as the radiation sensitizer, at least in the postoperative setting. Thus, we consider that FU-based chemoradiotherapy represents a standard approach. A randomized phase II trial comparing gemcitabine-based chemoradiotherapy versus 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 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 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 and radiotherapy for rectal adenocarcinoma", section on 'Oral fluoropyrimidines versus infusional FU' and "Initial chemotherapy and radiation for nonmetastatic locally advanced unresectable and borderline resectable exocrine pancreatic cancer", section on 'Oral fluoropyrimidines as a substitute for infusional FU'.)

Does chemoradiotherapy add benefit to chemotherapy — Few trials have directly compared chemotherapy with or 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/Francophone de Cancérologie Digestive (FFCD)-9203/GERCOR phase II study [30]. Ninety patients with resected pancreatic cancer (70 percent node-positive, 97 percent completely resected [R0]) 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); in 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) [19]. 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 in the risk of death 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 low rate of resectability, 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 [40] have led to the investigation of neoadjuvant therapy in patients with potentially resectable pancreatic exocrine cancer. While neoadjuvant therapy can be safely delivered to patients with localized, potentially resectable pancreatic cancer without adversely influencing perioperative morbidity or mortality, no study has clearly demonstrated improved resectability or survival compared to patients treated with surgery alone, and it remains unclear whether this approach provides benefit compared to adjuvant (postoperative) therapy. At present, neoadjuvant therapy is not yet considered a standard approach for patients with potentially resectable pancreatic cancer outside of the context of a clinical trial.

Most of the reported studies of neoadjuvant therapy have utilized chemoradiotherapy. Neoadjuvant chemotherapy alone, without radiation therapy (RT), is beginning to be studied, but experience is limited [41-43].

FU-based therapy — Although initial reports of preoperative RT with or without concurrent fluorouracil (FU) demonstrated that this approach did not worsen perioperative morbidity and mortality, there was no obvious improvement in either resectability or overall survival [44-48]. A possible limitation of these initial studies is that most used single-agent bolus FU. Subsequent studies have focused upon improving the treatment regimen by increasing the RT dose, adding intraoperative RT, and optimizing the chemotherapy regimen. These newer approaches appear to be tolerable, with low rates of hepatic toxicity, biliary stent-related complications, and perioperative morbidity [49-56]. However, none of these studies are randomized trials, and it remains uncertain whether outcomes are better than can be achieved with surgery followed by adjuvant therapy.

Gemcitabine-based chemoradiotherapy — Gemcitabine-based chemoradiotherapy may provide an enhanced local effect, although with the potential for more toxicity than FU-based regimens. Several early reports are promising, but complete pathologic response rates are not higher than have been seen with FU-based regimens [57-60]. Furthermore, as with FU-based chemoradiotherapy, none of these studies are randomized trials, and it remains uncertain whether outcomes are better than can be achieved with surgery followed by adjuvant therapy.

Meta-analyses — At least three meta-analyses have addressed the benefit of neoadjuvant therapy in patients with initially potentially resectable pancreatic cancer [61-63]:

The largest analysis of 111 studies, including 56 phase I/II trials, with 96 percent of the patients receiving chemotherapy and 94 percent RT, concluded that, among patients with initially resectable disease, 35 percent had an objective response to neoadjuvant therapy, while 21 percent had progressive disease [63]. Resectability rates were 74 percent.

However, whether these results represent an improvement in outcomes in patients who undergo resection without neoadjuvant therapy is unclear given the lack of a surgery-alone control arm in any of the trials included in any of the analyses.

NCDB analysis — The possibility of better outcomes with neoadjuvant therapy as compared with upfront surgery was 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) pancreatic cancer, were identified in the National Cancer Data Base (NCDB) from 2006 to 2012, and subjected to a propensity score matched analysis [64]. The conditional probability of receiving neoadjuvant therapy (the propensity score) was estimated based upon 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/T4 stage disease (73 versus 86 percent). The group receiving neoadjuvant therapy had a 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 patients in the neoadjuvant therapy group represented only those who tolerated neoadjuvant therapy and underwent resection; the number of patients who embarked upon neoadjuvant therapy for management of what was presumed to be resectable disease but 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.

In our view, these data underscore the need for a randomized trial comparing modern neoadjuvant therapy (which increasingly includes multiagent chemotherapy regimens) with upfront resection followed by adjuvant chemotherapy for patients with potentially resectable pancreatic cancer. (See "Initial chemotherapy and radiation for nonmetastatic locally advanced unresectable and borderline resectable exocrine pancreatic cancer", section on 'Initial chemotherapy'.)

POSTTREATMENT 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 posttreatment surveillance strategy in patients with pancreatic cancer, and clinical practice is variable, particularly with regard to computed tomography (CT) scanning [65,66].

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 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 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 pancreatic exocrine cancer occur within two years, and they can be locoregional or to distant sites, most often the liver, lung, and peritoneal cavity [67]. In one autopsy series of patients with known pancreatic cancer, approximately 30 percent died with locally destructive disease without evidence of metastases, while 70 percent died with widespread metastatic disease [29].

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, then annually, the surveillance regimen was able to detect asymptomatic recurrence in 55 percent of patients [68]. Although the median time to recurrence was not different between patients with a symptomatic versus asymptomatic recurrence, median survival was significantly less in symptomatic patients (5.1 versus 13.0 months). Asymptomatic patients were much more likely to receive treatment after 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 [69].

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 short-term infusional fluorouracil plus leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX), improve survival. (See "Chemotherapy for advanced exocrine pancreatic cancer", section on 'FOLFIRINOX'.)

Guidelines from expert groups — Recommendations for posttreatment 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 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.

Consensus-based guidelines from ESMO recommend that the posttreatment surveillance strategy be individualized to minimize emotional stress and economic burden [70]. In addition to repeat CT scans of the abdomen and pelvis every six months, they suggest monitoring CA 19-9 levels every three months for two years if CA 19-9 levels were elevated preoperatively.

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 5th to 6th 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 10th to 12th 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 topics (see "Patient education: Pancreatic cancer (The Basics)")

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

SUMMARY AND RECOMMENDATIONS

Surgical resection is a prerequisite for cure of pancreatic cancer. Unfortunately, only 15 to 20 percent of patients are candidates for pancreatectomy, mostly because of distant metastatic disease. Local unresectability is usually (but not always) due to vascular invasion. A multiphase 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 for the presence of intraabdominal metastases. (See 'Assessing resectability' above.)

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

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. 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'.)

We recommend adjuvant chemotherapy for all patients with resected pancreatic cancer, including those with resected T1N0 disease (Grade 1A) (table 1). (See 'Indications' above and 'Chemotherapy alone' above.)

The optimal timing of adjuvant chemotherapy is not established. Typically, it is started within four to six weeks of surgery and continued for a total of six months. However, at least some data support the view that delaying treatment initiation for up to 12 weeks to allow full recovery from surgery does not compromise the survival benefit. Prior to beginning adjuvant therapy, all patients should undergo formal 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.)

There is no consensus regarding the optimal adjuvant therapy strategy, and the approach differs in United States and elsewhere (see 'Choice of therapy' above):

Most clinicians outside of the United States use chemotherapy alone after resection of a pancreatic neoplasm. (See 'Chemotherapy alone' above.)

The American approach more often includes chemoradiotherapy as well as adjuvant chemotherapy. (See 'Chemoradiotherapy' above.)

All patients should be offered information about clinical trials. Eligible patients should be encouraged to enroll in clinical trials evaluating the potential benefits of adjuvant chemotherapy and/or chemoradiotherapy, as well as new therapies including neoadjuvant therapy.

If protocol therapy is not available or declined, we suggest six months of combination chemotherapy with gemcitabine plus capecitabine rather than gemcitabine monotherapy for most patients (Grade 2B). However, therapy with gemcitabine alone is a reasonable option, particularly for patients with a borderline performance status or a comorbidity profile that precludes intensive therapy. For Japanese patients, S-1, where available, represents a preferred alternative to gemcitabine 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 'Gemcitabine plus capecitabine' above and 'Gemcitabine versus a fluoropyrimidine' above.)

Full weight-based cytotoxic chemotherapy doses should be used to treat obese patients, particularly given that the goal of treatment is cure. (See 'Chemotherapy dosing in obese patients' above.)

Off-protocol, for most patients, we suggest the addition of concurrent chemoradiotherapy to chemotherapy (Grade 2C). During the concurrent chemoradiotherapy portion, we prefer infusional fluorouracil (FU) over either gemcitabine or bolus FU (see 'FU-based approaches' above). The substitution of capecitabine (or where available, S-1) for infusional FU during the chemoradiotherapy portion is reasonable in patients for whom ambulatory infusional FU therapy using a pump is not feasible. (See 'Oral fluoropyrimidines as a substitute for infusional FU' above.)

The optimal way to sequence FU-based chemoradiotherapy and gemcitabine chemotherapy is not established. For most patients, we prefer to initiate therapy with six months of adjuvant chemotherapy, proceeding with chemoradiotherapy for those without obvious disease progression.

While neoadjuvant therapy can be safely delivered to patients with localized, potentially resectable pancreatic cancer, no study has clearly demonstrated improved resectability or survival compared to patients treated with surgery alone, and it remains unclear whether this approach provides benefit compared to adjuvant therapy. Outside of a clinical protocol, we suggest not administering neoadjuvant chemotherapy or chemoradiotherapy to patients with potentially resectable pancreatic cancer in the absence of radiographic interface with the mesenteric vessels (ie, "borderline resectable" disease (algorithm 1)) (Grade 2C). (See 'Neoadjuvant therapy' above.)

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. (See 'Supportive care' above.)

The optimal posttreatment surveillance strategy is unknown. We perform a history and physical examination for symptom assessment every six months for two years, then annually, and check a CA 19-9 level (if initially elevated) at each of the visits. Given the lack of curative treatment for patients with recurrent pancreatic adenocarcinoma and the lack of data suggesting that early initiation of treatment for metastatic disease in asymptomatic patients provides a survival benefit over treatment in symptomatic patients, 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]. (See 'Guidelines from expert groups' above.)

However, others disagree, following the consensus-based guidelines of the National Comprehensive Cancer Network (NCCN), which suggest follow-up CT scans every three to six months for at least two years, then every 6 to 12 months, but on the basis of low-level evidence, albeit with uniform consensus. There may be benefit to detection of recurrence in an asymptomatic state to enable more aggressive chemotherapy, such as short-term infusional FU plus leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX). (See 'Posttreatment management' above.)

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