Adjuvant Therapy for Resected Exocrine Pancreatic Cancer

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Official reprint from UpToDate www.uptodate.com ©2015 UpToDate

AuthorsDavid P Ryan, MDHarvey Mamon, MD, PhD

Section EditorsRichard M Goldberg, MDChristopher G Willett, MD

Deputy EditorDiane MF Savarese, MD

Adjuvant therapy for resected exocrine pancreatic cancer

All topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through: Mar 2015. | This topic last updated: Jan 18, 2015.

INTRODUCTION — Approximately 48,960 people develop exocrine pancreatic cancer each year in the UnitedStates, and almost all are expected to die from the disease [1]. The majority of these tumors (85 percent) areadenocarcinomas 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 casesare potentially resectable at presentation. Furthermore, prognosis is poor, even for those undergoing complete (R0)resection. (See "Overview of surgery in the treatment of exocrine pancreatic cancer and prognosis", section on'Candidates for resection' and "Overview of surgery in the treatment of exocrine pancreatic cancer and prognosis",section on 'Prognosis and prognostic factors'.)

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 usedfollowing surgical resection in an effort to improve cure rates, an approach that is termed "adjuvant therapy."Although adjuvant chemotherapy has been associated with an improvement in overall survival, the benefits ofradiotherapy remain controversial; separating the independent effects of chemotherapy and RT has been difficult.

Adjuvant therapy for resected exocrine pancreatic cancer will be reviewed here. Neoadjuvant strategies forpotentially resectable, borderline resectable, and locally advanced unresectable exocrine pancreatic cancer,surgical management of localized exocrine pancreatic cancer, and chemotherapy for advanced disease arediscussed 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 chemotherapyand radiation for nonmetastatic locally advanced unresectable, borderline resectable, and potentially resectableexocrine pancreatic cancer" and "Chemotherapy for advanced exocrine pancreatic cancer".)

OVERVIEW OF THE TREATMENT APPROACH

Indications for adjuvant therapy — In the opinion of the authors (and the National Comprehensive CancerNetwork [NCCN] and the European Society for Medical Oncology [ESMO] [2]), all patients who have undergoneresection of an exocrine pancreatic cancer (including those with resected T1N0 disease (table 1)) should beoffered adjuvant therapy.

Prior to beginning adjuvant therapy, all patients should undergo formal restaging with computed tomography (CT)scans and a serum level of the tumor marker CA 19­9 (carbohydrate antigen 19­9, also called cancer antigen 19­9)l. Persistent postoperative elevations of the serum tumor marker CA 19­9 are associated with poor long­termprognosis. However, CA 19­9 levels are prognostic and not predictive of benefit from adjuvant therapy. Whilesome suggest withholding adjuvant therapy from such patients or treating them as if they have advancedmetastatic disease [3], we (and others [4]) suggest not using postoperative CA 19­9 levels to determine whether ornot to give postoperative adjuvant therapy. (See "Clinical manifestations, diagnosis, and staging of exocrinepancreatic cancer", section on 'CA 19­9' and "Overview of surgery in the treatment of exocrine pancreatic cancerand prognosis", section on 'Prognosis and prognostic factors'.)

Timing and duration — Adjuvant therapy is usually planned to start as soon as possible after surgery, typicallywithin four to six weeks, and administered for a total of six months. However, surgery for pancreatic cancer is

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associated with high morbidity, and patients do not recover at the same rate. There are no randomized trialsaddressing the impact of delayed initiation of adjuvant therapy on outcomes, or the effect of a longer duration oftherapy.

Some information on timing and duration of adjuvant chemotherapy is available from an analysis of the 985patients who received adjuvant gemcitabine or fluorouracil after resection of pancreatic cancer in the adjuvantESPAC­3 trial [5]. (See 'ESPAC­3 trial' below.)

Overall survival favored patients who completed the full six months of therapy versus those who did not (mediansurvival 28 versus 15 months, hazard ratio [HR] for death 0.61, 95% CI 0.44 to 0.60). The time to startchemotherapy (within eight weeks of surgery versus later) was an important survival factor only for the subgroupof patients who did not complete all six months of therapy (and in this group, survival inexplicably favored laterinitiation of therapy). There seemed to be no difference in outcomes if chemotherapy was delayed for up to 12weeks.

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

Choice of therapy — Pancreatic cancer has an extremely high rate of systemic recurrence (>80 percent) and avery high rate of local recurrence (>20 percent), which has led to efforts to improve outcomes through use of bothchemotherapy and radiation therapy (RT).

Adjuvant chemotherapy has been shown to improve overall survival by reducing systemic recurrence, withfluoropyrimidines and gemcitabine both demonstrating similarly beneficial effects. Adjuvant RT, which is oftengiven with sensitizing doses of chemotherapy, reduces local recurrences but there are no high­quality studiesdemonstrating an effect on survival that is independent of systemic chemotherapy. There are few randomizedtrials that have directly compared adjuvant chemotherapy with or without concomitant chemoradiotherapy, andextrapolating comparisons of the two strategies from historical trials is hazardous. Over the last 25 years, threemajor trends have impacted our ability to evaluate the effectiveness of various therapies and make the comparisonof studies across this time period very difficult.

The definition of an R0 (complete) resection has evolved dramatically. While it was previously thought thatonly the pancreatic transection margins were important in determining the completeness of the resection, it isnow clear that the retroperitoneal margin is the most frequently positive margin and that the presence of apositive retroperitoneal margin is associated with a very poor prognosis [6­9]. Nevertheless, many studiesinclude a large proportion of patients with positive retroperitoneal margins, and it must be assumed that manypatients in the older studies had a positive retroperitoneal margin, although this was usually not stated.

Radiation techniques have changed over the last 25 years. Among the most important changes are theabandonment of split course radiation, an acknowledgment that the optimal dose is 50.4 to 54 Gy for uppergastrointestinal cancers, and the use of computed tomography (CT) planning to better define the radiationboundaries.

In addition, the type of sensitizing chemotherapy that has been used in conjunction with RT complicates theability to compare between studies.

It is now recognized that the skills of both the surgeon and the institution caring for the patient affectoutcome dramatically (both in the short run and in the long term ). As an example, using volume as asurrogate for skill, one study showed that mortality rates following a Whipple procedure for a low­volume(fewer than two procedures per year), intermediate­volume (two to four per year), or high­volume (greater thanfour a year) surgeon in the late 1990s were 14.7, 8.5, and 4.6 percent, respectively [10]. Hospital volumewas also an independent predictor of mortality. Notably, 65 percent of the Whipple procedures in this study

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Significant disagreement exists between Europe and the United States with regard to the benefit of RT. As aresult, the approach differs:

In our view, all patients with resected pancreatic cancer should ideally be enrolled in clinical trials. One suchongoing study, Radiation Therapy Oncology Group (RTOG) trial 0848, is attempting to assess the independentcontributions of chemotherapy and chemoradiotherapy in patients with resected tumors of the head of thepancreas.

Off protocol, many American clinicians follow the approach utilized in the RTOG 9704 trial, which used FU­basedconcurrent chemoradiotherapy plus four months of adjuvant gemcitabine therapy. This approach is consistent withNCCN guidelines, which suggest that either FU­based chemoradiotherapy plus systemic gemcitabine orchemotherapy alone are acceptable options for adjuvant therapy. (See 'RTOG 9704' below and 'Gemcitabine'below.)

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

Chemotherapy alone — We recommend that all patients with resected pancreatic cancer receive adjuvantchemotherapy.

Multiple randomized controlled clinical trials and meta­analyses suggest a significant overall survival benefit fromchemotherapy alone without radiation therapy (RT) following resection of a pancreatic cancer [11­20].

Fluoropyrimidine­based regimens

were performed by surgeons who performed four or fewer Whipple procedures each year. (See "Overview ofsurgery in the treatment of exocrine pancreatic cancer and prognosis", section on 'Outcomes ofpancreaticoduodenectomy'.)

Most European clinicians advocate chemotherapy alone, emphasizing the survival benefit of chemotherapyalone as seen in the German Charité Onkologie (CONKO) 001 trial, the lack of a significant survival benefitwith chemoradiotherapy in the European Organization for Research and Treatment of Cancer (EORTC) trial,and the detrimental impact of chemoradiotherapy on survival seen in the European Study for PancreaticCancer (ESPAC)­1 trial. The most recent (2012) guidelines for treatment of pancreatic adenocarcinoma fromESMO suggest that chemoradiotherapy in the adjuvant setting should only be undertaken within the contextof a randomized controlled trial [2]. This is in contrast to NCCN guidelines, which suggest that either 5­fluorouracil (FU)­based chemoradiotherapy plus systemic gemcitabine or chemotherapy alone are acceptableoptions for adjuvant therapy. (See 'ESPAC­1 trial' below and 'EORTC study' below and 'Gemcitabine'below.)

Similarly, the Japanese approach also includes chemotherapy alone. However, for Japanese patients, oraltherapy with S­1, where available, represents a preferred alternative to gemcitabine monotherapy given theresult of a randomized trial demonstrating therapeutic non­inferiority and better tolerability for S­1. (See'Gemcitabine versus S­1' below.)

On the other hand, the American approach more often includes chemoradiotherapy in addition to adjuvantchemotherapy, and emphasizes the following points (see 'GITSG study' below and 'ESPAC­1 trial' belowand 'EORTC study' below):

The high risk of local failure and potential for benefit from chemoradiotherapy•The high rate of positive retroperitoneal margins and the 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 ESPAC­1 trial and the inherent difficulty in drawing definitiveconclusions from this study

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ESPAC­1 — An ambitious second trial sponsored by European investigators, the European Study forPancreatic Cancer (ESPAC)­1 trial, initially set out to randomize patients to a 2x2 factorial design in which therelative benefits of adjuvant chemotherapy, chemoradiotherapy, or chemoradiotherapy followed by chemotherapywould be compared with observation alone. However, fear of poor accrual led the investigators to permit theclinician to choose from this or two other randomization schemes (described below). The final results werepresented in two separate publications, one that pooled the results from the three parallel randomized trials [13]and a later report that focused on the 289 patients randomized to the four­arm study [14].

The pooled analysis included 541 patients (including those with positive margins) who were randomly assigned topostoperative treatment following resection of exocrine pancreatic cancer in the following three parallel studies[13]:

In the initial report of the pooled analysis, there was a significant survival benefit for adjuvant chemotherapy alonewhen 238 patients who received it were compared with 235 who did not receive it (median survival 19.7 versus 14months, respectively), but no survival difference when the 175 patients receiving postoperative chemoradiotherapywere compared with the 178 who did not receive it (median overall survival 15.5 versus 16.1 months, respectively)[13,14,16].

This analysis was criticized for the following reasons:

Some (but not all) of these concerns were addressed in a subsequent report that included only the 289 patientsrandomized to the four­arm study [14]. In an intent­to­treat analysis, both the two­year (40 versus 30 percent) andfive­year (21 versus 8 percent) survival rates were significantly greater among patients randomized topostoperative chemotherapy alone compared with those who did not receive it, despite the fact that 33 percent ofthose assigned to adjuvant chemotherapy did not complete all six courses, and 17 percent received nochemotherapy 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 five­year survival rates were 29 versus

Chemoradiotherapy versus no chemoradiotherapy – 68 patients enrolled; chemoradiotherapy consisted of 20Gy external beam radiation therapy (EBRT) plus three days of concomitant 5­fluorouracil (FU), repeated aftera planned break of two weeks.

Adjuvant chemotherapy versus no chemotherapy – 188 patients enrolled; adjuvant chemotherapy consistedof bolus leucovorin­modulated FU (leucovorin 20 mg/m , 5­FU 425 mg/m ) administered daily for five days,every 28 days, for six months.

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A 2x2 factorial design trial with four groups: chemoradiotherapy (n = 73), chemotherapy (n = 75), both (n =72), or observation (n = 69) [14]; the chemoradiotherapy and chemotherapy treatments were as describedabove.

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

Clinicians were allowed, according to their own preferences, to deliver "background" chemoradiation orchemotherapy.

Comparisons of treatment groups that were pooled together by treatment actually received, rather than"intent­to­treat" analysis, resulted in nearly one­third of the "no chemotherapy" and "chemotherapy alone"patients receiving chemoradiotherapy.

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

The chemoradiotherapy group did not include postradiotherapy adjuvant chemotherapy.

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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 similarin both groups, but there were more recurrences overall (84 versus 74) in the chemoradiotherapy group and ashorter recurrence­free interval (10.7 versus 15.2 months, respectively).

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

Norwegian trial — Comparable results were noted in a Norwegian trial that randomly assigned 61 patientswith curatively resected pancreatic cancer to six cycles of FU, doxorubicin, plus mitomycin (FAM) or observation[12]. As was seen in the ESPAC­1 trial, chemotherapy was associated with a significantly longer median survival(23 versus 11 months). However, long­term survival was similar at both three (30 versus 27 percent) and fiveyears (8 versus 4 percent).

Gemcitabine

CONKO­001 — A survival benefit from adjuvant gemcitabine monotherapy was shown in the multi­nationalEuropean Charité Onkologie (CONKO)­001 trial of 368 patients with grossly complete (R0 or R1) surgical resectionand a preoperative CA 19­9 level <2.5 times the upper limit of normal [11]. The patients were randomly assigned togemcitabine (1000 mg/m 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 about 17 percent of patients) and tumor (T)and nodal (N) status; the primary endpoint was disease­free survival (DFS).

In the most recent update, there was also a modest but significant improvement in overall survival that favoredgemcitabine and persisted long term (five­year overall survival 21 versus 10 percent; 10­year 12.2 versus 7.7percent) [17].

Japanese trial — A smaller phase III Japanese trial (JSAP­02) of surgery alone or followed by a shorterduration of gemcitabine (1000 mg/m days 1, 8, and 15 for three months only) in 119 patients also found asignificant improvement in DFS that favored gemcitabine (median 11.4 versus 5 months), but the difference inoverall survival (22 versus 18 months) was not statistically significant [19].

Gemcitabine versus a fluoropyrimidine — Gemcitabine is the preferred agent for adjuvant chemotherapywhen compared with monthly bolus (Mayo Clinic) of fluorouracil plus leucovorin (FU/LV), given its greatertolerability. Whether similar efficacy results and a more tolerable safety profile are possible with a weekly orinfusional fluoropyrimidine schedule are unknown. For Japanese patients, S­1, where available, represents apreferred alternative to gemcitabine because of its oral bioavailability and better tolerability.

ESPAC­3 trial — The multicenter ESPAC­3 trial randomly assigned 1088 patients with resected exocrinepancreatic cancer to six months of postoperative adjuvant treatment with either gemcitabine (1000 mg/m weeklyfor three of every four weeks) or leucovorin modulated FU (leucovorin 20 mg/m followed by FU 425 mg/m IVbolus days 1 through 5, every 28 days) [23]. At a median follow­up of 34 months, median survival was similar(23.6 versus 23 months with gemcitabine and fluoropyrimidine therapy, respectively). However, the patientsassigned to FU/leucovorin had more grade 3 to 4 treatment­related toxicity including stomatitis (10 versus 0percent), diarrhea (13 versus 2 percent), and more treatment­related hospitalizations. Otherwise, progression­freesurvival and global quality of life scores were similar between the two groups.

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RTOG 9704 — A slightly different question, the relative value of adjuvant gemcitabine monotherapy bothbefore and after concomitant FU­based chemoradiotherapy, versus all FU­based therapy in which FU was givenbefore, during, and after RT was addressed in a United States Intergroup study (Radiation Therapy OncologyGroup [RTOG] 9704) [24]. Patients who had undergone gross total resections for T1­4, N0­1 (table 1) exocrinepancreatic cancer and who were taking in at least 1500 calories daily postoperatively were randomly assigned toone of the following two treatment arms:

In the latest update, there were no significant differences in five­year overall or disease­free survival between thetwo groups [25]. 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 bettermedian (20.5 versus 17.1 months) and five­year survival (22 versus 18 percent, p = 0.08) with gemcitabine­basedadjuvant therapy, although neither difference was statistically significant.

There were no differences between the two treatments in patients with body/tail tumors (n = 63). Compared withthe all FU treatment, the gemcitabine group had similar rates of nonhematologic grade 3 or 4 toxicity and febrileneutropenia despite significantly more grade 4 hematologic toxicity (14 versus 1 percent) [24].

Gemcitabine versus S­1 — S­1 is an oral fluoropyrimidine that includes three different agents: ftorafur(tegafur), gimeracil (5­chloro­2,4 dihydropyridine, a potent inhibitor of DPD [dihydropyrimidine dehydrogenase]), andoteracil (potassium oxonate, which inhibits phosphorylation of intestinal FU, thought responsible for treatment­related diarrhea). It is approved in Japan for adjuvant treatment of gastric cancer and in Europe for treatment ofadvanced gastric cancer; it is not available in the United States.

S­1 (40 to 60 mg twice daily for four weeks and repeated every six weeks for four courses) was directly comparedwith gemcitabine (1000 mg/m on days 1, 8, and 15 and repeated every four weeks for six courses) in a trial of378 Japanese patients with resected pancreatic cancer [26]. In a preliminary report presented at the 2013American Society of Clinical Oncology (ASCO) annual meeting, S­1 was found to be non­inferior to gemcitabine,and patients treated with S­1 actually had a lower mortality rate (hazard ratio for death [HR] 0.56, 95% CI 0.42­0.74, two­year survival 70 versus 53 percent). Although both treatments were associated with similarly low ratesof grade 3 or 4 anorexia, thrombocytopenia, and anemia, gemcitabine was associated with more leukopenia (39versus 9 percent) and transaminitis (5 versus 1 percent). Whether these results can be extrapolated to otherpopulations is unclear.

Meta­analyses — Further support for the benefit of adjuvant chemotherapy alone in resected pancreatic cancercomes from two meta­analyses, both of which support a statistically significant survival benefit from adjuvantchemotherapy [18,20].

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 noevidence that fully­dosed obese patients experience greater toxicity from chemotherapy for pancreatic cancer.Guidelines from ASCO recommend that full weight­based cytotoxic chemotherapy doses be used to treat obesepatients with cancer, particularly when the goal of treatment is cure [27]. (See "Dosing of anticancer agents inadults", section on 'Overweight/obese patients'.)

Chemoradiotherapy — For most patients, we suggest the addition of concurrent chemoradiotherapy to adjuvant

FU arm – Three weeks of continuous infusion FU (250 mg/m daily) followed by chemoradiotherapy (50.4 Gyin 1.8 Gy daily fractions for 5.5 weeks with concurrent infusional FU 250 mg/m daily) and starting three tofive weeks later, two four­week courses of continuous infusion FU (250 mg/m daily, with a two­week rest inbetween courses)

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Gemcitabine arm – Three weekly doses of gemcitabine alone (1000 mg/m per week), followed by the samechemoradiotherapy protocol as for the conventional chemoradiotherapy arm, and starting three to five weekslater, three months of single­agent gemcitabine (1000 mg/m weekly for three of every four weeks)

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chemotherapy. However, others disagree, arguing that the benefits of chemoradiotherapy have not beenconclusively shown, particularly in patients receiving adjuvant chemotherapy. Ideally, patients should beencouraged to enroll on clinical trials testing the benefit of chemoradiotherapy when given in conjunction withsystemic 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 surgicalresection alone. In an autopsy series of 76 patients who had been treated for pancreatic cancer, 15 percent ofthose who had surgery alone for stage I or II disease had a local recurrence in the pancreatic bed alone, while 65percent had both locally recurrent and metastatic disease [28]. The local control benefit of adding radiotherapy canbe best illustrated by data from the Groupe Cooperateur Multidisciplinaire en Oncologie (GERCOR) trial ofpostoperative gemcitabine versus gemcitabine­based chemoradiotherapy [29]. The rate of local recurrence alone atfirst progression in the chemoradiotherapy group was notably lower (11 versus 24 percent), as was the rate ofsimultaneous local and distant progression (13 versus 20 percent). (See 'Does chemoradiotherapy add benefit tochemotherapy' below.)

However, not all studies have demonstrated improvements in local control with the use of combined modalitytherapy [14,30]. Furthermore, randomized trials and meta­analyses [18] have failed to confirm a survival benefitfrom radiotherapy. (See 'Meta­analysis' below.)

FU­based approaches

GITSG study — In a study conducted in the late 1970s and early 1980s by Gastrointestinal Tumor StudyGroup (GITSG), patients with resected pancreatic cancer were randomly assigned to either observation or externalbeam RT (EBRT, 40 Gy) plus concurrent bolus FU (500 mg/m per day on the first three and last three days ofRT), followed by maintenance chemotherapy (FU 500 mg/m per day for three days monthly) for two years or untildisease progression [31]. The study was terminated after eight years due to poor patient accrual. As a result, only43 patients were available for analysis.

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

EORTC study — In an effort to reproduce these findings, a study sponsored by the European Organizationfor Research and Treatment of Cancer (EORTC) randomly assigned 114 patients with resected pancreatic cancerto postoperative concurrent FU (25 mg/kg per day by continuous infusion) plus EBRT (40 Gy in split courses) orobservation [30]. In contrast to the GITSG findings, there was only a trend toward improved survival forchemoradiotherapy (at two years, 26 versus 34 percent, p = 0.099). No reduction in locoregional recurrence wasseen with combined modality therapy.

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

ESPAC­1 trial — As noted above, the ambitious ESPAC­1 trial initially set out to randomize patients to a2x2 factorial design in which the relative benefits of adjuvant chemotherapy, chemoradiotherapy, orchemoradiotherapy followed by chemotherapy would be compared with observation alone. However, fear of pooraccrual led the investigators to permit the clinician to choose from this or two other randomization schemes(described above). (See 'ESPAC­1' above.)

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As discussed above, the final results were presented in two separate publications (see 'ESPAC­1' above):

Many European clinicians cite these data as a main reason for not recommending concomitant chemoradiotherapyafter resection of pancreatic cancer, while others, especially American clinicians, consider that the study’s flawspreclude any ability to draw firm conclusions regarding the benefit of chemoradiotherapy.

Uncontrolled series — Other investigators have reported retrospective data that suggest benefit forpostoperative FU­based chemoradiotherapy in pancreatic cancer [21,33­36].

The largest series included 11,526 patients undergoing resection of pancreatic adenocarcinoma from 1998 to 2002and reported to the National Cancer Data Base, of whom 1029 (9 percent) had chemotherapy only, 5292 (46percent) had chemoradiotherapy, and 5205 (45 percent) received no adjuvant therapy [35]. Propensity scores weredeveloped for each treatment arm and used to produce matched samples for analysis to minimize selection bias.Twenty­five percent had surgically positive margins, and 57 percent had node­positive disease. In multivariateanalysis conducted in a subset of 7288 patients with sufficient data, the use of chemoradiotherapy was associatedwith a significant survival benefit over no adjuvant therapy (HR 0.784, 95% CI 0.74­0.83), but adjuvantchemotherapy alone was not (HR for death 1.08, p = 0.108). In a second analysis stratified by propensity score­matched groups (n = 1650 patients, 550 in each treatment group), the survival benefit for chemoradiotherapy wasgreater when compared with that of no adjuvant treatment (HR 0.70, 95% CI 0.61­0.80), but there was still nosurvival impact from chemotherapy alone (HR 1.04, p = 0.77).

Gemcitabine­based approaches — For patients undergoing concurrent chemoradiotherapy as a component ofadjuvant therapy, we prefer infusional FU rather than gemcitabine as a radiation sensitizer.

Preliminary data support the tolerability and favorable short­term outcomes of regimens that use gemcitabine as aradiation sensitizer [29,37­39]; but no trials have compared this approach with chemoradiotherapy using FU as theradiation sensitizer, at least in the postoperative setting. Thus, we consider that FU­based chemoradiotherapyrepresents a standard approach. A randomized phase II trial comparing gemcitabine­based chemoradiotherapyversus 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 whereavailable, S­1) for infusional FU is reasonable in patients for whom ambulatory infusional FU therapy using a pumpis not considered feasible.

Accumulating data from uncontrolled trials support the view that oral capecitabine can safely replace infusional FUas a radiation sensitizer in patients treated for locally advanced pancreatic cancer, although there are no data fromthe adjuvant setting. However, extrapolating from these and other data from phase III studies comparingcapecitabine versus infusional FU during chemoradiotherapy for rectal cancer, many investigators feel thatsubstituting capecitabine for infusional FU as a radiation sensitizer is reasonable for other gastrointestinalmalignancies and that the question is not worthy of phase III studies in each tumor type. We agree with this pointof view. (See "Neoadjuvant chemoradiotherapy and radiotherapy for rectal adenocarcinoma", section on 'Oralfluoropyrimidines versus infusional 5­FU' and "Initial chemotherapy and radiation for nonmetastatic locallyadvanced unresectable, borderline resectable, and potentially resectable exocrine pancreatic cancer", section on'Oral fluoropyrimidines as a substitute for infusional FU'.)

In an initial pooled analysis of the three parallel randomized trials [13], there was no survival difference whenthe 175 patients receiving postoperative chemoradiotherapy were compared with the 178 who did not receiveit (median overall survival 15.5 versus 16.1 months, respectively).

However, in a subsequent intent­treat analysis of the 289 patients randomized in the four­arm study, therewas a trend toward worse survival for this group receiving chemoradiotherapy (two­ and five­year survivalrates were 29 versus 41 percent, and 10 versus 20 percent for the chemoradiotherapy and nochemoradiotherapy groups, respectively) [14].

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Does chemoradiotherapy add benefit to chemotherapy — Few trials have directly compared chemotherapywith or without chemoradiotherapy as an adjuvant strategy. Besides the ESPAC­1 trial discussed above, the onlyother trial to compare the relative benefits of adding chemoradiotherapy to systemic therapy versus systemictherapy alone was the EORTC 40013/ FFCD­9203/GERCOR phase II study [29]. Ninety patients with resectedpancreatic cancer (70 percent node­positive, 97 percent completely resected [R0]) were randomly assigned togemcitabine­based chemoradiotherapy (two cycles of weekly gemcitabine alone [1000 mg/m weekly, three weekson, one week off] followed by RT [50.4 Gy in 28 daily 1.8 Gy fractions] with concurrent gemcitabine [300 mg/monce weekly four hours before RT for five to six weeks]) or a control group. Initially the control group wasobservation alone (n = 4), but the protocol was amended, and the remainder of the control group (n = 41) receivedfour cycles of gemcitabine alone (1000 mg/m for three consecutive weeks followed by a one week rest).Treatment started within eight weeks of surgery.

In contrast to the results of the ESPAC­1 analysis, chemoradiotherapy was not deleterious; median DFS was 12versus 11 months in the control group, and median overall survival was 24 months in both arms. Furthermore, therate of local recurrence alone at first progression in the chemoradiotherapy group was notably lower (11 versus 24percent) as was the rate of simultaneous local and distant progression (13 versus 20 percent); in contrast, therates of distant progression were similar (40 versus 42 percent). (See 'ESPAC­1 trial' above.)

Meta­analysis — The benefits of chemoradiotherapy with and without chemotherapy were addressed in a2013 network meta­analysis of nine randomized trials comparing six different adjuvant strategies (observationalone, FU alone, gemcitabine alone, chemoradiotherapy alone, chemoradiotherapy followed by FU, andchemoradiotherapy followed by gemcitabine) [18]. To optimize data extrapolation, the authors used Bayesiannetwork meta­analysis to compare treatments indirectly when no direct comparator trial existed. The followingresults were noted:

POSTTREATMENT SURVEILLANCE — There is no evidence to guide the posttreatment surveillance strategy inpatients with pancreatic cancer, and clinical practice is variable, particularly with regard to computed tomography(CT) scanning [40,41].

The majority of recurrences after potentially curative treatment of pancreatic exocrine cancer occur within twoyears, and they can be locoregional or to distant sites, most often liver, lung, and peritoneal cavity [42]. In oneautopsy series of patients with known pancreatic cancer, approximately 30 percent died with locally destructivedisease without evidence of metastases, while 70 percent died with widespread metastatic disease [28].

The primary goal of surveillance after curative treatment for any cancer is to detect local or distant recurrencewhen available interventions can prolong survival. However, for pancreatic cancer, the vast majority of recurrencesare not amenable to potentially curative therapy, and the evidence that early identification of recurrent ormetastatic disease in asymptomatic patients improves long­term survival is limited:

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

When chemoradiotherapy plus chemotherapy (FU or gemcitabine) was compared with chemotherapy alone(FU or gemcitabine), the point estimates of the hazard ratios for survival all favored the chemoradiotherapyarms; however, the confidence intervals were all wide, reflecting a lack of precision. As an example, in thecomparison of chemoradiotherapy plus gemcitabine versus gemcitabine alone, the HR for survival was 0.65(95 % CI 0.14­2.70). These results include the possibility of an 86 percent reduction in the risk of death and a2.7­fold increase in the risk of death with the addition of chemoradiotherapy. It is difficult to draw anymeaningful conclusions from these data.

In a study of 216 patients with pancreatic cancer who developed a postoperative recurrence during the

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Despite the lack of a consistent survival benefit, secondary benefits for detection of metastatic disease at anasymptomatic stage include early introduction of palliative chemotherapy or radiation therapy to slow diseaseprogression, and for patients who can tolerate an aggressive regimen such as FOLFIRINOX, improve survival.(See "Chemotherapy for advanced exocrine pancreatic cancer", section on 'FOLFIRINOX'.)

The American Society of Clinical Oncology (ASCO) does not provide formal recommendations regardingposttreatment surveillance for pancreatic cancer. Consensus­based guidelines from the National ComprehensiveCancer Network (NCCN) recommend a history and physical examination for symptom assessment every three tosix months for two years, then annually with low level of evidence but uniform consensus. They suggest the useof CA 19­9 determinations and follow­up CT scans at three to six month intervals for two years after surgicalresection, then annually, but on the basis of low­level evidence with nonuniform consensus. Consensus­basedguidelines from the European Society of Medical Oncology (ESMO) recommend that the posttreatmentsurveillance strategy be individualized to minimize emotional stress and economic burden [45]. In addition torepeat CT scans of the abdomen and pelvis every six months, they suggest monitoring CA 19­9 levels every threemonths for two years if CA 19­9 levels were elevated preoperatively.

Given that there is no known curative treatment for patients with recurrent pancreatic adenocarcinoma, we do notroutinely obtain CT scans in the follow­up of patients following resection of a pancreatic cancer. Patients withmetastatic 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. However, others disagree, following the NCCNguidelines.

Periodic assay of CA 19­9 can also be problematic in that mild elevations in CA 19­9 can occur with biliary tractdysfunction, which often occurs in patients after a pancreaticoduodenectomy. Thus, noncancerous causes canlead to abnormal results in these patients. However, at many institutions, CA 19­9 levels are followed periodicallyafter treatment of pancreatic cancer, with rising levels prompting a CT scan.

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 to 6 gradereading level, and they answer the four or five key questions a patient might have about a given condition. Thesearticles are best for patients who want a general overview and who prefer short, easy­to­read materials. Beyondthe Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are writtenat the 10 to 12 grade reading level and are best for patients who want in­depth information and are comfortablewith some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e­mail thesetopics 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.)

course of a surveillance regimen that consisted of physical examination, CA 19­9 assay, chest radiographand abdominal CT every three to four months for the first two years after surgery then every six months untilfive years, then annually, the surveillance regimen was able to detect asymptomatic recurrence in 55 percentof patients [43]. Although the median time to recurrence was not different between patients with asymptomatic versus asymptomatic recurrence, median survival was significantly less in symptomaticpatients (5.1 versus 13.0 months). Asymptomatic patients were much more likely to receive treatment afterrecurrence was identified.

On the other hand, analysis of a large national database demonstrated no significant survival benefit forannual radiographic surveillance among patients with curatively resected pancreatic cancer [44].

th th

th th

Basics topics (see "Patient information: Pancreatic cancer (The Basics)")

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

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SUMMARY AND RECOMMENDATIONS

The following represents our approach to patients with resected pancreatic tumors.

Cancer of the exocrine pancreas is associated with a poor prognosis, even if a complete (R0) resection canbe accomplished. Given the higher rates of distant (>80 percent) and local (>20 percent) recurrence,systemic chemotherapy, radiation therapy (RT), and a combination of chemotherapy and RT have all beenapplied following surgery in an effort to improve cure rates. Although the benefit of adjuvant therapy hasbecome clearer in recent years, the optimal choice of treatment modality (chemotherapy with or without RT)remains intensely controversial. (See 'Introduction' above.)

All patients with resected pancreatic cancer, including those with resected T1N0 disease (table 1), should beoffered adjuvant therapy after resection of an exocrine pancreatic cancer. (See 'Indications for adjuvanttherapy' above.)

The optimal timing of adjuvant chemotherapy is not established. Typically, it is started within four to sixweeks of surgery and continued for a total of six months. However, at least some data support the view thatdelaying treatment initiation for up to 12 weeks to allow full recovery from surgery does not compromise thesurvival benefit. (See 'Timing and duration' above.)

There is no consensus regarding the optimal therapeutic strategy, and the approach is different in UnitedStates and elsewhere (see 'Choice of therapy' above):

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

•

The American approach more often includes chemoradiotherapy as well as adjuvant chemotherapy.Guidelines from the National Comprehensive Cancer Network support either approach. (See'Chemoradiotherapy' above.)

•

Eligible patients should be encouraged to enroll in clinical trials evaluating the potential benefits ofchemotherapy and/or chemoradiotherapy as well as new therapies.

Off­protocol, we recommend adjuvant chemotherapy for all patients with resected pancreatic cancer (Grade1A). (See 'Chemotherapy alone' above.)

We suggest gemcitabine rather than a fluoropyrimidine­based regimen (Grade 2B). However, for Japanesepatients, S­1, where available, represents a preferred alternative to gemcitabine because of its oralbioavailability and better tolerability. There is not enough evidence to know whether S­1 is as beneficial innon­Japanese patients. (See 'Gemcitabine versus a fluoropyrimidine' above.)

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

Off­protocol, for most patients, we suggest the addition of concurrent chemoradiotherapy to chemotherapy(Grade 2B). During the concurrent chemoradiotherapy portion, we prefer infusional 5­fluorouracil (FU) overeither gemcitabine or bolus FU; and based upon data from Radiation Therapy Oncology Group (RTOG) 9704and the Charité Onkologie (CONKO)­001 trial, we suggest gemcitabine rather than a fluoropyrimidine­basedregimen for the chemotherapy portion (Grade 2B). (See 'RTOG 9704' above and 'CONKO­001' above.)

The substitution of capecitabine (or where available, S­1) for infusional FU during the chemoradiotherapyportion 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 FU­based chemoradiotherapy and gemcitabine chemotherapy is unclear. An

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REFERENCES

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surgery for ductal adenocarcinoma of the pancreas: ongoing lessons from the ESPAC­3 study. J Clin Oncol2014; 32:504.

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10. Birkmeyer JD, Siewers AE, Finlayson EV, et al. Hospital volume and surgical mortality in the United States.N Engl J Med 2002; 346:1128.

11. Oettle H, Post S, Neuhaus P, et al. Adjuvant chemotherapy with gemcitabine vs observation in patientsundergoing curative­intent resection of pancreatic cancer: a randomized controlled trial. JAMA 2007;

acceptable regimen is that used in RTOG 9704 [24], which consists of three weekly doses of gemcitabinealone (1000 mg/m per week), followed by chemoradiotherapy using concurrent infusional FU. Although theRTOG trial used 250 mg/m daily continuously, many clinicians, including our group, consider this too toxicand use 225 mg/m daily, five days per week. Following chemoradiotherapy and starting three to five weekslater, three months of single­agent gemcitabine (table 2) are given. (See 'Choice of therapy' above and'Gemcitabine­based approaches' above and "Treatment protocols for pancreatic cancer".)

However, based upon logistical concerns as well as postoperative morbidity, other approaches to sequencingchemoradiotherapy and gemcitabine differently than in the RTOG study are acceptable (eg, two months ofgemcitabine initially followed by chemoradiotherapy, and then two more months of gemcitabine alone).

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The optimal posttreatment surveillance strategy is unknown. We perform a history and physical examinationfor symptom assessment every six months for two years, then annually, and check a CA 19­9 level at eachof the visits. Given the lack of curative treatment for patients with recurrent pancreatic adenocarcinoma, andthe lack of data suggesting that early initiation of treatment for metastatic disease in asymptomatic patientsprovides a survival benefit over treatment in symptomatic patients, many clinicians, including some of theauthors of this topic review, do not routinely obtain computed tomography (CT) scans in the follow­up ofpatients after pancreaticoduodenectomy unless indicated by symptoms or a rising CA 19­9 level. However,others disagree, following the consensus­based guidelines of the National Comprehensive Cancer Network(NCCN), which suggest follow­up CT scans every three to six months for two years, then annually, but onthe basis of low­level evidence with nonuniform consensus. There may be benefit to detection of recurrencein an asymptomatic state to enable more aggressive chemotherapy, such as FOLFIRINOX. (See'Posttreatment surveillance' above.)

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297:267.12. Bakkevold KE, Arnesjø B, Dahl O, Kambestad B. Adjuvant combination chemotherapy (AMF) following

radical resection of carcinoma of the pancreas and papilla of Vater­­results of a controlled, prospective,randomised multicentre study. Eur J Cancer 1993; 29A:698.

13. Neoptolemos JP, Dunn JA, Stocken DD, et al. Adjuvant chemoradiotherapy and chemotherapy in resectablepancreatic cancer: a randomised controlled trial. Lancet 2001; 358:1576.

14. Neoptolemos JP, Stocken DD, Friess H, et al. A randomized trial of chemoradiotherapy and chemotherapyafter resection of pancreatic cancer. N Engl J Med 2004; 350:1200.

15. Butturini G, Stocken DD, Wente MN, et al. Influence of resection margins and treatment on survival inpatients with pancreatic cancer: meta­analysis of randomized controlled trials. Arch Surg 2008; 143:75.

16. Neoptolemos JP, Stocken DD, Tudur Smith C, et al. Adjuvant 5­fluorouracil and folinic acid vs observationfor pancreatic cancer: composite data from the ESPAC­1 and ­3(v1) trials. Br J Cancer 2009; 100:246.

17. Oettle H, Neuhaus P, Hochhaus A, et al. Adjuvant chemotherapy with gemcitabine and long­term outcomesamong patients with resected pancreatic cancer: the CONKO­001 randomized trial. JAMA 2013; 310:1473.

18. Liao WC, Chien KL, Lin YL, et al. Adjuvant treatments for resected pancreatic adenocarcinoma: asystematic review and network meta­analysis. Lancet Oncol 2013; 14:1095.

19. Ueno H, Kosuge T, Matsuyama Y, et al. A randomised phase III trial comparing gemcitabine with surgery­only in patients with resected pancreatic cancer: Japanese Study Group of Adjuvant Therapy for PancreaticCancer. Br J Cancer 2009; 101:908.

20. Yu Z, Zhong W, Tan ZM, et al. Gemcitabine Adjuvant Therapy for Resected Pancreatic Cancer: A Meta­analysis. Am J Clin Oncol 2013.

21. Hsu CC, Herman JM, Corsini MM, et al. Adjuvant chemoradiation for pancreatic adenocarcinoma: the JohnsHopkins Hospital­Mayo Clinic collaborative study. Ann Surg Oncol 2010; 17:981.

22. Hattangadi JA, Hong TS, Yeap BY, Mamon HJ. Results and patterns of failure in patients treated withadjuvant combined chemoradiation therapy for resected pancreatic adenocarcinoma. Cancer 2009; 115:3640.

23. Neoptolemos JP, Stocken DD, Bassi C, et al. Adjuvant chemotherapy with fluorouracil plus folinic acid vsgemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA 2010; 304:1073.

24. Regine WF, Winter KA, Abrams RA, et al. Fluorouracil vs gemcitabine chemotherapy before and afterfluorouracil­based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlledtrial. JAMA 2008; 299:1019.

25. Regine WF, Winter KA, Abrams R, et al. Fluorouracil­based chemoradiation with either gemcitabine orfluorouracil chemotherapy after resection of pancreatic adenocarcinoma: 5­year analysis of the U.S.Intergroup/RTOG 9704 phase III trial. Ann Surg Oncol 2011; 18:1319.

26. Fukutomi A, Uesaka K, Boku N, et al. JASPAC 01: Randomized phase III trial of adjuvant chemotherapywith gemcitabine versus S­1 for patients with resected pancreatic cancer (abstract). J Clin Oncol 31,2013(suppl; abstr 4008). http://meetinglibrary.asco.org/content/116237­132 (Accessed on June 10, 2013).

27. Griggs JJ, Mangu PB, Anderson H, et al. Appropriate chemotherapy dosing for obese adult patients withcancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 2012; 30:1553.

28. Iacobuzio­Donahue CA, Fu B, Yachida S, et al. DPC4 gene status of the primary carcinoma correlates withpatterns of failure in patients with pancreatic cancer. J Clin Oncol 2009; 27:1806.

29. Van Laethem JL, Hammel P, Mornex F, et al. Adjuvant gemcitabine alone versus gemcitabine­basedchemoradiotherapy after curative resection for pancreatic cancer: a randomized EORTC­40013­22012/FFCD­9203/GERCOR phase II study. J Clin Oncol 2010; 28:4450.

30. Klinkenbijl JH, Jeekel J, Sahmoud T, et al. Adjuvant radiotherapy and 5­fluorouracil after curative resectionof cancer of the pancreas and periampullary region: phase III trial of the EORTC gastrointestinal tract cancercooperative group. Ann Surg 1999; 230:776.

31. Kalser MH, Ellenberg SS. Pancreatic cancer. Adjuvant combined radiation and chemotherapy followingcurative resection. Arch Surg 1985; 120:899.

32. Further evidence of effective adjuvant combined radiation and chemotherapy following curative resection ofpancreatic cancer. Gastrointestinal Tumor Study Group. Cancer 1987; 59:2006.

33. Sohn TA, Yeo CJ, Cameron JL, et al. Resected adenocarcinoma of the pancreas­616 patients: results,outcomes, and prognostic indicators. J Gastrointest Surg 2000; 4:567.

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34. Vanderveen KA, Chen SL, Yin D, et al. Benefit of postoperative adjuvant therapy for pancreatic cancer: Apopulation­based analysis. Cancer 2009; 115:2420.

35. Kooby DA, Gillespie TW, Liu Y, et al. Impact of adjuvant radiotherapy on survival after pancreatic cancerresection: an appraisal of data from the national cancer data base. Ann Surg Oncol 2013; 20:3634.

36. Sugawara A, Kunieda E. Effect of adjuvant radiotherapy on survival in resected pancreatic cancer: apropensity score surveillance, epidemiology, and end results database analysis. J Surg Oncol 2014;110:960.

37. Demols A, Peeters M, Polus M, et al. Adjuvant gemcitabine and concurrent continuous radiation (45 Gy) forresected pancreatic head carcinoma: a multicenter Belgian Phase II study. Int J Radiat Oncol Biol Phys2005; 62:1351.

38. Wilkowski R, Thoma M, Dühmke E, et al. Concurrent chemoradiotherapy with gemcitabine and cisplatinafter incomplete (R1) resection of locally advanced pancreatic carcinoma. Int J Radiat Oncol Biol Phys2004; 58:768.

39. Blackstock AW, Mornex F, Partensky C, et al. Adjuvant gemcitabine and concurrent radiation for patientswith resected pancreatic cancer: a phase II study. Br J Cancer 2006; 95:260.

40. Sheffield KM, Crowell KT, Lin YL, et al. Surveillance of pancreatic cancer patients after surgical resection.Ann Surg Oncol 2012; 19:1670.

41. Castellanos JA, Merchant NB. Intensity of follow­up after pancreatic cancer resection. Ann Surg Oncol2014; 21:747.

42. Van den Broeck A, Sergeant G, Ectors N, et al. Patterns of recurrence after curative resection of pancreaticductal adenocarcinoma. Eur J Surg Oncol 2009; 35:600.

43. Tzeng CW, Fleming JB, Lee JE, et al. Yield of clinical and radiographic surveillance in patients withresected pancreatic adenocarcinoma following multimodal therapy. HPB (Oxford) 2012; 14:365.

44. Witkowski ER, Smith JK, Ragulin­Coyne E, et al. Is it worth looking? Abdominal imaging after pancreaticcancer resection: a national study. J Gastrointest Surg 2012; 16:121.

45. Cascinu S, Falconi M, Valentini V, et al. Pancreatic cancer: ESMO Clinical Practice Guidelines fordiagnosis, treatment and follow­up. Ann Oncol 2010; 21 Suppl 5:v55.

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GRAPHICS

TNM staging system for exocrine and endocrine tumors of thepancreas

Primary tumor (T)

TX Primary tumor cannot be assessed

T0 No evidence of primary tumor

Tis Carcinoma in situ*

T1 Tumor limited to the pancreas, 2 cm or less in greatest dimension

T2 Tumor limited to the pancreas, more than 2 cm in greatest dimension

T3 Tumor extends beyond the pancreas but without involvement of the celiac axis or thesuperior mesenteric artery

T4 Tumor involves the celiac axis or the superior mesenteric artery (unresectable primarytumor)

Regional lymph nodes (N)

NX Regional lymph nodes cannot be assessed

N0 No regional lymph node metastasis

N1 Regional lymph node metastasis

Distant metastasis (M)

M0 No distant metastasis

M1 Distant metastasis

Anatomic stage/prognostic groups

Stage0

Tis N0 M0

StageIA

T1 N0 M0

StageIB

T2 N0 M0

StageIIA

T3 N0 M0

StageIIB

T1 N1 M0

T2 N1 M0

T3 N1 M0

StageIII

T4 Any N M0

StageIV

Any T Any N M1

Note: cTNM is the clinical classification, pTNM is the pathologic classification.

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* This includes lesions classified as PanInIII classification.

Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. Theoriginal source for this material is the AJCC Cancer Staging Manual, Seventh Edition (2010) published bySpringer New York, Inc.

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Gemcitabine for nonmetastatic pancreatic and biliary cancer

Cycle length: 4 weeks.

DrugDoseandroute

AdministrationAdministrationschedule

Gemcitabine 1000mg/mIV

Dilute in 100 mL normal saline (concentrationno greater than 40 mg/mL) and administerover 30 minutes.

Weekly for threeweeks followed by oneweek of rest.

Pretreatment considerations:

• Emesis risk: LOW. Refer to UpToDate topic on "Prevention and treatment of chemotherapy­induced nausea and vomiting".

• Infection prophylaxis: Primary prophylaxis with granulocyte colony stimulating factors notindicated (risk of neutropenic fever <1 percent). Refer to UpToDate topic on "Use of granulocytecolony stimulating factors in adult patients with chemotherapy­induced neutropenia andconditions other than acute leukemia, myelodysplastic syndrome, and hematopoietic celltransplantation".

• Dose adjustment for baseline liver or renal dysfunction: A lower starting dose may beneeded for patients with liver impairment. Refer to UpToDate topic on "Chemotherapyhepatotoxicity and dose modification in patients with liver disease".

Monitoring parameters:

• CBC with differential and platelet count weekly during treatment.

• Assess basic metabolic panel (including serum creatinine) and liver function prior to each cycleand otherwise as indicated during treatment.

Suggested dose alterations for toxicity:

• Myelotoxicity: This regimen should not be initiated unless the white blood cell count is>3500 cells/microL and platelets are ≥100,000/microL . During therapy, the dose ofgemcitabine should be decreased by 25 percent if the absolute neutrophil count decreases to<1000 cells/microL but ≥500 cells/microL, or the platelets decrease to <100,000/microL and≥50,000/microL . The US FDA approved product information recommends holdinggemcitabine for an absolute neutrophil count <500 cells/microL or platelets <50,000/microL .

• Hepatotoxicity: Gemcitabine is commonly associated with a transient rise in serumtransaminases, but these are seldom of clinical significance. There is insufficient informationfrom clinical studies to allow clear dose recommendations in these patients.

• Hemolytic­uremic syndrome (HUS): In clinical trials, HUS was reported in 0.25 percent ofpatients receiving gemcitabine. Consider diagnosis if the patient develops hemolysis and severethrombocytopenia, with or without renal failure or central nervous system findings. Discontinuegemcitabine immediately and permanently. Refer to UpToDate topic on "Causes of thromboticthrombocytopenic purpura­hemolytic uremic syndrome in adults".

• Pulmonary toxicity: A variety of manifestations of pulmonary toxicity have been reported.Discontinue gemcitabine immediately and permanently. Refer to UpToDate topic on "Pulmonarytoxicity associated with antineoplastic therapy: Cytotoxic agents".

[1]

2

[1]

[2][2]

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If there is a change in body weight of at least 10 percent, dose should be recalculatedfor all drugs.

This table is provided as an example of how to administer this regimen. There may beother acceptable methods. This regimen must be administered by a clinician trained inthe use of chemotherapy. The clinician is expected to use his or her independentmedical judgment in the context of individual circumstances to make adjustments, asnecessary.

IV: intravenous; CBC: complete blood count; US FDA: United States Food and Drug Administration.

References:1. Oettle H, et al. JAMA 2007; 297:267.2. Gemcitabine hydrochloride injection. US FDA approved manufacturer's package insert. US National

Library of Medicine. (Available online at dailymed.nlm.nih.gov, accessed on November 28, 2011).

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Disclosures: David P Ryan, MD Consultant/Advisory Board: Boehringer Ingelheim [GI cancers (drugs in development)]; Medimmune [GI cancers (drugs in development)]. Trial Support: Sanofi [Colon cancer (Afibercept)]; Bayer [Colon cancer (Regorafinib)]; Medimmune [Colon cancer (Experimental agent)]; Merck [Colon cancer (PD­1 inhibitor MK­3475)]; Kanghong [Colon cancer (Experimental drug)]; Biothera [Colon cancer (Data SafetyMonitoring Committee Chair for a phase III trial)]; Baxter [Colon cancer (Experimental drug)]; Taiho [Colon cancer (Experimental drug)];Lilly [Colon cancer (Ramicurimab)]. Christopher G Willett, MD Nothing to disclose. Diane MF Savarese, MD Nothing to disclose.Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi­level review process, and through requirements for references to be provided to support the content. Appropriately referencedcontent is required of all authors and must conform to UpToDate standards of evidence.Conflict of interest policy

Disclosures