Cancer Treatment Reviews xxx (2012) xxx–xxx

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Cancer Treatment Reviews

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Neoadjuvant therapy in resectable pancreatic cancer: A critical review

Carmen Belli a,c, Stefano Cereda a,c, Santosh Anand b,d, Michele Reni a,⇑a Department of Medical Oncology, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italyb Centre for Translational Genomics and Bioinformatics, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy

a r t i c l e i n f o s u m m a r y

Article history:Received 1 May 2012Received in revised form 6 August 2012Accepted 23 September 2012Available online xxxx

Keywords:ChemotherapyNeoadjuvant therapyPancreatic cancerRadiotherapyResectable diseaseSurgery

0305-7372/$ - see front matter � 2012 Elsevier Ltd. Ahttp://dx.doi.org/10.1016/j.ctrv.2012.09.008

⇑ Corresponding author. Tel.: +39 02 26437644; faxE-mail addresses: belli.carmen@hsr.it (C. Belli), cere

anand.santosh@hsr.it (S. Anand), reni.michele@hsr.itc Tel.: +39 02 26437616; fax: +39 02 26437625.d Tel.: +39 02 26439140; fax: +39 02 26434153.

Please cite this article in press as: Belli C et al.dx.doi.org/10.1016/j.ctrv.2012.09.008

Background: Pancreatic cancer is among the deadliest tumors. Due to intrinsic chemo- and radio-resistance, surgical resection remains the only chance for cure. However surgery alone is unable toconsiderably improve survival and complementary chemotherapy and radiotherapy in a multimodalapproach have been tested. Adjuvant chemotherapy yielded a modest outcome improvement, whereasthe use of adjuvant chemoradiation is highly controversial. In this scenario, the neoadjuvant approachhas a strong theoretical rationale, but limited information on the efficacy of this strategy is available.Materials and methods: This review critically overviews the current knowledge, the rationale, the avail-able data and information on neoadjuvant treatment in resectable pancreatic cancer.Results: The very early systemic dissemination of pancreatic cancer endorses the rationale for an up-frontuse of systemic therapy. However, evidence collected so far depends on retrospective data, small case ser-ies that did not balance the different characteristics of patients suitable for surgery before or after neo-adjuvant chemotherapy.Conclusion: Currently there is no straightforward evidence to support the routine clinical use of this strat-egy. Only a properly designed randomized trial testing combination chemotherapy regimens selected onthe basis of their efficacy and activity against metastatic disease can address this issue.

� 2012 Elsevier Ltd. All rights reserved.

Introduction

Pancreatic cancer is an aggressive tumor and only 10–20% of pa-tients are considered candidates for curative resection at diagno-sis1,2 because surgery is possible only in the absence of distantmetastases, peritoneal carcinomatosis, and lack of any involve-ment of celiac axis and superior mesenteric artery. Due to intrinsicchemo- and radio-resistance, surgical resection is considered asthe only therapy that may have an impact on the natural historyof this disease and may increase chance for cure. However, surgicalresection alone results in a very modest median overall survival ofaround 20 months due to the high rate of relapse.3,4 A recent reporton long-term survival after pancreaticoduodenectomy gave a dis-mal outlook with low 5- and 10-year survival rates of 18% and13%, respectively.5 These data clearly demonstrate that surgeryalone is unable to considerably improve survival of patients af-fected by pancreatic cancer and hence other complementary treat-ments such as chemotherapy and radiotherapy in a multimodalapproach have been tested.

ll rights reserved.

: +39 02 26437625.da.stefano@hsr.it (S. Cereda),

(M. Reni).

Neoadjuvant therapy in resec

Data from randomized phase III trials have shown that adjuvantchemotherapy with 5-FU/FA6 and with gemcitabine4 provide amodest improvement in median survival of 1.9–4.7 months andof 6–10% in 2-year overall survival (OS) compared to pancreaticresection alone with no significant difference between these twochemotherapeutic agents.7,8 The use of adjuvant chemoradiationtherapy is highly controversial with a few randomized clinical tri-als showing conflicting results, ranging from a significant improve-ment,9 to only a small benefit,10 to a detrimental impact on OS.6

Altogether, available data show that surgery followed by adjuvanttreatment yields disappointing outcome figures in patients withresectable pancreatic cancer. Due to the high mortality and mor-bidity risk of pancreatic surgery and, accordingly, to the narrowtherapeutic window, the neoadjuvant approach has a strong theo-retical rationale in this disease, but limited information on the effi-cacy of this strategy is available.

This review critically overviews the current knowledge, therationale, the available data and information on neoadjuvant treat-ment of patients with resectable pancreatic cancer.

Rationale for preoperative therapy

Neoadjuvant treatment may offer several theoretical advanta-ges over adjuvant approach. Pancreatic cancer should be consid-ered as a systemic disease ‘‘ab initio’’ due to the presence of

table pancreatic cancer: A critical review. Cancer Treat Rev (2012), http://

2 C. Belli et al. / Cancer Treatment Reviews xxx (2012) xxx–xxx

micro-metastatic disease in lymph nodes, liver, peritoneum andlung at time of diagnosis, which is responsible for most of the earlyrelapses after curative surgery. Pre-operative chemotherapy timelyaddresses the undetected part of the disease thus avoiding thedelay of at least 2 months between diagnosis and start of post-operative chemotherapy, which usually occurs due to surgicalwaiting list and time for postoperative recovery for patientssubmitted to upfront surgery. Furthermore, a larger proportion ofpatients may receive the treatment compared to the adjuvant set-ting. In fact, about a quarter of patients submitted to curativeresection do not receive the planned postoperative treatment dueto the surgical complications, poor performance status, comorbid-ity, patient refusal, and early disease recurrence.10,11 In addition,the treatment itself may be tolerated much better, resulting in ahigher rate of treatment compliance and improved dose-intensity.Another potential advantage is that neoadjuvant treatment mayreduce intraoperative tumor spillage thus reducing the risk of per-itoneal tumor cell implantation during surgery. The administrationof chemotherapy before surgery also allows an in vivo assessmentof tumor chemo-sensitivity. Finally, neoadjuvant treatment mayalso lead to more definitive surgical resections by reducing the riskof tumoral infiltration of lymph nodes and of resection margins inthe surgical specimen.

Conversely, neoadjuvant approach raises several concernsamong detractors such as inaccuracy of staging and consequentlythe risk of overtreatment of very early disease; erroneous histol-ogy; diagnostic imprecision due to difficulties in distinguishing be-tween intra-pancreatic bile duct adenocarcinoma and pancreaticadenocarcinoma; increase in operative morbidity and mortality;and the possibility that the disease might metastasize or becomeunresectable during the course of induction therapy. The first topicappears of little relevance in pancreatic cancer since systemictreatment is virtually recommended at any stage of disease, withthe possible exception of stage I, which is exceedingly rare. Cur-rently, the widespread and systematic use of endoscopic ultra-sound (EUS) and EUS-guided fine needle aspiration (EUS-FNA)considerably reduces the risk of inaccurate pathological diagnosis.Regarding surgical complications, no increase in morbidity or mor-tality after neoadjuvant therapy has been reported in previous tri-als.12–14 On the other hand, the concern for disease progressionduring pre-surgical treatment is not negligible due to the low rateof curative resections performed among patients whose diseasewas deemed resectable at the time of start of neoadjuvant therapyboth after induction chemoradiation (45–74%)14–17 and afterinduction chemotherapy (38–70%).12 However, advocates of neo-adjuvant therapy claim these data as an advantage of this strategy,arguing that the patients who experience disease progression dur-ing induction treatment suffer from an extremely aggressive tu-mor, which cannot be cured by extensive surgery. It might beappealing to avoid the risk of surgical mortality and morbidity inthis subset of patients, but not necessarily for patients experienc-ing only local progression during neoadjuvant therapy. But thereis not randomized trial comparing different management strate-gies in order to confirm a detrimental impact of delaying surgery.Also, the proper goal of pre-operative therapy should be that ofdownstaging the disease thereby improving both cure rate and dis-ease control, rather than improving patient selection for surgery.

Studies of neoadjuvant treatment in resectable pancreaticcancer

Since the early eighties, several clinical trials have evaluated therole of neoadjuvant radiotherapy, chemotherapy, or various combi-nations of these therapeutic modalities in resectable pancreaticcancer.

Please cite this article in press as: Belli C et al. Neoadjuvant therapy in resecdx.doi.org/10.1016/j.ctrv.2012.09.008

For the purposes of this review, prospective, retrospective andcohort studies, meta-analyses and pooled analysis focusing on neo-adjuvant therapy of treatment-naïve patients with resectable pan-creatic adenocarcinoma were considered. Articles from whichseparate results of resectable, borderline and unresectable tumorsor of pancreatic and periampullary tumors were not retrievable,were excluded. Studies to be considered for this review were iden-tified by a Medline search of articles published between January1992 and December 2011. The search strategy included the follow-ing key words: (‘‘pancreas’’ or ‘‘pancreatic’’) and (‘‘cancer’’ or ‘‘neo-plasm’’ or ‘‘carcinoma’’ or ‘‘adenocarcinoma’’) and (‘‘neoadjuvant’’or ‘‘preoperative’’) and (‘‘radiation’’ or ‘‘chemotherapy’’ or ‘‘chemo-radiation’’ or ‘‘target therapy’’) and (‘‘resectable’’). No languagerestrictions were applied. Manual searching for eligible studies tocapture missing studies that met our inclusion criteria was per-formed by reading through reference lists of relevant articles. Fur-thermore, the ClinicalTrials.gov database was explored to identifyprospective ongoing trials.

Radiotherapy

The role of neoadjuvant radiation therapy in pancreatic cancerpatients has been rarely addressed. A retrospective study evaluatedthe role of neoadjuvant radiotherapy compared to upfront surgeryin 54 consecutive patients during the period of 1985–1989, inwhom pancreatic cancer was deemed to be resectable by preoper-ative imaging technique.18 Out of 54 patients, 23 (43%) receivedpreoperative radiotherapy before surgery (group A) while theremaining 31 (57%) went directly to laparotomy (group B). Theindication for preoperative irradiation was determined by the con-sent of both the patients and their family. Surgery was possible in17 patients (74%) in group A and 19 patients (61%) in group B. Themedian survival of all patients was 15 months in group A and11 months in group B. No significant difference in OS was ob-served: 2- and 3-year survival rates were quite similar in bothgroups (30% vs. 24% and 22% vs. 19%, respectively). Similar resultswere observed in the subset of resected patients. In fact, there wasno difference in 3- and 5-year rates between two groups (28% vs.32%, and 22% vs. 26%, respectively). A lower rate of loco-regionalrecurrences was reported among patients receiving neoadjuvantirradiation albeit this had no impact on long term survival due tothe prevalence of systemic failure.

While the retrospective nature and the small sample size do notallow drawing firm conclusions, these data confirm that the pat-tern of failure of pancreatic cancer, even at early stages, is charac-terized by a tendency to metastasize at distant sites. Accordingly, alocal therapy might not be sufficient to have an impact on the nat-ural history of the disease.

Radiotherapy concomitant to mono-chemotherapy

Starting in the early 1990s, several trials addressed the feasibil-ity and the efficacy of radiotherapy concomitant to chemotherapyas upfront therapeutic management of resectable pancreatic can-cer (Table 1).

Chemotherapy with 5FU (300 mg/m2/day) concomitant to radi-ation therapy (50.4 Gy given over 5.5 weeks) was administered to28 patients with resectable pancreatic cancer.19 Combined treat-ment was poorly tolerated due to gastrointestinal toxicity requiringhospitalization in 9 (32%) patients. A total of 17 patients (61%)underwent to curative surgery. None of the patients showed partialresponse (PR). Perioperative complications occurred in 3 patients(18%) and 1 patient (6%) died postoperatively from myocardialinfarction. These data suggested that preoperative chemoradiationdoes not appear to increase the risk of pancreaticoduodenectomymorbidity and mortality. On the other hand, this small series raises

table pancreatic cancer: A critical review. Cancer Treat Rev (2012), http://

Table 1Neoadjuvant trials of radiotherapy concomitant to monochemotherapy.

Trial Chemotherapy Radiotherapy Population Rate ofresectabilityN (%)

Node negativeN (%)

R0 resectionN (%)

Localfailure

Distantfailure

Median survival months

N (%) N (%) Global Resected Nonresected

Evans19 5-FUa 50 Gy/Sa-IORTa

28 17 (61) 12 (43%) 14 (50%) 3 (11%) 8 (28%) – 18 –

Pister20 5-FUa 30 Gy/Ra-IORT

35 20 (57) 7 (20%) 18 (51%) 2 (6%) 24 (68%) 37 25 7

Evans14 GEMa 30 Gy/R 86 64 (74) 40 (46%) 57 (66%) 7 (8%) 55 (64%) 23 34 7Pister22 PTXa 30 Gy/R-IORT 35 20 (57)b 9 (26%) 12 (34%) 1 (3%) 29 (85%) 12 19 10Calvo23 Tegafur 45–50.4 Gy/

S-IORT15 9 (60) – 7 (46%) 3 (20%) 4 (26%) 17 23 8

a Abbreviations: 5-FU: 5 Fluorouracil; GEM: gemcitabine; PTX: paclitaxel; S: standard fractionation regimen; R: rapid fractionation regimen; IORT: intraoperative radiationtherapy.

b One patient underwent surgery in other institute so was excluded by histological analysis. One patients included in this study treated by surgery had neuroendocrinetumor and developed metastatic disease.

C. Belli et al. / Cancer Treatment Reviews xxx (2012) xxx–xxx 3

remarkable concern due to the high rate of initially resectable pa-tients who were not submitted to curative surgery. The same groupalso tested a rapid fractionation chemoradiation (30 Gy in 2 weeksin combination with 5FU at the same dosage of the previous study),in the attempt to reduce the delay of surgery.20 The modified sche-dule was better tolerated and, only 3 patients (9%) out of 35 patientsenrolled in this study experienced grade 3–4 toxicity. However,only 20 of 35 (57%) patients were submitted to pancreaticoduoden-ectomy, thus confirming the disappointing resectability rate of theprevious study (61%). The median OS of the subset of resectedpatients was 25 months, while the median OS of non-resectedpatients was only 7 months. Altogether, these results do not appearto be promising when compared to the outcome of series submittedto surgery alone.

A retrospective study11 compared the role of preoperative vs.postoperative chemoradiation in patients treated with curative in-tent over a 5-year period at M. D. Anderson Cancer Center. Alto-gether, 142 patients having cancer of pancreatic head orperiampullary region, whose tumors were deemed to be resectableon the basis of pre-treatment CT images, were included in thisstudy. The patients’ selection for preoperative chemoradiationwas based on a pre-defined protocol which required a pathologicconfirmation of adenocarcinoma and the presence of a low densitymass in the pancreatic head on CT scan. Conversely, patients notfulfilling these criteria immediately underwent surgery. A total of91 patients were treated by preoperative chemoradiation using5FU and a heterogeneous radiotherapy schedule, including intra-operative radiotherapy (IORT) in 68% of cases. Also in this series,the rate of pancreaticoduodenectomy was disappointingly low asonly 52 (57%) patients underwent curative surgery. Among theremaining 51 patients who were referred to immediate surgery,9 (18%) were found to have unresectable disease intra-operatively,25 (49%) had pancreatic adenocarcinoma while 17 (33%) werefound to have no-primary pancreatic tumors (duodenum, ampulla,distal biliary tract cancers). Adjuvant therapy was administered in19 of the 25 patients with pancreatic adenocarcinoma as 6 of themhad a delayed postoperative recovery or bad performance statusafter pancreaticoduodenectomy. No OS difference was reported be-tween the subset of 41 patients completing the whole neoadjuvantprotocol and that of 19 patients completing the whole adjuvantprotocol. However, the results of this study are extremely difficultto interpret due to its retrospective nature, to the divergent group-allocation criteria, to the intra-group heterogeneous therapy andstaging procedures, and to the lack of information on the outcomeof the whole population.

More recently, neoadjuvant chemotherapy with gemcitabineconcomitant to radiation has been tested in resectable pancreatic

Please cite this article in press as: Belli C et al. Neoadjuvant therapy in resecdx.doi.org/10.1016/j.ctrv.2012.09.008

cancer.14 The rationale derives from in vitro studies in which thisdrug showed to have radiosensitization properties in pancreaticcancer cell lines.21 Eighty-six patients were enrolled in a largestudy cohort and received neoadjuvant gemcitabine at 400 mg/m2 once a week for 7 weeks concomitant to radiation therapy(30 Gy in 10 fractions in weeks 2 and 3).14 Pancreaticoduodenecto-my was performed in 64 patients (74%). Median survival was22.7 months for the whole study and 34 months for the 64 patientswho underwent surgery. Fifty-seven patients (66%) had R0 resec-tion, 40 (46%) had negative lymph nodes, and 13 (20%) of themunderwent to vascular resection that may suggest a local progres-sion of the disease during neoadjuvant treatment. Local failuredeveloped in 7 patients (8%), while distant failure in 55 of cases(64%). Grade 3 and 4 toxicity in this trial consisted of granulocyto-penia 30%, neutropenic fever 2%, fatigue 31%, anorexia 11%, nausea16%, emesis 18%, stent occlusion 18% and increased transaminaseslevels 10%, but all the patients concluded the planned treatmentand no toxic death occurred. Major surgical complications wereobserved in 6 patients (9%) and were not linked to preoperativetreatment. This trial shows that this approach is safe and feasiblewhile OS figures are difficult to interpret due to the lack of a com-parative arm.

Paclitaxel22 and tegafur23 were also tested concomitantly toradiotherapy in resectable pancreatic cancer patients. Paclitaxel(weekly 3-h infusion of 60 mg/m2 for 3-consecutive weeks) con-comitant to radiotherapy (30 Gy; 3 Gy/Fx � 10 Fx) was adminis-tered to a small cohort of 35 patients without yielding promisingresults neither in terms of median survival (19 mo) nor in termsof toxicity (46% grade 3 toxicity; 11% hospitalization for dehydra-tion due to grade 3 nausea and vomiting), when compared to thehistorical experience of the same group with 5FU-based neoadju-vant chemoradiation.20 Oral tegafur was administered at the doseof 1200 mg/d in combination with radiotherapy (45–50 Gy)23 toa cohort of 15 patients. Only 9 (60%) patients underwent to pan-creaticoduodenectomy yielding a median survival of 23 monthswhereas the median survival for the whole population was17 months. The small sample size and the use of IORT boost ham-per the interpretation of results.

Polychemotherapy in combination with radiotherapy

Combination chemotherapy concomitant to radiation has alsobeen tested (Table 2). 5FU (1000 mg/m2/d continuous infusion ondays 2–5 and 29–32) and mitomycin C (10 mg/m2 on day 2) com-bined with 50.4 Gy of radiation were tested in a pilot study involving34 patients with localized pancreatic adenocarcinoma.24 Only onethird of patients (N = 11; 32%) underwent pancreatic resection.

table pancreatic cancer: A critical review. Cancer Treat Rev (2012), http://

4 C. Belli et al. / Cancer Treatment Reviews xxx (2012) xxx–xxx

Despite this very disappointing result, Eastern Cooperative OncologyGroup (ECOG) conducted a phase II trial15 on 53 patients confirmingthe previous results: 24 patients (45%) were submitted to pancreaticresection. The median survival for the entire population was9.7 months, which is inferior to that expected with surgery alone.

The results of 5FU-cisplatin combination were retrospectivelyreported.17,25–27 Altogether, 62 (61%) out of 102 patients with ini-tially resectable pancreatic head adenocarcinoma treated with thiscombination in 10 years underwent pancreatic resection.27 Themedian survival for the resected patients and whole populationwas 23 months and 17 months, respectively, which appears worsethan in series treated with adjuvant therapy. Similarly, a prospec-tive phase II study with this combination failed to produce anypromising result: out of the 41 treated patients, 26 (63%) under-went pancreatic resection, the median survival was 11.7 monthsfor the resected patients and 9.4 months for the whole populationsuggesting a possible detrimental effect with this approach.28

Chemotherapy

The very early systemic dissemination of pancreatic cancer en-dorses the rationale for an up-front use of systemic therapy.Accordingly, the administration of chemotherapy alone (Table 3)or followed by chemoradiation (Table 4) was also prospectivelyassessed.

An exploratory phase II trial randomized patients with resect-able pancreatic cancer to receive either gemcitabine alone or gem-citabine-cisplatin combination in order to identify the mostpromising regimen for future study.12 Dose-intensity and toxicityprofile were superimposable in both arms. No complete responsewas obtained in any arm; PR was observed in 4% of patients treatedwith combination chemotherapy and in none of those that re-ceived gemcitabine only. Nine patients (38%) in the gemcitabinearm and 18 (70%) in the combination arm underwent curativeresection, without differences in terms of surgical complications.Histology showed that 12% of patients treated with gemcitabineand in 19% treated with gemcitabine plus cisplatin did not have apancreatic adenocarcinoma. The median survival was poor:9.9 months in gemcitabine arm and 15.6 months in combinationarm. Given the small sample size and the high rate of diagnosticmistakes, these results are difficult to interpret but do not appearencouraging.

Similar results were also reported in another prospective phaseII trial.29 In this single arm trial, 28 patients with cytologically pro-ven resectable pancreatic head adenocarcinoma received fourbiweekly cycles of gemcitabine and cisplatin. Adverse events weremild and mainly consisted of grade 6 3 gastrointestinal and hema-tologic toxicity. At restaging, 2 patients had peritoneal metastases.At surgical exploration, one patient was found to have unresectabledisease because of infiltration of the mesenteric axis. Twenty (71%)

Table 2Neoadjuvant trials of polychemotherapy in combination with radiotherapy.

Trial Chemotherapy Radiotherapy Population Rate ofresectability N (%)

NodeN (%

Hoffman24 5FUa + MMCa 50.4 Gy/Sa 53 24 (45) 19 (3Moutadier25 5-FU + CISa 45 Gy/Sa 61 40 (66) 30 (4Magnin26 5-FU + CISa 45 Gy/S or

15 Gy-SCa32 19 (59%) 7 (22

Turrini27 5-FU + CISa 45Fy/Sa 102 62 (61) 47 (4Mornex28 5-FU + CISa 50 Gy/Sa 41 26 (63) 11 (2

a Abbreviations: 5-FU: 5 Fluorouracil; CIS: cisplatin; MMC: mitomycin C; S: standard fb Resection margins were analyzed in 21 rested patients.c Three patients with local recurrence also had distant recurrence.

Please cite this article in press as: Belli C et al. Neoadjuvant therapy in resecdx.doi.org/10.1016/j.ctrv.2012.09.008

patients had an R0 resection and 5 (18%) an R1 resection. The med-ian survival for the whole series was 26.5 months on intention-to-treat (ITT) analysis, while it was 19.1 months for patients whounderwent successful resection.

Chemotherapy followed by chemoradiation therapy

Another approach tested in resectable pancreatic cancer pa-tients was the sequential treatment, first using induction chemo-therapy followed by chemoradiation therapy (Table 4).

The impact of sequential chemotherapy with gemcitabine andcisplatin, followed by gemcitabine-based chemoradiation was as-sessed in a phase II study on 90 patients with resectable pancreaticcancer,13 based on the better activity of this doublet compared tosingle agent gemcitabine in advanced disease.30 Again, only 52 pa-tients (58%) underwent curative surgery and the median survivalfor the whole series was 17.4 months which appears inferior tothe results reported with surgery alone in modern series.

In another phase II trial,31 20 patients were treated with threecycles of gemcitabine (1000 mg/m2 intravenously) and radiother-apy (36 Gy in 15 fractions delivered during the second cycle).Pancreatic resection was done in 17 (85%) patients. The medianand 2-year OS for 17 patients treated with surgery were 26 monthsand 61%, respectively, while survival data for the whole populationwere omitted. Only three patients (15%) showed partial responseand no complete response was observed at radiological exam. Fiveof the resected patients (29%) had vascular resection. At patholog-ical analysis of pancreatic specimens, 1 (5%) did not contain resid-ual tumor, and 3 (15%) had only microscopic foci of residualdisease.

The results of chemotherapy, followed or not by chemoradia-tion, suggest that a poorly active combination chemotherapywhich did not show superiority against single agent gemcitabinein the context of advanced disease has also a limited role in theneoadjuvant treatment of resectable pancreatic adenocarcinomabecause of the low rate of downstaging, of the weak activityagainst microscopic disease and of the high rate of tumor progres-sion. In fact, the apparent advantage in survival of chemoradia-tion14 over systemic chemotherapy followed by the samechemoradiation regimen13 may be related to the shorter durationof an ineffective therapy.

Targeted therapies in pancreatic cancer

During the last years the improvement in the knowledge of pan-creatic cancer biology and the development of new drugs have madepossible to test new targeted agents in PC. Several drugs like epider-mal growth factor (EGFR) receptor inhibitors, vascular endothelialgrowth factor (VEGF) inhibitors, matrix metalloproteinase inhibitors,and insulin-like growth factor receptor (IGF-1R) inhibitors were

negative)

R0 resectionN (%)

Local failureN (%)

Distant failureN (%)

Median survivalmonths

Global Resected NRa

6%) 11 (20%)b 12 (22%)c 36 (68%) 9.7 15.7 –9%) 37 (60%) 2 (3%) 41 (67%) 20 26.6 9%) 7 (22%) 5 (16%) 11 (34%) 16 30 –

6%) 57 (56%) 18 (18%) 65 (64%) 17 23 117%) 21 (80%) 9 (22%) 31 (75%) 9.4 11.7 8.5

ractionation regimen; SC split course, NR: Non Resected.

table pancreatic cancer: A critical review. Cancer Treat Rev (2012), http://

Table 3Neoadjuvant trials of chemotherapy alone.

Trial Chemotherapy Population Rate ofresectability N (%)

Node negativeN (%)

R0 resectionN (%)

Local failureN (%)

Distant failureN (%)

Median survival months

Global Resected Nonresected

Palmer12 GEM 24 9 (38) 2 (8%) 6 (25%) — — 9.9 – –vs vs vs vs vsGEM + CDDPa 26 18 (69) 7 (27%) 12 (46%) 15.6 – –

Heinrich29 GEM + CDDPa 28 25 (89) 6 (21%) 20 (71%) 8 (29) 15 (54) 26.5 19.1 –

a Abbreviations: GEM: gemcitabine; CDDP: cisplatin.

Table 4Neoadjuvant trials of chemotherapy followed by chemoradiation therapy.

Trial Chemotherapy Radiotherapy Population Rate ofresectabilityN (%)

NodenegativeN (%)

R0 resectionN (%)

LocalfailureN (%)

DistantfailureN (%)

Median survival months

Global Resected Nonresected

Talamonti31 GEMa ? GEM + RTa 36 Gy/Ra 20 17 (85) 11 (55%) 16 (80%) 3 (30%) 10 (50%) – 26 –Varadhachary13 CIS + GEM ? GEM + RTa 45 Gy/Sa 90 52 (58) 20 (22%) 50 (55%) 18 (20%) 56 (62%) 17 31 18.7

a Abbreviations: GEM: gemcitabine; CIS: cisplatin; RT: radiotherapy; S: standard fractionation regimen; R: rapid.

C. Belli et al. / Cancer Treatment Reviews xxx (2012) xxx–xxx 5

tested in advanced disease with disappointing results.32–35 Never-theless, several prospective clinical trials using targeted agents inthe neoadjuvant therapy for resectable disease are ongoing.

A couple of phase II clinical trials are evaluating the role of tyro-sine kinase inhibitor (TKI) erlotinib in combination with chemo-therapy with or without radiotherapy in patients affected bystage I–II pancreatic cancer (NCT00733746 and NCT01389440). Amulticenter study conducted by the American College of Surgeons(NCT00733746) is evaluating a combination of gemcitabine admin-istered on days 1, 8, 15, 29, 36 and 43 in combination with oral erl-otinib once daily on days 1–43 in patients with potentiallyresectable pancreatic cancer. In absence of disease progression orunacceptable toxicity at 3–6 weeks after completion of neoadju-vant therapy, patients will undergo to surgery and after 5–10 weeksthey will begin adjuvant chemotherapy with the same drugsadministered using the same schedule of preoperative treatment.The primary endpoint of this study is the estimation of the propor-tion of patients alive at 2 years from the study enrolment. Second-ary endpoints consist in evaluation of resection rate, the rate of R0,R1, and R2 resection and the toxicity profile of chemotherapy com-bined with targeted therapies. This study will also evaluate the roleof molecular profiling by assessing the epithelial-mesenchimal(EMT) markers and EGFR intron 1 polymorphism, and will identifythe genetic profile by RNA analysis, which could predict the re-sponse to this regimen. Another phase II clinical trial(NCT01389440) is studying in stage I–II PC the efficacy of neoadju-vant therapy with gemcitabine (1000 mg/m2/week) and erlotinib(100 mg/day) followed by gemcitabine (300 mg/m2/week) plus erl-otinib (100 mg/day) and radiotherapy (45 Gy) for 5 cycles. The pri-mary endpoint of this study is to evaluate the percentage of patientsundergoing R0 resection after neoadjuvant chemoradiotherapy.

A phase II study is evaluating the role of anti-VEGF monoclonalantibody bevacizumab in potentially resectable pancreatic cancerpatients (NCT00557492). This is a 2-stage study of bevacizumabplus gemcitabine, administered as fixed dose rate, in combinationwith sequential rapid fractionation radiotherapy (30 Gy) in neoad-juvant setting. The purpose of this study is to determine the rate ofR0 resection and the rate of pathological complete response afterneoadjuvant therapy to establish if this regimen merits furtherstudies in a phase III trial.

Considering the disappointing results of studies using targetedtherapy in advanced pancreatic cancer,32–35 there is very little hopethat these drugs could affect the natural history of this disease.However, using these drugs could possibly permit to understand

Please cite this article in press as: Belli C et al. Neoadjuvant therapy in resecdx.doi.org/10.1016/j.ctrv.2012.09.008

their mechanism of action in vivo and ultimately could help to se-lect a group of patients that might benefit from these therapies.

Discussion

Despite the numerous theoretical benefits that it holds, there iscurrently no straightforward evidence to support the routine clin-ical use of neoadjuvant therapy in resectable pancreatic cancer. Infact, several single arm studies have reported a median survivalranging from 8 to 23 months and 2-year OS rate from 27% to40%.12–17,22,36 These figures are of the same order of magnitudethan those achieved in modern series of patients undergoing sur-gery alone3,4 (median survival 18–20 months; 2-year OS 40–42%,)and appear worse than those observed in series of patients treatedwith single agent chemotherapy3,4,7,8 (median survival 21–25 months, 2 year OS 41–48%) or with combination chemother-apy37–39 (median survival 25.4–32.1 months; 2-year OS 59–62%)as adjuvant treatment. A recent systematic review and meta-analysis of 111 controlled trials confirmed that neoadjuvanttreatment does not seem to provide any benefit over the adjuvanttherapy in resectable pancreatic cancer.40 However, inter-trialcomparisons, which already have many serious limitations, in thisparticular case are also hampered by the fact that the typical pop-ulation enrolled in adjuvant trials is better selected than in neoad-juvant trials. For example, patients in which metastatic disease isdetected intraoperatively or at the time of post-surgical re-stagingor those who die perioperatively are enrolled in neoadjuvant trialsbut are not eligible for adjuvant trials. Similarly, patients who donot recover after surgery or who refuse postoperative treatmentare also excluded from adjuvant trials.

Apart from difficulties in the interpretation of trials results,hypothetical causes of disappointing results of the neoadjuvant ap-proach include methodological issues and strategy issues. Retro-spective series, single arm trials without a control or acalibration arm, randomized phase II trials with limited samplesize, the lack of a confirmed pathological diagnosis, the incompletedata reporting, different enrolment timings, divergent study designand entry criteria, and population heterogeneity do not allow toproperly explore the role of neoadjuvant therapy in resectable pan-creatic cancer.

To answer the question on the role of neoadjuvant therapy inresectable pancreatic cancer and to produce an evidence-basedrationale supporting the routine use of this strategy, there is noalternative to properly designed randomized trials. Patients should

table pancreatic cancer: A critical review. Cancer Treat Rev (2012), http://

6 C. Belli et al. / Cancer Treatment Reviews xxx (2012) xxx–xxx

be randomized to receive exactly the same treatment for the sameamount of time before and after surgery to avoid interpretativebias related to different treatment duration or treatment regimen.

From the therapeutic strategy point of view, the choice of localtherapy such as chemoradiation, or of chemotherapy regimenswhich achieve a low rate of tumor shrinkage against advanced dis-ease unlikely may have a remarkable impact against early micro-metastatic disease. In fact, single agent gemcitabine and 5FUobtained a very low objective response of around 10%41,42 whilechemotherapy combination yielded 9–28% of responses in ad-vanced disease.43–47

Interestingly, the response rate was increased by using morethan two chemotherapeutic agents in advanced pancreatic cancer:triplets including gemcitabine, a fluoropyrimidin and either aplatinating agent (18–41%)48–51 or docetaxel (29%),52 FOLFOXIRI(5-fluorouracil-oxaliplatin-irinotecan; 26–32%)53,54 and G-FLIP(gemcitabine-5FU-irinotecan-cisplatin; 26%)55 regimens showedpromising results in phase II series.

Similarly, four drug combinations, PEFG (cisplatin, epirubicin,5FU, gemcitabine)56–60 PEXG (cisplatin, epirubicin, capecitabine,gemcitabine) and PDXG (cisplatin, docetaxel, capecitabine, gemcit-abine) yielded a radiological response rate in the range of 38.5–51%. The reliability of the response rate was also supported by aconcordant biochemical response rate. In effect, a major biochem-ical response (i.e. CA19.9 reduction at nadir relative to baselinevalue reduction P90%) was observed in 30% of patients treatedwith quadruplets versus 7% with single agent gemcitabine.61 Thesuperiority of this four-drug combination over other regimenswas also suggested by a recent survey on treatment trends andoutcomes of 650 patients with stage III and on 943 patients withstage IV pancreatic adenocarcinoma.62,63 Based on these data andconsiderations, 3- or 4-drug regimens are suitable candidates anddeserve a prospective assessment in the neoadjuvant setting.

Conclusion

More than two decades of active research have not as yetdefined the role of neoadjuvant therapy in resectable pancreaticcancer. However, evidence collected so far depends on retrospec-tive data, small case series and approaches that did not balancethe different characteristics of patients suitable for surgery beforeor after neoadjuvant chemotherapy. Only the use of the mostactive combination chemotherapy regimens within a properlydesigned randomized controlled trial can properly address theissue of the benefits of the neoadjuvant strategy with respect tothe conventional adjuvant approach. A multicenter prospectiverandomized three arms phase II–III trial (NCT01150630) is cur-rently underway in Italy with the goal of defining the role of eitherperioperative or postoperative PEXG regimen as compared to adju-vant gemcitabine in the therapeutic management of patients withresectable pancreatic cancer.

Conflict of interest

There are not financial or commercial interests or relationshipsthat may pose conflict of interest.

Author contributions

Dr. Michele Reni conceived the paper, contributed to draftingthe article and critically reviewed the data and the final version.Dr. Stefano Cereda and Dr. Santosh Anand contributed to the anal-ysis and interpretation of data. Dr. Carmen Belli drafted the articleand revised it critically for important intellectual content. Allauthors approved the final version.

Please cite this article in press as: Belli C et al. Neoadjuvant therapy in resecdx.doi.org/10.1016/j.ctrv.2012.09.008

This article is dedicated to the memory of Steve Jobs whose lifewas unfortunately cut short by Pancreatic Cancer.

References

1. Neoptolemos JP, Stocken DD, Dunn JA, et al. Influence of resection margins onsurvival for patients with pancreatic cancer treated by adjuvantchemoradiation and/or chemotherapy in the ESPAC-1 randomized controlledtrial. Ann Surg 2001;234:758–68.

2. Li D, Xie K, Wolff R, Abbruzzese JL. Pancreatic cancer. Lancet 2004;363:1049–57.3. Ueno H, Kosuge T, Matsuyama Y, et al. A randomised phase III trial comparing

gemcitabine with surgery-only in patients with resected pancreatic cancer:Japanese Study Group of Adjuvant Therapy for Pancreatic Cancer. Br J Cancer2009;101:908–15.

4. Oettle H, Post S, Neuhaus P, et al. Adjuvant chemotherapy with gemcitabine vsobservation in patients undergoing curative-intent resection of pancreaticcancer: a randomized controlled trial. JAMA 2007;297:267–77.

5. Schnelldorfer T, Ware AL, Sarr MG, et al. Long-term survival afterpancreatoduodenectomy for pancreatic adenocarcinoma: is cure possible?Ann Surg 2008;247:456–62.

6. Neoptolemos JP, Stocken DD, Friess H, et al. A randomized trial ofchemoradiotherapy and chemotherapy after resection of pancreatic cancer. NEngl J Med 2004;350:1200–10.

7. Regine WF, Winter KA, Abrams RA, et al. Fluorouracil vs gemcitabinechemotherapy before and after fluorouracil-based chemoradiation followingresection of pancreatic adenocarcinoma: a randomized controlled trial. JAMA2008;299:1019–26.

8. Neoptolemos J, Stocken DD, Bassi C, et al. Adjuvant chemotherapy withfluorouracil plus folinic acid vs gemcitabine following pancreatic cancerresection: a randomized controlled trial. JAMA 2010;304:1073–81.

9. Kalser MH, Ellenberg SS. Pancreatic cancer. Adjuvant combined radiation andchemotherapy following curative resection. Arch Surg 1985;120:899–903.

10. Klinkenbijl JH, Jeekel J, Sahmoud T, et al. Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas andperiampullary region: phase III trial of the EORTC gastrointestinal tractcancer cooperative group. Ann Surg 1999;230:776–82. discussion 82–84.

11. Spitz FR, Abbruzzese JL, Lee JE, et al. Preoperative and postoperativechemoradiation strategies in patients treated with pancreaticoduodenectomyfor adenocarcinoma of the pancreas. J Clin Oncol 1997;15:928–37.

12. Palmer DH, Stocken DD, Hewitt H, et al. A randomized phase 2 trial ofneoadjuvant chemotherapy in resectable pancreatic cancer: gemcitabine aloneversus gemcitabine combined with cisplatin. Ann Surg Oncol 2007;14:2088–96.

13. Varadhachary GR, Wolff RA, Crane CH, et al. Preoperative gemcitabine andcisplatin followed by gemcitabine-based chemoradiation for resectableadenocarcinoma of the pancreatic head. J Clin Oncol 2008;26:3487–95.

14. Evans DB, Varadhachary GR, Crane CH, et al. Preoperative gemcitabine-basedchemoradiation for patients with resectable adenocarcinoma of the pancreatichead. J Clin Oncol 2008;26:3496–502.

15. Hoffman JP, Lipsitz S, Pisansky T, Weese JL, Solin L, Benson 3rd AB. Phase II trialof preoperative radiation therapy and chemotherapy for patients withlocalized, resectable adenocarcinoma of the pancreas: an Eastern CooperativeOncology Group Study. J Clin Oncol 1998;16:317–23.

16. White RR, Hurwitz HI, Morse MA, et al. Neoadjuvant chemoradiation forlocalized adenocarcinoma of the pancreas. Ann Surg Oncol 2001;8:758–65.

17. Moutardier V, Magnin V, Turrini O, et al. Assessment of pathologic responseafter preoperative chemoradiotherapy and surgery in pancreaticadenocarcinoma. Int J Radiat Oncol Biol Phys 2004;60:437–43.

18. Ishikawa O, Ohigashi H, Imaoka S, et al. Is the long-term survival rate improvedby preoperative irradiation prior to Whipple’s procedure for adenocarcinoma ofthe pancreatic head? Arch Surg 1994;129:1075–80.

19. Evans DB, Rich TA, Byrd DR, et al. Preoperative chemoradiation andpancreaticoduodenectomy for adenocarcinoma of the pancreas. Arch Surg1992;127:1335–9.

20. Pisters PW, Abbruzzese JL, Janjan NA, et al. Rapid-fractionation preoperativechemoradiation, pancreaticoduodenectomy, and intraoperative radiationtherapy for resectable pancreatic adenocarcinoma. J Clin Oncol 1998;16:3843–50.

21. Lawrence TS, Chang EY, Hahn TM, Hertel LW, Shewach DS. Radiosensitization ofpancreatic cancer cells by 20 ,20-difluoro-20-deoxycytidine. Int J Radiat Oncol BiolPhys 1996;34:867–72.

22. Pisters PW, Wolff RA, Janjan NA, et al. Preoperative paclitaxel and concurrentrapid-fractionation radiation for resectable pancreatic adenocarcinoma:toxicities, histologic response rates, and event-free outcome. J Clin Oncol2002;20:2537–44.

23. Calvo FA, Matute R, Garcia-Sabrido JL, et al. Neoadjuvant chemoradiation withtegafur in cancer of the pancreas: initial analysis of clinical tolerance andoutcome. Am J Clin Oncol 2004;27:343–9.

24. Hoffman JP, Weese JL, Solin LJ, et al. A pilot study of preoperativechemoradiation for patients with localized adenocarcinoma of the pancreas.Am J Surg 1995;169:71–7. discussion 7–8.

25. Moutardier V, Giovannini M, Lelong B, et al. A phase II single institutionalexperience with preoperative radiochemotherapy in pancreaticadenocarcinoma. Eur J Surg Oncol 2002;28:531–9.

table pancreatic cancer: A critical review. Cancer Treat Rev (2012), http://

C. Belli et al. / Cancer Treatment Reviews xxx (2012) xxx–xxx 7

26. Magnin V, Moutardier V, Giovannini MH, et al. Neoadjuvant preoperativechemoradiation in patients with pancreatic cancer. Int J Radiat Oncol Biol Phys2003;55:1300–4.

27. Turrini O, Viret F, Moureau-Zabotto L, et al. Neoadjuvant 5 fluorouracil-cisplatin chemoradiation effect on survival in patients with resectablepancreatic head adenocarcinoma: a ten-year single institution experience.Oncology 2009;76:413–9.

28. Mornex F, Girard N, Scoazec JY, et al. Feasibility of preoperative combinedradiation therapy and chemotherapy with 5-fluorouracil and cisplatin inpotentially resectable pancreatic adenocarcinoma: The French SFRO-FFCD 97–04 Phase II trial. Int J Radiat Oncol Biol Phys 2006;65:1471–8.

29. Heinrich S, Pestalozzi BC, Schafer M, et al. Prospective phase II trial ofneoadjuvant chemotherapy with gemcitabine and cisplatin for resectableadenocarcinoma of the pancreatic head. J Clin Oncol 2008;26:2526–31.

30. Philip PA, Zalupski MM, Vaitkevicius VK, et al. Phase II study of gemcitabine andcisplatin in the treatment of patients with advanced pancreatic carcinoma.Cancer 2001;92:569–77.

31. Talamonti MS, Small Jr W, Mulcahy MF, et al. A multi-institutional phase II trialof preoperative full-dose gemcitabine and concurrent radiation for patientswith potentially resectable pancreatic carcinoma. Ann Surg Oncol2006;13:150–8.

32. Moore MJ, Goldstein D, Hamm J, et al. Erlotinib plus gemcitabine comparedwith gemcitabine alone in patients with advanced pancreatic cancer: a phase IIItrial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol2007;25:1960–6.

33. Philip PA, Benedetti J, Corless CL, et al. Phase III study comparing gemcitabineplus cetuximab versus gemcitabine in patients with advanced pancreaticadenocarcinoma: Southwest Oncology Group-directed intergroup trial S0205. JClin Oncol 2010;28:3605–10.

34. Kindler HL, Ioka T, Richel DJ, et al. Axitinib plus gemcitabine versus placeboplus gemcitabine in patients with advanced pancreatic adenocarcinoma: adouble-blind randomised phase 3 study. Lancet Oncol 2011;12:256–62.

35. Kindler HL, Friberg G, Singh DA, et al. Phase II trial of bevacizumab plusgemcitabine in patients with advanced pancreatic cancer. J Clin Oncol2005;23:8033–40.

36. Yeung RS, Weese JL, Hoffman JP, et al. Neoadjuvant chemoradiation inpancreatic and duodenal carcinoma. A phase II Study. Cancer 1993;72:2124–33.

37. Reni M, Balzano G, Aprile G, et al. Adjuvant PEFG (Cisplatin, Epirubicin, 5-Fluorouracil, Gemcitabine) or gemcitabine followed by chemoradiation inpancreatic cancer: a randomized phase II trial. Ann Surg Oncol 2012;19:2256–63.

38. Picozzi VJ, Abrams RA, Decker PA, et al. Multicenter phase II trial of adjuvanttherapy for resected pancreatic cancer using cisplatin, 5-fluorouracil, andinterferon-alfa-2b-based chemoradiation: ACOSOG Trial Z05031. Ann Oncol2011;22:348–54.

39. Marten A, Schmidt J, Debus J, et al. CapRI: final results of the open-label,multicenter, randomized phase III trial of adjuvant chemoradiation plusinterferon-a2b (CRI) versus 5-FU alone for patients with resected pancreaticadenocarcinoma (PAC). J Clin Oncol 2010;28:18s (abstr LBA4012).

40. Gillen S, Schuster T, Meyer Zum Buschenfelde C, Friess H, Kleeff J. Preoperative/neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis of response and resection percentages. PLoS Med 2010;7:e1000267.

41. Burris 3rd HA, Moore MJ, Andersen J, et al. Improvements in survival andclinical benefit with gemcitabine as first-line therapy for patients withadvanced pancreas cancer: a randomized trial. J Clin Oncol 1997;15:2403–13.

42. Maisey N, Chau I, Cunningham D, et al. Multicenter randomized phase III trialcomparing protracted venous infusion (PVI) fluorouracil (5-FU) with PVI 5-FUplus mitomycin in inoperable pancreatic cancer. J Clin Oncol 2002;20:3130–6.

43. Colucci G, Giuliani F, Gebbia V, et al. Gemcitabine alone or with cisplatin for thetreatment of patients with locally advanced and/or metastatic pancreaticcarcinoma: a prospective, randomized phase III study of the Gruppo Oncologiadell’Italia Meridionale. Cancer 2002;94:902–10.

44. Louvet C, Labianca R, Hammel P, et al. Gemcitabine in combination withoxaliplatin compared with gemcitabine alone in locally advanced or metastatic

Please cite this article in press as: Belli C et al. Neoadjuvant therapy in resecdx.doi.org/10.1016/j.ctrv.2012.09.008

pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol2005;23:3509–16.

45. Heinemann V, Wilke H, Mergenthaler HG, et al. Gemcitabine and cisplatin inthe treatment of advanced or metastatic pancreatic cancer. Ann Oncol2000;11:1399–403.

46. Colucci G, Labianca R, Di Costanzo F, et al. Randomized phase III trial ofgemcitabine plus cisplatin compared with single-agent gemcitabine as first-line treatment of patients with advanced pancreatic cancer: the GIP-1 study. JClin Oncol 2010;28:1645–51.

47. Poplin E, Feng Y, Berlin J, et al. Phase III, randomized study of gemcitabine andoxaliplatin versus gemcitabine (fixed-dose rate infusion) compared withgemcitabine (30-minute infusion) in patients with pancreatic carcinomaE6201: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol2009;27:3778–85.

48. Correale P, Montagnani F, Miano S, et al. Biweekly triple combinationchemotherapy with gemcitabine, oxaliplatin, levofolinic acid and 5-fluorouracil (GOLF) is a safe and active treatment for patients withinoperable pancreatic cancer. J Chemother 2008;20:119–25.

49. Novarino A, Chiappino I, Bertelli GF, et al. Phase II study of cisplatin,gemcitabine and 5-fluorouracil in advanced pancreatic cancer. Ann Oncol2004;15:474–7.

50. Wagner AD, Buechner-Steudel P, Wein A, et al. Gemcitabine, oxaliplatin andweekly high-dose 5-FU as 24-h infusion in chemonaive patients with advancedor metastatic pancreatic adenocarcinoma: a multicenter phase II trial of theArbeitsgemeinschaft Internistische Onkologie (AIO). Ann Oncol 2007;18:82–7.

51. Hess V, Pratsch S, Potthast S, et al. Combining gemcitabine, oxaliplatin andcapecitabine (GEMOXEL) for patients with advanced pancreatic carcinoma(APC): a phase I/II trial. Ann Oncol 2010;21:2390–5.

52. Fine RL, Fogelman DR, Schreibman SM, et al. The gemcitabine, docetaxel, andcapecitabine (GTX) regimen for metastatic pancreatic cancer: a retrospectiveanalysis. Cancer Chemother Pharmacol 2008;61:167–75.

53. Conroy T, Paillot B, Francois E, et al. Irinotecan plus oxaliplatin and leucovorin-modulated fluorouracil in advanced pancreatic cancer–a Groupe TumeursDigestives of the Federation Nationale des Centres de Lutte Contre le Cancerstudy. J Clin Oncol 2005;23:1228–36.

54. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine formetastatic pancreatic cancer. N Engl J Med 2011;364:1817–25.

55. Goel A, Grossbard ML, Malamud S, et al. Pooled efficacy analysis from a phase I-II study of biweekly irinotecan in combination with gemcitabine, 5-fluorouracil, leucovorin and cisplatin in patients with metastatic pancreaticcancer. Anticancer Drugs 2007;18:263–71.

56. Reni M, Cordio S, Milandri C, et al. Gemcitabine versus cisplatin, epirubicin,fluorouracil, and gemcitabine in advanced pancreatic cancer: a randomisedcontrolled multicentre phase III trial. Lancet Oncol 2005;6:369–76.

57. Reni M, Passoni P, Panucci MG, et al. Definitive results of a phase II trial ofcisplatin, epirubicin, continuous-infusion fluorouracil, and gemcitabine in stageIV pancreatic adenocarcinoma. J Clin Oncol 2001;19:2679–86.

58. Reni M, Cereda S, Bonetto E, et al. Dose-intense PEFG (cisplatin, epirubicin, 5-fluorouracil, gemcitabine) in advanced pancreatic adenocarcinoma: a dose-finding study. Cancer Invest 2007;25:594–8.

59. Reni M, Cereda S, Bonetto E, et al. Dose-intense PEFG (cisplatin, epirubicin, 5-fluorouracil, gemcitabine) in advanced pancreatic adenocarcinoma. CancerChemother Pharmacol 2007;59:361–7.

60. Reni M, Cereda S, Rognone A, et al. A randomized phase II trial of two different4-drug combinations in advanced pancreatic adenocarcinoma: cisplatin,capecitabine, gemcitabine plus either epirubicin or docetaxel (PEXG or PDXGregimen). Cancer Chemother Pharmacol 2012;69:115–23.

61. Reni M, Cereda S, Balzano G, et al. Carbohydrate antigen 19–9 change duringchemotherapy for advanced pancreatic adenocarcinoma. Cancer 2009;115:2630–9.

62. Reni M, Sartori N, Mambrini A, et al. An Italian study on treatment trends andoutcomes of patients with stage III pancreatic adenocarcinoma in thegemcitabine era: is it time to change? Anticancer Drugs 2010;21:459–64.

63. Reni M, Pasetto LM, Passardi A, et al. Treatment trends in metastatic pancreaticcancer patients: is it time to change? Dig Liver Dis 2011;43:225–30.

table pancreatic cancer: A critical review. Cancer Treat Rev (2012), http://