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. 2015 Mar 13;4(8):1224–1239. doi: 10.1002/cam4.444

Multidisciplinary neoadjuvant management for potentially curable pancreatic cancer

Neelam V Desai 1, Sarunas Sliesoraitis 1, Steven J Hughes 2, Jose G Trevino 2, Robert A Zlotecki 3, Alison M Ivey 4, Thomas J George 1,✉
PMCID: PMC4559034  PMID: 25766842

Abstract

Pancreatic adenocarcinoma remains the fourth leading cause of cancer mortality in the U.S. Despite advances in surgical technique, radiotherapy technologies, and chemotherapeutics, the 5-year survival rate remains approximately 20% for the 15% of patients who are eligible for surgical resection. The majority of this group suffers metastatic recurrence. However, despite advances in therapies for patients with advanced pancreatic cancer, only surgery has consistently proven to improve long-term survival. Various combinations of chemotherapy, biologic-targeted therapy, and radiotherapy have been evaluated in different settings to improve outcomes. In this context, a neoadjuvant (preoperative) treatment strategy offers numerous potential benefits: (1) ensuring delivery of early, systemic therapy, (2) improving selection of patients for surgical therapy with truly localized disease, (3) potential downstaging of the neoplasm facilitating a negative margin resection in patients with locally advanced disease, and (4) providing a superior clinical trial mechanism capable of rapid assessment of the efficacy of novel therapeutics. This article reviews the recent trends in the management of pancreatic adenocarcinoma, with a particular emphasis on a multidisciplinary neoadjuvant approach to treatment.

Keywords: Chemotherapy, neoadjuvant, pancreatic cancer, personalized oncology, radiation, surgery

Background

Pancreatic adenocarcinoma is the fourth leading cause of cancer deaths in the United States 1. The annual incidence of pancreatic cancer is rising with approximately 46,420 new cases and nearly 39,590 patient deaths in 2014 2. Without any substantive improvement in curative therapies, it is anticipated to be the second leading cause of cancer deaths by 2030 3. Surgical resection is currently the only treatment option that offers the potential of long-term survival. However, only 20% of patients with pancreatic cancer are candidates for resection. Another 30–40% of patients have locally advanced or unresectable pancreatic cancer without measurable metastatic disease. For this group, chemotherapy with radiotherapy (chemoRT) was established as the standard of care over radiation or chemotherapy alone a few decades ago by the Gastrointestinal Tumor Study Group (GITSG) 4,5. For these patients, chemotherapy with radiation is palliative in nature with a median survival of 8–12 months and virtually no long-term survivors 6,7. Of the patients that present with resectable disease, surgical resection provides a 5-year survival of approximately 20%. This article focuses on the recent advances made in combined modality treatment of early stage resectable and borderline-resectable pancreatic adenocarcinoma with the goal of making a compelling case for a multidisciplinary, collaborative, and neoadjuvant approach for optimal outcomes. This strategy also facilitates an ideal clinical research platform capable of rapidly assessing the efficacy of novel therapeutic agents.

Role of Adjuvant Therapy in Pancreatic Cancer

Despite improvements in surgical techniques that allow more patients to undergo successful R0 resection, the prognosis even for small tumors without nodal involvement remains poor due to progressive systemic disease. In an effort to improve long-term survival after surgical resection, adjuvant therapy has been studied in various combinations. In 1985, the GITSG conducted a trial that was one of the first to show the benefit of adjuvant therapy by demonstrating that 5-Fluorouracil (5-FU) combined with radiotherapy (RT) after surgical resection led to improved survival compared to observation (2-year survival 42% vs. 15%; P = 0.03) 8. The EORTC 40891 trial similarly compared 5-FU-based chemoRT to observation after surgical resection of pancreatic and periampullary adenocarcinoma with median overall survival (OS) of 24.5 versus 19 months (P = 0.21) 9. One of the major criticisms of the latter study was that it included periampullary adenocarcinomas, which have a better prognosis compared to pancreatic ductal adenocarcinomas. The rationale for adjuvant chemoRT was established with these early studies.

The role of adjuvant chemoRT was subsequently called into question in the European ESPAC-1 trial 10. Following surgical resection, patients were randomized to either receive 5-FU-based chemotherapy, 5-FU-based chemoRT, both or no treatment following surgical resection. Results were analyzed (in a two-by-two factorial design) based on groups having received chemotherapy or not and those having received chemoRT or not. Median OS in the chemotherapy group was 20.1 versus 15.5 months in the no chemotherapy group (P = 0.009). However, in the chemoRT analysis, the median OS was worse at 15.9 months compared to 17.9 months in patients who did not receive chemoRT (P = 0.05). This controversial trial is criticized for the lack of radiation quality control, use of outdated radiotherapy delivery techniques, no central review of radiographic response and poor compliance to subscribed treatment. Such limitations confound the ability to accurately and conclusively interpret the results. Nevertheless, the utilization of adjuvant chemoRT remains common in the United States with the benefit of this approach continuing to be actively investigated.

Subsequent European adjuvant clinical trials focused on the relative value of adjuvant chemotherapy rather than chemoRT. In the CONKO-1 trial, patients with resected pancreatic cancer were randomly assigned to either receive six cycles of gemcitabine or observation 11. The use of adjuvant gemcitabine resulted in significant gains in disease-free survival (DFS) from 6.7 to 13.4 months (P < 0.001) and a significant, albeit small, improvement in OS from 20.2 to 22.8 months (P = 0.01). Following this trial, the ESPAC-3 study compared adjuvant gemcitabine to 5-FU-based chemotherapy for 6 months 12. Median OS was not statistically different between the two treatment groups (23.6 vs. 23 months; P = NS). The overall rates of serious adverse events were significant reduced in the gemcitabine group (7.5%) compared to 5-FU-based treatment (7.5% vs. 14%; P < 0.001), with the toxicity profile also favoring gemcitabine with less stomatitis and diarrhea but more myelosuppression.

In the United States, the incorporation of adjuvant chemoRT continues to be investigated with trials designed to determine the optimal chemotherapy agents and sequencing for use in combination with radiotherapy. The RTOG 97-04 trial compared gemcitabine to 5-FU in a sequential combination of systemic chemotherapy (gemcitabine vs. 5-FU) for 3 weeks followed by 5-FU-based chemoRT and then 3 months of chemotherapy with the same previously used agent. Median OS was 20.5 months for gemcitabine versus 16.9 months for 5-FU (P = 0.09) 13. The above trials suggest that whether combined with radiation or not, gemcitabine may be a preferred agent in the adjuvant setting given a better side-effect profile; whereas 5-FU remains the next best option.

Adjuvant Versus Neoadjuvant Debate

Despite the noted improvements in survival with the addition of adjuvant therapy, the 5-year OS still averages 20% in patients who undergo curative treatment, leaving significant opportunities for improvement. This has led to an increasing interest to incorporate chemotherapy and/or radiation therapy into the neoadjuvant setting. Neoadjuvant treatment may have several advantages over adjuvant therapy (Table1). First, as the vast majority of patients who undergo complete surgical resection still succumb to distant relapse, delivery of systemic treatment earlier in the disease course; particularly, when the anatomy and vasculature have not yet been disrupted by surgery, might lead to improved treatment effect. Second, almost 30–40% of postoperative patients do not receive any adjuvant therapy either secondary to surgical complications and delayed recovery or patient refusal 14. Third, tumor downstaging resulting from effective neoadjuvant treatment could lead to more effective R0 (complete) resections, which has been shown to be a predictor of survival 15. However, tumor downstaging requires accurate confirmation of the clinical stage prior to initiation of therapy, which is limited by the accuracy of current imaging modalities. Finally, the neoadjuvant platform is perhaps the most efficient in vivo model to test novel therapies as the treatment period is finite and pre/posttreatment tissue collection allows for a variety of molecular analyses to gain further insight into tumor biology and mechanisms of resistance. Opponents of neoadjuvant treatment voice concerns that the use of preoperative therapy can lead to a missed window of opportunity for surgical resection, which is the only potentially curative treatment. Such missed opportunities can result from progression of disease (typically distant metastases) or a decline in performance status from treatment toxicities or cancer cachexia. However, the issue of disease progression can also be seen as a paradoxical benefit given the morbidity of a major operative procedure such as pancreaticoduodenectomy in a patient with a biologically aggressive disease that might have likely relapsed soon after surgery. However, delaying surgical resection due to performance status decline from treatment side effects remains a legitimate concern. While no phase III trials exist, several retrospective series, prospective phase II, and systematic reviews have been published which provide some data with regards to neoadjuvant therapy outcomes.

Table 1.

Potential advantages and disadvantages of neoadjuvant treatment in pancreatic adenocarcinoma

Neoadjuvant treatment
Advantages Disadvantages
Intact tumor vasculature not disrupted by surgery Progression of disease during neoadjuvant treatment leading to missed window of opportunity for resection
Early treatment of micrometastatic disease Toxicity from neoadjuvant treatment precluding definitive surgical resection
Ensures delivery of systemic treatment Need tissue confirmation of neoplastic process
Improved RO resection rate; especially in borderline-resectable cases
Ideal in vivo platform for research
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Neoadjuvant Treatment of Pancreatic Cancer

The concept of incorporating neoadjuvant therapy into pancreatic cancer management started soon after early studies demonstrated a benefit of adjuvant treatment as compared to surgery alone. As early as 1980, Pipelich et al. showed that preoperative radiotherapy was not only feasible but allowed for downstaging of primary tumors and thus successful surgical resection 16. Since then, various combinations of chemotherapy, chemoRT or induction chemotherapy followed by chemoRT have been studied in relatively small phase I–II trials.

Early studies focused on 5-FU-based treatment combinations. The combination of 5-FU and mitomycin C (MMC) with external beam radiotherapy (EBRT) was particularly popular at that time. This was in part related to the widespread availability of the agents and their well-established role as potent radiosensitizers. Most of these trials consistently showed superior survival with the use of neoadjuvant treatment in resected patients as compared to historical controls who only received surgical resection. However, the direct impact of this treatment modality on resection rates is difficult to quantify for several reasons. First, the preoperative imaging quality during that time was limited in determining resectability. Second, even in cases where resectability status was based on laparotomy, there was institutional and surgeon variability with regards to expertise and definitions of resectability. While most of these studies demonstrated safety and feasibility, some showed survival comparable to that of studies involving adjuvant therapy. One such study by Hoffman et al. in 1995 included patients with both unresectable and resectable pancreatic cancers of adenocarcinoma and adenosquamous histology 17. Patients received preoperative 5-FU plus MMC with concurrent radiotherapy. The resection rate for all patients was 32% with resected patients having a reported median survival of 45 months; which is almost twice as long as reported in other studies. Promising as these results appear, it is hard to apply data from such small, single arm, single institution studies due to inherent selection bias and the heterogeneity of the study population.

In the decade following, gemcitabine-based neoadjuvant combinations gained popularity due to the positive findings reported by Burris and colleagues in the metastatic setting with regards to clinical benefit as well as a modest survival advantage 18. As a result of that latter study, gemcitabine received FDA approval and has become an established standard of care in advanced disease and in the adjuvant setting. The most frequently used neoadjuvant combinations were gemcitabine with or without an additional agent (including radiotherapy in some studies). The resection rate was noted to be variable depending on the initial resectability status of the patients enrolled. In the earlier trials, the overall resection rate after neoadjuvant therapy for patients who were deemed to have resectable disease upfront ranged from 50% to 70%. For those patients judged to be unresectable at the time of enrollment, the overall resection rate after neoadjuvant treatment ranged from 5% to 30%. More recent trials have shown an improved trend in both resection rates and survival for patients resected after preoperative treatment. In the modern era of studies, patients initially deemed resectable have resection rates in the 60–80% range with OS improving from 20 to 30 months for those patients receiving preoperative therapy. However, most of these studies were single institution or retrospective in design.

In an initial phase II trial from MD Anderson Cancer Center, 86 patients with resectable, histologically proven adenocarcinomas of pancreatic head or uncinate process were treated with neoadjuvant therapy 19. These patients underwent preoperative treatment with gemcitabine weekly for 7 weeks along with 30 Gy of EBRT over 2 weeks. The overall resection rate was 74%, (57/64 patients had R0 resections) with median survival of those patients undergoing resection noted to be 34 months. However, the majority of cases that relapsed did so with distant metastases. Therefore, in an attempt to improve the OS, Varadhachary and colleagues incorporated more systemic therapy by adding induction chemotherapy with gemcitabine plus cisplatin for four doses followed by chemoRT using gemcitabine weekly with 30 Gy EBRT 20. Of the 90 patients enrolled, 79 were able to complete neoadjuvant treatment. The overall resection rate for these 79 patients was 66% (51/52 patients had R0 resections) with median OS for those resected being 31 months. Memorial Sloan-Kettering Cancer Center treated 38 patients with gemcitabine with oxaliplatin for four cycles neoadjuvantly 21. Thirty-five patients (92%) completed neoadjuvant chemotherapy; 27 were ultimately resected (72%) and 23 (60.5%) were able to complete all planned treatments including additional adjuvant chemotherapy. Median OS was 27.2 months suggesting improvement in ability to complete the delivery of multimodality therapy. Additional prospective and retrospective neoadjuvant trials are summarized in Table2.

Table 2.

Neoadjuvant therapy trials in pancreatic adenocarcinoma

Author/year Location Resectability (n) Neoadjuvant therapy Resection rate Median OS unresected Median OS resected
Prospective studies
 Weese JL 1990 33 Head (14), Body (1) R = 15 5-FU + Mitomycin-C + EBRT ORR = 60% 7 month NR
R0 = 60%
 Coia LR 1994 34 Pancreatic head/body (27) Duodenum (4) R = 10 5-FU + Mitomycin-C + EBRT ORR = 55% (48% panc) R0 = 49% Pancreatic cancer only 15% 1-year Pancreatic cancer only 60% 1-year
UR = 21 (all panc)
 Hoffman JP 1995 17 Head/body/tail adenosquamous included R = 21 5-FU + Mitomycin-C + EBRT ORR = 32% NS 45 month
UR = 13 R0 = 29%
 Kamthan AG 1997 35 Head/body/tail UR = 35 5-FU + Streptozocin + Cisplatin + EBRT → 5FU/leucovorin ORR = 15% All patients = 15 month 31 month
R0 = NS
 Hoffman JP 1998 36 Head/body/tail R = 53 5-FU + Mitomycin-C + EBRT ORR – 45% No surg – 5 month, Surg and no resection – 8 month 15 month
R0 – 32%
 Staley CA 1996 37 Head R = 39 5-FU + EBRT ORR = 100% NA 19 month
R0 = 82%
 Pisters PW 1998 38 Head R = 35 5-FU + rapid fractionation EBRT. Additional intraop RT only if PD ORR = 57% 7 month 25 month
R0 = 51%
 Bajetta E 1999 39 Head/body/tail UR = 32 5-deoxyfluridine/leucovorin + EBRT ORR = 16% All patients = 9 month NS
R0 = 16%
 Snady H 2000 40 Head/body/tail UR = 68 5-FU + Streptozocin + Cisplatin + EBRT ORR = 29% 21 month 32 month
R0 = 28%
 Wanebo HJ 2000 41 Head/body R = 5 5FU + Cisplatin + EBRT ORR = 64% 9 month 19 month
UR = 6 R0 = 64%
Unk = 3
 Pipas JM 2001 42 Head/body/tail UR = 21 Gemcitabine + EBRT (Phase I study) ORR = 24% NS NS
R0 = 24%
 Wolff RA 2001 43 Head UR = 18 Gemcitabine + EBRT (Phase I study) ORR = 5% All patients = 6 month NS
R0 = 5%
 De Lange SM 2002 44 Head/body/tail UR = 24 Gemcitabine + EBRT → Gemcitabine ORR = 4% All patients = 10 month NS
R0 = 4%
 Epelbaum R 2002 45 Head/body/tail UR = 20 Gemcitabine → Gemcitabine + EBRT ORR = 15% All patients = 8 month 24 month
R0 = 10%
 Pisters PW 2002 46 Head/uncinate process R = 35 Paclitaxel + EBRT Additional intraop RT only if PD ORR = 57% All patients = 12 month 19 month
R0 = 40%
 Al-Sukhun S 2003 47 Head/body/tail UR = 20 Cisplatin + 5-FU + Cytarabine → Caffeine → 5-FU + EBRT ORR = 15% All patients = 13 month 24 month
R0 = NS
R1 = NS
 Brunner TB 2003 48 Head/body/tail UR = 30 Cisplatin + Gemcitabine + EBRT ORR = 31% 11 month 18 month
R0 = 28%
 Joensuu 2004 49 Head/body/tail R = 28 Gemcitabine + EBRT ORR = 71% NS NS
R0 = 71%
 Moutardier V 2004 50 Head/body R = 61 5-FU + Cisplatin + EBRT ORR = 65% All patients = 13 month 26.6 month
R0 = 60% UR = 8.6 month
 Magnino A 2005 51 Head/body/tail UR = 23 Gemcitabine + EBRT ORR = 26% All patients = 14 month 20 month
R0 = 22% UR = 12 month
 Pipas JM 2005 52 Head/body R = 4 Docetaxel + Gemcitabine → Gemcitabine + EBRT ORR = 71% All patients = 14 month NS
BR = 7 R0 = 54%
UR = 13
 Mornex F 2006 53 Head/body/tail R = 41 5-FU + Cisplatin + EBRT ORR = 63% All patients = 9.4 month 11.7 month
R0 = 51%
 Talamonti MS 2006 54 Head/body/tail R = 20 Gemcitabine → Gemcitabine + EBRT ORR = 85% All patients = 18 month 26 month
R0 = 80%
 Wilkowski R 2006 55 Head/body/tail UR = 32 Gemcitabine + 5-FU + EBRT → Gemcitabine + Cisplatin ORR = 18% All patients = 13.6 month 16.4 month
R0 = 12%
 Desai SP 2007 56 Head/body/tail/mets R = 12 Gemcitabine + Oxaliplatin + EBRT ORR = 16% UR/metastatic = 9.1 month 20.8 month
UR = 29 R0 = 16%
*metastatic = 3
 Palmer DH 2007 57 Head of pancreas by radiology R = 50 Randomized phase II study: (A)Gemcitabine (N = 24) (B)Gemcitabine + Cisplatin (N = 26) ORR = 38% in A and 70% in BR0 = 75% in both All patients (A) = 9.9 month, (B) = 15.6 month 28.4 month
Sp resection 3 pts had malignancy other than pancreatic adenoca
 Evans DB 2008 19 Head/uncinate process R = 86 Gemcitabine + EBRT ORR = 74% All patients = 22.7 month 34 month
R0 = 66% UR = 7 month
 Heinrich S 2008 58 Head R = 28 Gemcitabine + Cisplatin ORR = 86% NS 26.5 month
R0/R1 = NS
 Le Scodan 2008 59 Head/body/tail R = 41 5-FU + Cisplatin + EBRT ORR = 63% All patients = 9.4 month 11.7 month
R0 = 51%
 Marti JL 2008 60 Head/body/tail UR = 23 Gemcitabine + Cisplatin (n = 26) → Gemcitabine + Cisplatin + EBRT (n = 18) ORR = 15% All patients = 13 month 17 month
BR = 3 R0 = 12%
 Small W 2008 61 Head/body/tail R = 16 Gemcitabine + EBRT ORR = 81% for R, 33% for BR, 7% for UR All patients 1-year 73% NS
BR = 9
UR = 14
 Varadhachary GR 2008 20 Head/uncinate R = 90 Gemcitabine + Cisplatin → Gemcitabine + EBRT ORR = 58% All patients 17.4 month, UR 10 month 31 month
R0 = 56%
 Bjerregaard JK 2009 62 Head/body/tail UR = 63 UFT + folinic acid + EBRT ORR = 17% 8.8 month 46 month
R0 = 17%
 Choi M 2010 63 Head/body/tail UR = 20 Cisplatin + Cytarabine + Caffeine + 5-FU → 5-FU + EBRT ORR = 15% All patients = 13.7 month 24.3 month
R0 = NS
 Laurent S 2009 64 Head/body/tail *also had biliary cancer but outcomes separated UR = 17 Gemcitabine + Oxaliplatin → Gemcitabine + Oxaliplatin + EBRT ORR = 17% All patients = 17 month NS
R0 = 17%
 Maximous DW 2009 65 Head/body/tail R = 25 Gemcitabine + EBRT ORR = 32% All patients = 12 month 1-year = 87%
R0 = NS Unresected 1-year = 22%
 Turrini O 2010 66 Head/body/tail R = 34 Docetaxel + EBRT ORR = 50% All patients = 15.5 month, unresected 11 month 32 month
R0 = 50%
 Landry J 2010 67 Head/body/tail R = 10 Randomized phase II: [A] Gemcitabine + EBRT (n = 10) [B] Gemcitabine + Cisplatin + 5-FU → 5-FU + EBRT (n = 11). ORR, A = 30%, B = 18% All patients, arm A = 19.4 month, arm B = 14.2 month 22 month in both A and B
4 with “other” histology UR = 8
? = 3
All patients got adjuvant Gemcitabine
 Sahora K 2010 68 Head/body/tail UR = 18 Gemcitabine + Oxaliplatin ORR = 39% 12 month 22 month
BR = 15 R0 = 27%
R1 = 9%
Lee JL 2012 69 Head/body/tail BR = 18 Dose Dense Gemcitabine + Capecitabine PR = 18.6% 13.1 month 23.1 month
UR = 25 SD = 69.8%
R0 = 82% out of 17 resected
R1 = 18%
 Pipas JM 2012 70 Head/body/tail R = 4 Cetuximab load then ORR = 91% (PR = 30%) 10 month 24.3 month
BR = 23 Cetuximab + Gemcitabine + EBRT
UR = 6 R0 = 92% out of 70% resected
 Satoi S 2012 71 Head/body/tail R = 23 S1 + EBRT ORR = 88% (PR = 18%) NS NS
BR/UR = 7 R0 = 93%
 Chao YJ 2014 72 Head/body/tail UR=41 Gemcitabine+5FU+Oxaliplatin+Thalidomide or Gemcitabine+5FU+Oxaliplatin+Sunitinib or Gemcitabine-based Chemoradiation RR=51.2% (CR=5%, PR=46%)R0 = 31%, R1 = 5%, R2 = 2% 9 month 21 month
 Golcher H 2014 73 Head R = 73 Primary surgery or Gemcitabine + Cisplatin + EBRT 4 PR, 8 SD in treatment group NR 18.9 versus 25 month
R0 = 48 and 52%
 O’Reilly EM 2014 21 Head/body/tail R = 38 Gemcitabine + Oxaliplatin PR = 10.5% 27.2 month (all) NS
SD = 73.7%
R0/R1 = 77%
Retrospective studies
 White RR 2001 74 Pancreatic head/body/tail R = 53, 5-FU-based chemotherapy + EBRT 53% in R group, 19% in BR or UR NS Actuarial 2 year OS 32%
BR or UR = 58 [5FU alone (n = 71), w mitomycin (n = 17), with cisplatin (n = 4), combination of 5Fu/mito/cis (n = 13), oral 5FU (n = 6)]
 Aristu J 2003 75 head/body/tail, UR = 49 Chemotherapy + EBRT (one of 3 chemo): ORR = 19% 10 month 22 month
Cisplatin + 5FU
Cisplatin + 5FU +/− Paclitaxel
Gemcitabine + Docetaxel.
(23 UR pts got additional EBRT)
 Calvo FA 2004 76 Head/body R = 15 Tegafur + EBRT ORR = 60% 8 month (UR) 17 month (all) 23 month
R0 = 46% overall
 Sa Cunha 2005 77 Head/body/tail UR = 61 5-FU + Cisplatin + EBRT ORR = 21% 11 month (nonresponders) 28 month
 Brown KM 2008 78 Head/body/tail BR = 13 Chemo + EBRT (chemo): ORR-100% NS NS
5FU (n = 3), Gemcitabine (n = 9), Capecitabine + Bevacizumab (n = 1) R0 = 85%
 Allendorf JD 2008 79 Head/body/tail UR = 78 (preop CRT) versus R = 167 (upfront resection) Gem + Taxotere + Xeloda (81% of pts) ORR = 76% 16.6 month upfront resection 17.7 month resected sp CRT
75% pts also got EBRT R0 = 84.7% of resected
 Golcher H 2008 80 Head/body UR = 121 (preop CRT) (5FU + Mitomycin) or (Gemcitabine + Cisplatin) + EBRT ORR = 17% 21 month upfront resection 54 month resected sp CRT
versus R = 58 (upfront resection) R0 = 90% of 17%
 Turrini O 2009 81 Head BR = 49, UR = 15 5-FU + Cisplatin + EBRT ORR = 14% 13 month (UR), 14 month (all) 24 month
 Stokes JB 2011 82 Head/body/tail BR = 34 Capecitabine + EBRT ORR = 46% NS 23 month
R0 = 75% of 46%
 Patel M 2011 83 Head/body/tail BR = 17 Gemcitabine + Taxotere + Capecitabine → 5-FU + IMRT ORR = 53% 15.6 month (all) NS
R0 = 89% of 53%
 Arvold ND 2012 22 Head/body/tail BR = 24 5FU or Capecitabine + EBRT PR = 30% 13.2 mo 19.4 month
UR = 46 R0 = 79% of 20%
 Sho M 2012 84 NR R = 61 Gemcitabine + EBRT R0 92% versus 52% controls 28 month (neoadjuvant) NS
BR = 71
 Strobel O 2012 23 Head/body/tail R = 120 (5FU, Gemcitabine, or Cetuximab-based) Chemoradiation or Chemotherapy R0 35%, R1 50.8%, R2 13.3% of 46.7% resected 9 month 13 month
UR = 137
 Boone BA 2013 25 Head/body/tail BR = 12 FOLFIRINOX + EBRT R0 = 33% NS NS
UR = 13
 Faris JE 2013 26 Head/uncinated/tail UR = 22 FOLFIRINOX +/− 5FU or Capecitabine + EBRT PR = 27.3% NS NS
SD = 72.7%
R0 = 23%
 Papavasiliou P 2014 24 Head/uncinate NS Gemcitabine or 5FU + EBRT RR = NS 22 month (all) NS
R0 = 68.5%, R1 = 30.6%, R2 = 0.9%
 Rose JB 2014 32 Head/body/tail BR = 64 Gemcitabine + Docetaxel R0 = 87% of 61% 15.4 month NR
23.6 month (all)
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R, resectable; BR, borderline resectable; UR, unresectable; UNK, unknown; ORR, overall resection rate; R0, complete microscopically negative; R1, positive margin; PD, pancreaticoduodenectomy; EBRT, external beam radiotherapy; OS, overall survival; NS, not specified; NR, not reached; NA, not applicable; 5-FU, 5-Fluorouracil; FOLFIRINOX, Folinic acid, 5-Fluorouracil, Irinotecan, Oxaliplatin; C, cycle; →, followed by.

Given the risk of incomplete resection, neoadjuvant chemotherapy may similarly improve outcomes in borderline-resectable pancreatic cancer. In a retrospective report from Massachusetts General Hospital, 46 patients with unresectable and 24 patients with borderline-resectable disease were treated with neoadjuvant fluoropyrimidine-based chemoRT. Approximately 30 of these patients additionally received gemcitabine-based chemotherapy sequenced before the chemoRT. Compared with chemoRT alone, the use of neoadjuvant chemotherapy before chemoRT achieved improved median overall (18.7 vs. 12.4 months; P = 0.02) and progression-free survival (11.4 vs. 6.7 months; P = 0.02) 22.

The development of novel targeted or more contemporary cytotoxic therapeutics in metastatic pancreatic cancer was also investigated in the neoadjuvant setting. In a retrospective large single center study by Strobel and colleagues, 257 patients received neoadjuvant chemotherapy or chemoradiation 23. Only 120 (46.7%) underwent successful resection. Median postoperative survival was highest at R0 resected patients (24.6 months) compared to R1 (11.9 months) and R2 (8.9 months) demonstrating that margin status at surgery is still a major determinant of outcome, even with contemporary neoadjuvant therapy. The incorporation of FOLFIRINOX chemotherapy in the neoadjuvant setting has been explored in relatively small pilot studies. Boone and colleagues at the University of Pittsburgh treated 21 unresectable and borderline-resectable patients with this regimen. Two patients (9%) could not tolerate treatment and another three (14%) had disease progression. Overall, seven patients ultimately underwent resection of which 2 (10%) were initially unresectable and were felt to have been converted. Five (24%) of the treated and resected patients had significant histopathological response 24. Massachusetts General investigators treated 22 locally advanced pancreatic cancer patients in this manner with five of 22 patients achieving R0 resections after completing FOLFIRINOX, 5FU-based chemoradiation and surgical resection. However, three had distant recurrence and toxicity was significant with this approach 25.

While it is clear from the published studies that neoadjuvant therapy for pancreatic cancer appears feasible, the demonstrated benefits have been inconsistent. One of the primary limitations of these studies has been the use of historical controls as a comparison group. Over the intervening years, imaging technology has become increasingly accurate in delineating vessel involvement by pancreatic cancer, which is a major barrier to successful surgical resection. Indeed, such stage migration will, by definition, improve the apparent survival of patients newly diagnosed with both resectable as well as locally advanced pancreatic cancer. Similarly, advances in surgical techniques with more sophisticated vascular reconstruction capabilities, have also impacted the ability to obtain complete resections. However, it is not clear if complete resection in these borderline or previously unresectable patients with the use of modern vascular reconstruction techniques affords a similar long-term benefit as a complete resection in an initially clearly resectable patient. Another limitation includes an evolving definition of resectable disease. Surgical perspective by the treating physician adds a nongeneralizable bias to patient selection in regards to generating a homogenous treatment group as well as appropriate control matching. Only recently has a consistent definition been applied to studies, thus allowing cross-study comparisons. The summary data of neoadjuvant treatments (Table2) inventories the outcomes of patients organized by resectable, borderline resectable, and unresectable disease.

Further confounding the response of neoadjuvant treatment was a publication by the MD Anderson group. These authors reported that routine imaging does not reflect anatomic-pathologic changes associated with the effectiveness of neoadjuvant therapy 26. This retrospective study reviewed 122 patients with borderline-resectable pancreatic adenocarcinoma who had restaging of their disease after neoadjuvant treatment. Even though only 12% of patients met the RECIST imaging criteria for a partial response and only one patient (0.8%) was officially downstaged to resectable, (69% had stable disease and 19% had progressive disease), 66% of the patients were able to undergo pancreaticoduodenectomy. Median OS for patients who underwent surgery was 33 versus 12 months for those who did not.

In an attempt to determine aggregate outcome measures; Gillen et al. performed a systematic review on neoadjuvant therapy trials in pancreatic cancer 27. This meta-analysis looked at more than 100 neoadjuvant trials published since 1980, despite the heterogeneity of patients enrolled and regimens used. Of those patients considered resectable at diagnosis, approximately 74% went on to have surgical resection after neoadjuvant treatment with an R0 resection rate of 82%. Median survival in this group was 23.3 months (range 12–54 months) with 2-year survival of 47%. These survival results are comparable to patients who had initial surgery first followed by adjuvant therapy. Among the patients that were deemed to be initially unresectable, the overall resection rate after neoadjuvant treatment was 33% with R0 resection rate of 79%. The median OS was 20.5 months (range 9–62 months) with a 2-year survival of 50% for this group. Median survival, however, was only 10.2 months for those patients whose disease remained unresectable despite neoadjuvant treatment, which is similar to patients who were treated with palliative intentions (median survival 8–12 months). Despite the data, no standard regimen or sequence of treatment could be conclusively determined.

Further adding to the published data on this topic, Artinyan and colleagues conducted a population-based cohort series 28. Using the California Cancer Surveillance Program, 458 patients with pancreatic adenocarcinoma who underwent surgical resection and received systemic chemotherapy between 1987 and 2006 were retrospectively analyzed. Neoadjuvant treatment was delivered in about 9% of the patients and adjuvant treatment given in 91% cases. Patient characteristics such as age, gender, and tumor size were similar between the two groups; however, data on performance status or co-morbidities were not reported. There was a significantly lower rate of positive pathologic lymph nodes in the neoadjuvant group (45% vs. 65%) despite a higher rate of extra-pancreatic tumor extension. The neoadjuvant group also had significantly better OS compared with the adjuvant group (median survival, 34 vs. 19 months). While there are obvious limitations of a population-based cohort study, it is clear that only a small percentage of patients in that clinical practice environment received neoadjuvant treatment. Thus, such patients are likely highly selected individuals.

Nonetheless, this summative data combined with the systematic review and meta-analyses suggest that neoadjuvant therapy can be conducted safely in select patients and may possibly benefit a subset of those with resectable and borderline-resectable disease. By introducing early systemic treatment to combat distant relapses coupled with avoidance of a radical surgical resection in patients whose disease is biologically aggressive, neoadjuvant treatment offers many advantages. However, the magnitude of the impact has yet to be demonstrated or validated in a randomized controlled trial.

Final Thoughts

Despite the opportunity to improve survival by incorporating systemic treatment in the neoadjuvant setting and better selection of patients with truly localized cancer, survival in this dreaded disease still remains modest. The key to significantly impacting survival, short of prevention, would be the identification of therapeutic interventions tailored to the patient, which can overcome the inherent resistance mechanisms evoked by the cancer. To achieve this goal of appropriate patient selection based on patient and disease characteristics and to optimize their chance of receiving the optimal medical, radiation and surgical treatment, a multidisciplinary, collaborative approach to the care of each and every patient with pancreatic adenocarcinoma is imperative. Despite all the strides in various oncologic disciplines the ability to offer a cure to most patients remains unachievable. Perhaps the best case for neoadjuvant multidisciplinary approach is to rapidly test novel hypotheses and the effects of various treatments on the tumor and the surrounding microenvironment. A neoadjuvant platform could gain insights into the tumor biology, which may ultimately hold the key to achieving cure for most, if not all patients afflicted with this deadly disease. However, this requires adequate tissue acquisition of the tumor tissue to confirm the initial diagnosis. Increased cytologic yield through endoscopically obtained core biopsies or circulating tumor cells will be required in the future to fully realize the molecular characterization and personalized therapeutics potential.

The less than ideal response to cytotoxic and targeted therapies is evident in the abundant trials in the metastatic setting that have consistently failed to demonstrate a statistically significant or clinically meaningful advantage over single agent gemcitabine (Table3). Only recently have FOLFIRINOX and gemcitabine with nab-paclitaxel raised the bar 29–31. While the use of two or three cytotoxic drugs showed significant survival advantage over gemcitabine alone (median OS 11.1 vs. 6.8 months; P < 0.001) in patients with metastatic disease, toxicities limit use to select patients with excellent performance status and no major comorbidities.

Table 3.

Outcomes of selected randomized controlled clinical trials in metastatic pancreatic adenocarcinoma

Reference Treatment Total N Median survival (month) P-value
Bramhall SR, BJC 2002 85 Gemcitabine +/− Marimastat 239 5.4 versus 5.5 0.95
Berlin JD, JCO 2002 86 Gemcitabine +/− 5-FU 322 5.7 versus 6.5 0.09
Colucci G, Cancer 2002 87 Gem versus Gem + Cisplatin 107 5 versus 7.5 0.43
Rocha Lima CM, JCO 2004 88 Gemcitabine +/− Irinotecan 342 6.3 versus 6.6 0.78
Van Custem E, JCO 2004 89 Gemcitabine +/− Tipifarnib 688 6.1 versus 6.4 0.75
Louvet C, JCO 2005 90 Gemcitabine +/− Oxaliplatin 313 7.1 versus 9 0.13
Oettle H, Ann Oncol 2005 91 Gemcitabine +/− Premetexed 565 6.3 versus 6.2 0.84
Abou-Alfa GK, JCO 2006 92 Gemcitabine +/− Exatecan 349 6.2 versus 6.7 0.52
Heinemann V, JCO 2006 93 Gem versus Gem+Cisplatin 195 6 versus 7 0.15
Stathopoulous GP, BJC 2006 94 Gemcitabine +/− Irinotecan 145 6.4 versus 6.5 0.97
Herrmann R, JCO 2007 95 Gemcitabine +/− Capecitabine 319 7.2 versus 8.4 0.23
Moore MJ, JCO 2007 96 Gemcitabine +/− Erlotinib 569 5.9 versus 6.3 0.03
Poplin E, JCO 2009 97 Gemcitabine versus fixed dose rate Gemcitabine versus Gemcitabine + Oxaliplatin 832 4.9 versus 6 versus 5.7 0.04
0.22
Van Custem E, JCO 2009 98 Gemcitabine+Erlotinib +/− Bevacizumab 301 6.0 versus 7.1 0.20
Kindler HL, JCO 2010 99 Gemcitabine +/− Bevacizumab 602 5.9 versus 5.8 0.95
Philip PA, JCO 2010 100 Gemcitabine +/− Cetuximab 745 5.9 versus 6.3 0.23
Conroy T, NEJM 2011 24 Gemcitabine versus FOLFIRINOX 342 6.8 versus 11.1 <0.001
Von Hoff, NEJM 2013 101 Gemcitabine +/− nab-paclitaxel 861 8.5 versus 6.7 P < 0.001
Open in a new tab

5-FU, 5-fluorouracil; +/−, one arm with and one arm without the drug following the sign.

Bold indicates statistically significant.

Thus, the future of effective pancreatic cancer therapy must take into consideration not just the cancer, but also the interplay of the tumor microenvironment, the inherent biologic features that confer early metastatic potential to the cancer, the role of cancer stem cells in therapy resistance mechanisms, and novel gain of function mutations that may serve as new targets for therapeutic disruption. Only an adequately powered prospective study will be able to determine if neoadjuvant therapy provides a survival advantage for early stage pancreatic cancer patients. This study should randomize patients with borderline-resectable disease to the most effective systemic chemotherapy and/or chemoradiotherapy before or after surgery, and explore important outcomes such as relapse free survival and OS. Secondary end points should include resection rates, toxicity and surgical complications. At this moment, however, no such trial exists and neoadjuvant therapy should be conducted as part of an investigational program.

Conflict of Interest

None declared.

References

  1. American Cancer Society. 2014. Facts and figures.
  2. NCI – cancer.gov. 2014. SEER Stat Fact Sheets: Pancreatic cancer.
  3. Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM. Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014;74:2913–2921. doi: 10.1158/0008-5472.CAN-14-0155. [DOI] [PubMed] [Google Scholar]
  4. The Gastrointestinal Tumor Study Group. A multi-institutional comparative trial of radiation therapy alone and in combination with 5-fluorouracil for locally unresectable pancreatic carcinoma. Ann. Surg. 1979;189:205–208. [PMC free article] [PubMed] [Google Scholar]
  5. Gastrointestinal Tumor Study Group. Treatment of locally unresectable carcinoma of the pancreas: comparison of combined-modality therapy (chemotherapy plus radiotherapy) to chemotherapy alone. J. Natl Cancer Inst. 1988;80:751–755. [PubMed] [Google Scholar]
  6. Stathis A. Moore MJ. Advanced pancreatic carcinoma: current treatment and future challenges. Nat. Rev. Clin. Oncol. 2010;7:163–172. doi: 10.1038/nrclinonc.2009.236. [DOI] [PubMed] [Google Scholar]
  7. Russo S, Butler J, Ove R. Blackstock AW. Locally advanced pancreatic cancer: a review. Semin. Oncol. 2007;34:327–334. doi: 10.1053/j.seminoncol.2007.05.007. [DOI] [PubMed] [Google Scholar]
  8. Kalser MH. Ellenberg SS. Pancreatic cancer. Adjuvant combined radiation and chemotherapy following curative resection. Arch. Surg. 1985;120:899–903. doi: 10.1001/archsurg.1985.01390320023003. [DOI] [PubMed] [Google Scholar]
  9. Klinkenbijl JH, Jeekel J, Sahmoud T, van Pel R, Couvreur ML, Veenhof CH, et al. Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: phase III trial of the EORTC gastrointestinal tract cancer cooperative group. Ann. Surg. 1999;230:776–782. doi: 10.1097/00000658-199912000-00006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, et al. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N. Engl. J. Med. 2004;350:1200–1210. doi: 10.1056/NEJMoa032295. [DOI] [PubMed] [Google Scholar]
  11. Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K, et al. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA. 2007;297:267–277. doi: 10.1001/jama.297.3.267. [DOI] [PubMed] [Google Scholar]
  12. Neoptolemos JP, Stocken DD, Bassi C, Ghaneh P, Cunningham D, Goldstein D, et al. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA. 2010;304:1073–1081. doi: 10.1001/jama.2010.1275. [DOI] [PubMed] [Google Scholar]
  13. Regine WF, Winter KA, Abrams RA, Safran H, Hoffman JP, Konski A, et al. Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial. JAMA. 2008;299:1019–1026. doi: 10.1001/jama.299.9.1019. [DOI] [PubMed] [Google Scholar]
  14. Abbott DE, Baker MS. Talamonti MS. Neoadjuvant therapy for pancreatic cancer: a current review. J. Surg. Oncol. 2010;101:315–320. doi: 10.1002/jso.21469. [DOI] [PubMed] [Google Scholar]
  15. Ferrone CR, Brennan MF, Gonen M, Coit DG, Fong Y, Chung S, et al. Pancreatic adenocarcinoma: the actual 5-year survivors. J Gastro Surg. 2008;12:701–706. doi: 10.1007/s11605-007-0384-8. [DOI] [PubMed] [Google Scholar]
  16. Pilepich MV. Miller HH. Preoperative irradiation in carcinoma of the pancreas. Cancer. 1980;46:1945–1949. doi: 10.1002/1097-0142(19801101)46:9<1945::aid-cncr2820460908>3.0.co;2-x. [DOI] [PubMed] [Google Scholar]
  17. Hoffman JP, Weese JL, Solin LJ, Engstrom P, Agarwal P, Barber LW, et al. A pilot study of preoperative chemoradiation for patients with localized adenocarcinoma of the pancreas. Am. J. Surg. 1995;169:71–77. doi: 10.1016/s0002-9610(99)80112-3. [DOI] [PubMed] [Google Scholar]
  18. Burris HA, Moore MJ, Andersen J, Green MJ, Rothenberg ML, Modiano MR, et al. Improvements in survival and clinical benefit with gemcitabine as first- line therapy for patients with advanced pancreas cancer: a randomized trial. J. Clin. Oncol. 1997;1997:2403–2413. doi: 10.1200/JCO.1997.15.6.2403. [DOI] [PubMed] [Google Scholar]
  19. Evans DB, Varadhachary GR, Crane CH, Sun CC, Lee JE, Pisters PW, et al. Preoperative gemcitabine-based chemoradiation for patients with resectable adenocarcinoma of the pancreatic head. J. Clin. Oncol. 2008;26:3496–3502. doi: 10.1200/JCO.2007.15.8634. [DOI] [PubMed] [Google Scholar]
  20. Varadhachary GR, Wolff RA, Crane CH, Sun CC, Lee JE, Pisters PW, et al. Preoperative gemcitabine and cisplatin followed by gemcitabine-based chemoradiation for resectable adenocarcinoma of the pancreatic head. J. Clin. Oncol. 2008;26:3487–3495. doi: 10.1200/JCO.2007.15.8642. [DOI] [PubMed] [Google Scholar]
  21. O’Reilly EM, Perelshteyn A, Jarnagin WR, Schattner M, Gerdes H, Capanu M, et al. A single-arm, nonrandomized phase II trial of neoadjuvant gemcitabine and oxaliplatin in patients with resectable pancreas adenocarcinoma. Ann. Surg. 2014;260:142–148. doi: 10.1097/SLA.0000000000000251. doi: 10.1097/SLA.0000000000000251. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Arvold ND, Ryan DP, Niemierko A, Blaszkowsky LS, Kwak EL, Wo JY, et al. Long-term outcomes of neoadjuvant chemotherapy before chemoradiation for locally advanced pancreatic cancer. Cancer. 2011;118:3026–3035. doi: 10.1002/cncr.26633. [DOI] [PubMed] [Google Scholar]
  23. Strobel O, Berens V, Hinz U, Hartwig W, Hackert T, Bergmann F, et al. Resection after neoadjuvant therapy for locally advanced, “unresectable” pancreatic cancer. Surgery. 2012;152(3 Suppl 1):S33–S42. doi: 10.1016/j.surg.2012.05.029. doi: 10.1016/j.surg.2012.05.029. [DOI] [PubMed] [Google Scholar]
  24. Papavasiliou P, Hoffman JP, Cohen SJ, Meyer JE, Watson JC. Chun YS. Impact of preoperative therapy on patterns of recurrence inpancreatic cancer. HPB (Oxford) 2014;16:34–39. doi: 10.1111/hpb.12058. doi: 10.1111/hpb.12058. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Boone BA, Steve J, Krasinskas AM, Zureikat AH, Lembersky BC, Gibson MK, et al. Outcomes with FOLFIRINOX for borderline resectable and locally unresectable pancreatic cancer. J. Surg. Oncol. 2013;108:236–241. doi: 10.1002/jso.23392. doi: 10.1002/jso.23392. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Faris JE, Blaszkowsky LS, McDermott S, Guimaraes AR, Szymonifka J, Huynh MA, et al. FOLFIRINOX in locally advanced pancreatic cancer: the Massachusetts General Hospital Cancer Center experience. Oncologist. 2013;18:543–548. doi: 10.1634/theoncologist.2012-0435. doi: 10.1634/theoncologist.2012-0435. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Katz MH, Fleming JB, Bhosale P, Varadhachary G, Lee JE, Wolff R, et al. Response of borderline resectable pancreatic cancer to neoadjuvant therapy is not reflected by radiographic indicators. Cancer. 2012;118:5749–5756. doi: 10.1002/cncr.27636. [DOI] [PubMed] [Google Scholar]
  28. Gillen S, Schuster T, Buschenfelde CM, Freiss 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. doi: 10.1371/journal.pmed.1000267. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Artinyan A, Anaya DA, McKenzie S, Ellenhorn JD. Kim J. Neoadjuvant therapy is associated with improved survival in resectable pancreatic adenocarcinoma. Cancer. 2011;117:2044–2049. doi: 10.1002/cncr.25763. [DOI] [PubMed] [Google Scholar]
  30. Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N. Engl. J. Med. 2011;364:1817–1825. doi: 10.1056/NEJMoa1011923. [DOI] [PubMed] [Google Scholar]
  31. Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N. Engl. J. Med. 2013;369:1691–1703. doi: 10.1056/NEJMoa1304369. doi: 10.1056/NEJMoa1304369. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Rose JB, Rocha FG, Alseidi A, Biehl T, Moonka R, Ryan JA, et al. Extended neoadjuvan tchemotherapy for borderline resectable pancreatic cancer demonstrates promising postoperative outcomes and survival. Ann. Surg. Oncol. 2014;21:1530–1537. doi: 10.1245/s10434-014-3486-z. doi: 10.1245/s10434-014-3486-z. [DOI] [PubMed] [Google Scholar]
  33. Weese JL, Nussbaum ML, Paul AR, Engstrom PF, Solin LJ, Kowalyshyn MJ, et al. Increased resectability of locally advanced pancreatic and periampullary carcinoma with neoadjuvant chemoradiotherapy. Int. J. Pancreatol. 1990;7:177–185. doi: 10.1007/BF02924235. [DOI] [PubMed] [Google Scholar]
  34. Coia L, Hoffman J, Scher R, Weese J, Solin L, Weiner L, et al. Preoperative chemoradiation for adenocarcinoma of the pancreas and duodenum. Int. J. Radiat. Oncol. Biol. Phys. 1994;30:161–167. doi: 10.1016/0360-3016(94)90531-2. [DOI] [PubMed] [Google Scholar]
  35. Kamthan AG, Morris JC, Dalton J, Mandeli JP, Chesser MR, Leben D, et al. Combined modality therapy for stage II and stage III pancreatic carcinoma. J. Clin. Oncol. 1997;15:2920–2927. doi: 10.1200/JCO.1997.15.8.2920. [DOI] [PubMed] [Google Scholar]
  36. Hoffman JP, Lipsitz S, Pisansky T, Weese JL, Solin L. Benson AB., 3rd Phase II trial of preoperative radiation therapy and chemotherapy for patients with localized, resectable adenocarcinoma of the pancreas: an Eastern Cooperative Oncology Group Study. J. Clin. Oncol. 1998;16:317–323. doi: 10.1200/JCO.1998.16.1.317. [DOI] [PubMed] [Google Scholar]
  37. Staley CA, Lee JE, Cleary KR, Abbruzzese JL, Fenoglio CJ, Rich TA, et al. Preoperative chemoradiation, pancreaticoduodenectomy, and intraoperative radiation therapy for adenocarcinoma of the pancreatic head. Am. J. Surg. 1996;171:118–124. doi: 10.1016/S0002-9610(99)80085-3. [DOI] [PubMed] [Google Scholar]
  38. Pisters PW, Abbruzzese JL, Janjan NA, Cleary KR, Charnsangavej C, Goswitz MS, et al. Rapid-fractionation preoperative chemoradiation, pancreaticoduodenectomy, and intraoperative radiation therapy for resectable pancreatic adenocarcinoma. J. Clin. Oncol. 1998;16:3843–3850. doi: 10.1200/JCO.1998.16.12.3843. [DOI] [PubMed] [Google Scholar]
  39. Bajetta E, Di Bartolomeo M, Stani SC, Artale S, Ricci SB, Bozzetti F, et al. Chemoradiotherapy as preoperative treatment in locally advanced unresectable pancreatic cancer patients: results of a feasibility study. Int. J. Radiat. Oncol. Biol. Phys. 1999;45:285–289. doi: 10.1016/s0360-3016(99)00205-9. [DOI] [PubMed] [Google Scholar]
  40. Snady H, Bruckner H, Cooperman A, Paradiso J. Kiefer L. Survival advantage of combined chemoradiotherapy compared with resection as the initial treatment of patients with regional pancreatic carcinoma. An outcomes trial. Cancer. 2000;89:314–327. doi: 10.1002/1097-0142(20000715)89:2<314::aid-cncr16>3.0.co;2-v. [DOI] [PubMed] [Google Scholar]
  41. Wanebo HJ, Glicksman AS, Vezeridis MP, Clark J, Tibbetts L, Koness RJ, et al. Preoperative chemotherapy, radiotherapy, and surgical resection of locally advanced pancreatic cancer. Arch. Surg. 2000;135:81–87. doi: 10.1001/archsurg.135.1.81. [DOI] [PubMed] [Google Scholar]
  42. Pipas JM, Mitchell SE, Vera-Gimon RJ, Jr, Barth R, Rathmann J, Meyer LP, et al. Phase I study of twice-weekly gemcitabine and concomitant external-beam radiotherapy in patients with adenocarcinoma of the pancreas. Int. J. Radiat. Oncol. Biol. Phys. 2001;50:1317–1322. doi: 10.1016/s0360-3016(01)01580-2. [DOI] [PubMed] [Google Scholar]
  43. Wolff RA, Evans DB, Gravel DM, Lenzi R, Pisters PW, Lee JE, et al. Phase I trial of gemcitabine combined with radiation for the treatment of locally advanced pancreatic adenocarcinoma. Clin. Cancer Res. 2001;7:2246–2253. [PubMed] [Google Scholar]
  44. de Lange SM, van Groeningen CJ, Meijer OW, Cuesta MA, Langendijk JA, van Riel JM, et al. Gemcitabine-radiotherapy in patients with locally advanced pancreatic cancer. Eur. J. Cancer. 2002;38:1212–1217. doi: 10.1016/s0959-8049(02)00076-x. [DOI] [PubMed] [Google Scholar]
  45. Epelbaum R, Rosenblatt E, Nasrallah S, Faraggi D, Gaitini D, Mizrahi S, et al. Phase II study of gemcitabine combined with radiation therapy in patients with localized, unresectable pancreatic cancer. J. Surg. Oncol. 2002;81:138–143. doi: 10.1002/jso.10159. [DOI] [PubMed] [Google Scholar]
  46. Pisters PW, Wolff RA, Janjan NA, Cleary KR, Charnsangavej C, Crane CN, et al. Preoperative paclitaxel and concurrent rapid-fractionation radiation for resectable pancreatic adenocarcinoma: toxicities, histologic response rates, and event-free outcome. J. Clin. Oncol. 2002;20:2537–2544. doi: 10.1200/JCO.2002.11.064. [DOI] [PubMed] [Google Scholar]
  47. Al-Sukhun S, Zalupski MM, Ben-Josef E, Vaitkevicius VK, Philip PA, Soulen R, et al. Chemoradiotherapy in the treatment of regional pancreatic carcinoma: a phase II study. Am. J. Clin. Oncol. 2003;26:543–549. doi: 10.1097/01.coc.0000037143.60502.54. [DOI] [PubMed] [Google Scholar]
  48. Brunner TB, Grabenbauer GG, Klein P, Baum U, Papadopoulos T, Bautz W, et al. Phase I trial of strictly time-scheduled gemcitabine and cisplatin with concurrent radiotherapy in patients with locally advanced pancreatic cancer. Int. J. Radiat. Oncol. Biol. Phys. 2003;55:144–153. doi: 10.1016/s0360-3016(02)03818-x. [DOI] [PubMed] [Google Scholar]
  49. Joensuu TK, Kiviluoto T, Kärkkäinen P, Vento P, Kivisaari L, Tenhunen M, et al. Phase I-II trial of twice-weekly gemcitabine and concomitant irradiation in patients undergoing pancreaticoduodenectomy with extended lymphadenectomy for locally advanced pancreatic cancer. Int. J. Radiat. Oncol. Biol. Phys. 2004;60:444–452. doi: 10.1016/j.ijrobp.2004.03.026. [DOI] [PubMed] [Google Scholar]
  50. Moutardier V, Magnin V, Turrini O, Viret F, Hennekinne-Mucci S, Gonçalves A, et al. Assessment of pathologic response after preoperative chemoradiotherapy and surgery in pancreatic adenocarcinoma. Int. J. Radiat. Oncol. Biol. Phys. 2004;60:437–443. doi: 10.1016/j.ijrobp.2004.04.004. [DOI] [PubMed] [Google Scholar]
  51. Magnino A, Gatti M, Massucco P, Sperti E, Faggiuolo R, Regge D, et al. Phase II trial of primary radiation therapy and concurrent chemotherapy for patients with locally advanced pancreatic cancer. Oncology. 2005;68:493–499. doi: 10.1159/000086993. [DOI] [PubMed] [Google Scholar]
  52. Pipas JM, Zaki RJ, Jr, Barth B, Tsapakos MJ, Suriawinata AA, Bettmann MA, et al. Docetaxel/Gemcitabine followed by gemcitabine and external beam radiotherapy in patients with pancreatic adenocarcinoma. Ann. Surg. Oncol. 2005;12:995–1004. doi: 10.1245/ASO.2005.04.503. [DOI] [PubMed] [Google Scholar]
  53. Mornex F, Girard N, Scoazec JY, Bossard N, Ychou M, Smith D, et al. Feasibility of preoperative combined radiation therapy and chemotherapy with 5-fluorouracil and cisplatin in potentially resectable pancreatic adenocarcinoma: The French SFRO-FFCD 97-04 Phase II trial. Int. J. Radiat. Oncol. Biol. Phys. 2006;65:1471–1478. doi: 10.1016/j.ijrobp.2006.02.054. [DOI] [PubMed] [Google Scholar]
  54. Talamonti MS, Mulcahy W, Jr, Small MF, Wayne JD, Attaluri V, Colletti LM, et al. A multi-institutional phase II trial of preoperative full-dose gemcitabine and concurrent radiation for patients with potentially resectable pancreatic carcinoma. Ann. Surg. Oncol. 2006;13:150–158. doi: 10.1245/ASO.2006.03.039. [DOI] [PubMed] [Google Scholar]
  55. Wilkowski R, Thoma M, Bruns C, Wagner A. Heinemann V. Chemoradiotherapy with gemcitabine and continuous 5-FU in patients with primary inoperable pancreatic cancer. JOP. 2006;7:349–360. [PubMed] [Google Scholar]
  56. Desai SP, Ben-Josef E, Normolle DP, Francis IR, Greenson JK, Simeone DM, et al. Phase I study of oxaliplatin, full-dose gemcitabine, and concurrent radiation therapy in pancreatic cancer. J. Clin. Oncol. 2007;25:4587–4592. doi: 10.1200/JCO.2007.12.0592. [DOI] [PubMed] [Google Scholar]
  57. Palmer DH, Stocken DD, Hewitt H, Markham CE, Hassan AB, Johnson PJ, et al. A randomized phase 2 trial of neoadjuvant chemotherapy in resectable pancreatic cancer: gemcitabine alone versus gemcitabine combined with cisplatin. Ann. Surg. Oncol. 2007;14:2088–2096. doi: 10.1245/s10434-007-9384-x. [DOI] [PubMed] [Google Scholar]
  58. Heinrich S, Schäfer M, Weber A, Hany TF, Bhure U, Pestalozzi BC, et al. Neoadjuvant chemotherapy generates a significant tumor response in resectable pancreatic cancer without increasing morbidity: results of a prospective phase II trial. Ann. Surg. 2008;248:1014–1022. doi: 10.1097/SLA.0b013e318190a6da. [DOI] [PubMed] [Google Scholar]
  59. Le Scodan R, Mornex F, Partensky C, Mercier C, Valette PJ, Ychou M, et al. Histopathological response to preoperative chemoradiation for resectable pancreatic adenocarcinoma: the French Phase II FFCD 9704-SFRO Trial. Am. J. Clin. Oncol. 2008;31:545–552. doi: 10.1097/COC.0b013e318172d5c5. [DOI] [PubMed] [Google Scholar]
  60. Marti JL, Hochster HS, Hiotis SP, Donahue B, Ryan T. Newman E. Phase I/II trial of induction chemotherapy followed by concurrent chemoradiotherapy and surgery for locoregionally advanced pancreatic cancer. Ann. Surg. Oncol. 2008;15:3521–3531. doi: 10.1245/s10434-008-0152-3. [DOI] [PubMed] [Google Scholar]
  61. Small W, Jr, Berlin J, Freedman GM, Lawrence T, Talamonti MS, Mulcahy MF, et al. Full-dose gemcitabine with concurrent radiation therapy in patients with nonmetastatic pancreatic cancer: a multicenter phase II trial. J. Clin. Oncol. 2008;26:942–947. doi: 10.1200/JCO.2007.13.9014. [DOI] [PubMed] [Google Scholar]
  62. Bjerregaard JK, Mortensen MB, Jensen HA, Fristrup C, Svolgaard B, Schønnemann KR, et al. Long-term results of concurrent radiotherapy and UFT in patients with locally advanced pancreatic cancer. Radiother. Oncol. 2009;92:226–230. doi: 10.1016/j.radonc.2009.04.010. [DOI] [PubMed] [Google Scholar]
  63. Choi M, Heilbrun LK, Venkatramanamoorthy R, Lawhorn-Crews JM, Zalupski MM. Shields AF. Using 18F-fluorodeoxyglucose positron emission tomography to monitor clinical outcomes in patients treated with neoadjuvant chemo-radiotherapy for locally advanced pancreatic cancer. Am. J. Clin. Oncol. 2010;33:257–261. doi: 10.1097/COC.0b013e3181a76a0b. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Laurent S, Monsaert E, Boterberg T, Demols A, Borbath I, Polus M, et al. Feasibility of radiotherapy with concomitant gemcitabine and oxaliplatin in locally advanced pancreatic cancer and distal cholangiocarcinoma: a prospective dose finding phase I-II study. Ann. Oncol. 2009;20:1369–1374. doi: 10.1093/annonc/mdp005. [DOI] [PubMed] [Google Scholar]
  65. Maximous DW, Abdel-Wanis ME, El-Sayed MI. Abd-Elsayed AA. Preoperative gemcitabine based chemo-radiotherapy in locally advanced non metastatic pancreatic adenocarcinoma. Int Arch Med. 2009;2:7. doi: 10.1186/1755-7682-2-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. Turrini O, Ychou M, Moureau-Zabotto L, Rouanet P, Giovannini M, Moutardier V, et al. Neoadjuvant docetaxel-based chemoradiation for resectable adenocarcinoma of the pancreas: New neoadjuvant regimen was safe and provided an interesting pathologic response. Eur. J. Surg. Oncol. 2010;36:987–992. doi: 10.1016/j.ejso.2010.07.003. [DOI] [PubMed] [Google Scholar]
  67. Landry J, Catalano PJ, Staley C, Harris W, Hoffman J, Talamonti M, et al. Randomized phase II study of gemcitabine plus radiotherapy versus gemcitabine, 5-fluorouracil, and cisplatin followed by radiotherapy and 5-fluorouracil for patients with locally advanced, potentially resectable pancreatic adenocarcinoma. J. Surg. Oncol. 2010;101:587–592. doi: 10.1002/jso.21527. [DOI] [PMC free article] [PubMed] [Google Scholar]
  68. Sahora K, Kuehrer I, Eisenhut A, Akan B, Koellblinger C, Goetzinger P, et al. Gemcitabine and oxaliplatin as neoadjuvant treatment for locally advanced, nonmetastasized pancreatic cancer. Surgery. 2011;149:311–320. doi: 10.1016/j.surg.2010.07.048. [DOI] [PubMed] [Google Scholar]
  69. Lee JL, Kim SC, Kim JH, Lee SS, Kim TW, Park do H, et al. Prospective efficacy and safety study of neoadjuvant gemcitabine with capecitabine combination chemotherapy for borderline-resectable or unresectable locally advanced pancreatic adenocarcinoma. Surgery. 2012;152:851–862. doi: 10.1016/j.surg.2012.03.010. doi: 10.1016/j.surg.2012.03.010. [DOI] [PubMed] [Google Scholar]
  70. Pipas JM, Zaki BI, McGowan MM, Tsapakos MJ, Ripple GH, Suriawinata AA, et al. Neoadjuvant cetuximab, twice-weekly gemcitabine, and intensity-modulated radiotherapy (IMRT) in patients with pancreatic adenocarcinoma. Ann. Oncol. 2012;23:2820–2827. doi: 10.1093/annonc/mds109. doi: 10.1093/annonc/mds109. [DOI] [PMC free article] [PubMed] [Google Scholar]
  71. Satoi S, Toyokawa H, Yanagimoto H, Yamamoto T, Kamata M, Ohe C, et al. Neo-adjuvant chemoradiation therapy using S-1 followed by surgical resection in patients with pancreatic cancer. J Gastrointest Surg. 2012;16:784–792. doi: 10.1007/s11605-011-1795-0. doi: 10.1007/s11605-011-1795-0. [DOI] [PubMed] [Google Scholar]
  72. Chao YJ, Sy ED, Hsu HP. Shan YS. Predictors for resectability and survival in locally advanced pancreatic cancer after gemcitabine-based neoadjuvant therapy. BMC Surg. 2014;25:72. doi: 10.1186/1471-2482-14-72. doi: 10.1186/1471-2482-14-72. [DOI] [PMC free article] [PubMed] [Google Scholar]
  73. Golcher H, Brunner TB, Witzigmann H, Marti L, Bechstein WO, Bruns C, et al. Neoadjuvant chemoradiation therapy with gemcitabine/cisplatin and surgery versus immediate surgery in resectable pancreatic cancer: Results of the first prospective randomized phase II trial. Strahlenther Onkol. 2014;191:7–16. doi: 10.1007/s00066-014-0737-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  74. White RR, Hurwitz HI, Morse MA, Lee C, Anscher MS, Paulson EK, et al. Neoadjuvant chemoradiation for localized adenocarcinoma of the pancreas. Ann. Surg. Oncol. 2001;8:758–765. doi: 10.1007/s10434-001-0758-1. [DOI] [PubMed] [Google Scholar]
  75. Aristu J, Cañón R, Pardo F, Martínez-Monge R, Martin-Algarra S, Manuel Ordoñez J, et al. Surgical resection after preoperative chemoradiotherapy benefits selected patients with unresectable pancreatic cancer. Am. J. Clin. Oncol. 2003;26:30–36. doi: 10.1097/00000421-200302000-00007. [DOI] [PubMed] [Google Scholar]
  76. Calvo FA, Matute R, García-Sabrido JL, Gómez-Espí M, Martínez NE, Lozano MA, et al. Neoadjuvant chemoradiation with tegafur in cancer of the pancreas: initial analysis of clinical tolerance and outcome. Am. J. Clin. Oncol. 2004;27:343–349. doi: 10.1097/01.coc.0000071462.12769.35. [DOI] [PubMed] [Google Scholar]
  77. Sa Cunha A, Rault A, Laurent C, Adhoute X, Vendrely V, Béllannée G, et al. Surgical resection after radiochemotherapy in patients with unresectable adenocarcinoma of the pancreas. J. Am. Coll. Surg. 2005;201:359–365. doi: 10.1016/j.jamcollsurg.2005.04.008. [DOI] [PubMed] [Google Scholar]
  78. Brown KM, Siripurapu V, Davidson M, Cohen SJ, Konski A, Watson JC, et al. Chemoradiation followed by chemotherapy before resection for borderline pancreatic adenocarcinoma. Am. J. Surg. 2008;195:318–321. doi: 10.1016/j.amjsurg.2007.12.017. [DOI] [PubMed] [Google Scholar]
  79. Allendorf JD, Lauerman M, Bill A, DiGiorgi M, Goetz N, Efsevia V, et al. Neoadjuvant chemotherapy and radiation for patients with locally unresectable pancreatic adenocarcinoma: feasibility, Efficacy, and Survival. Journal of Gastrointestinal Surgery. 2008;12:91–100. doi: 10.1007/s11605-007-0296-7. [DOI] [PubMed] [Google Scholar]
  80. Golcher H, Brunner T, Grabenbauer G, Merkel S, Papadopoulos T, Hohenberger W, et al. Preoperative chemoradiation in adenocarcinoma of the pancreas. A single centre experience advocating a new treatment strategy. Eur. J. Surg. Oncol. 2008;34:756–764. doi: 10.1016/j.ejso.2007.11.012. [DOI] [PubMed] [Google Scholar]
  81. Turrini O, Viret F, Moureau-Zabotto L, Guiramand J, Lelong MoutardierV, Giovannini BM, et al. Neoadjuvant chemoradiation and pancreaticoduodenectomy for initially locally advanced head pancreatic adenocarcinoma. Eur. J. Surg. Oncol. 2009;35:1306–1311. doi: 10.1016/j.ejso.2009.06.005. [DOI] [PubMed] [Google Scholar]
  82. Stokes JB, Nolan NJ, Stelow EB, Walters DM, Weiss GR, de Lange EE, et al. Preoperative capecitabine and concurrent radiation for borderline resectable pancreatic cancer. Ann. Surg. Oncol. 2011;18:619–627. doi: 10.1245/s10434-010-1456-7. [DOI] [PubMed] [Google Scholar]
  83. Patel M, Hoffe S, Malafa M, Hodul P, Klapman J, Centeno B, et al. Neoadjuvant GTX chemotherapy and IMRT-based chemoradiation for borderline resectable pancreatic cancer. J. Surg. Oncol. 2011;104:155–161. doi: 10.1002/jso.21954. [DOI] [PMC free article] [PubMed] [Google Scholar]
  84. Sho M, Akahori T, Tanaka T, Kinoshita S, Tamamoto T, Nomi T, et al. Pathological and clinical impact of neoadjuvant chemoradiotherapy using full-dose gemcitabine and concurrent radiation for resectable pancreatic cancer. J Hepatobiliary Pancreat Sci. 2013;20:197–205. doi: 10.1007/s00534-012-0532-8. doi: 10.1007/s00534-012-0532-8. [DOI] [PubMed] [Google Scholar]
  85. Bramhall SR, Schulz J, Nemunaitis J, Brown PD, Baillet M. Buckels JA. A double-blind placebo-controlled, randomised study comparing gemcitabine and marimastat with gemcitabine and placebo as first line therapy in patients with advanced pancreatic cancer. BJC. 2002;87:161–167. doi: 10.1038/sj.bjc.6600446. [DOI] [PMC free article] [PubMed] [Google Scholar]
  86. Berlin JD, Catalano P, Thomas JP, Kugler JW, Haller DG. Benson AB., 3rd Phase III study of gemcitabine in combination with fluorouracil versus gemcitabine alone in patients with advanced pancreatic carcinoma: Eastern Cooperative Oncology Group Trial E2297. J. Clin. Oncol. 2002;20:3270–3275. doi: 10.1200/JCO.2002.11.149. [DOI] [PubMed] [Google Scholar]
  87. Colucci G, Giuliani F, Gebbia V, Biglietto M, Rabitti P, Uomo G, et al. Gemcitabine alone or with cisplatin for the treatment of patients with locally advanced and/or metastatic pancreatic carcinoma: a prospective, randomized phase III study of the Gruppo Oncologia dell’Italia Meridionale. Cancer. 2002;94:902–910. [PubMed] [Google Scholar]
  88. Rocha Lima CM, Green MR, Rotche R, Miller WH, Jeffrey GM, Cisar LA, et al. Irinotecan Plus Gemcitabine Results in No Survival Advantage Compared With Gemcitabine Monotherapy in Patients With Locally Advanced or Metastatic Pancreatic Cancer Despite Increased Tumor Response Rate. JCO. 2004;22:3776–3783. doi: 10.1200/JCO.2004.12.082. Jr. [DOI] [PubMed] [Google Scholar]
  89. Van Cutsem E, de van Velde H, Karasek P, Oettle H, Vervenne WL, Szawlowski A, et al. Phase III Trial of Gemcitabine plus Tipifarnib compared with Gemcitabine plus placebo in Advanced Pancreatic Cancer. JCO. 2004;22:1430–1438. doi: 10.1200/JCO.2004.10.112. [DOI] [PubMed] [Google Scholar]
  90. Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, André T, et al. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J. Clin. Oncol. 2005;23:3509–3516. doi: 10.1200/JCO.2005.06.023. [DOI] [PubMed] [Google Scholar]
  91. Oettle H, Richards D, Ramanathan RK, van Laethem JL, Peeters M, Fuchs M, et al. A phase III trial of pemetrexed plus gemcitabine versus gemcitabine in patients with unresectable or metastatic pancreatic cancer. Ann. Oncol. 2005;16:1639–1645. doi: 10.1093/annonc/mdi309. [DOI] [PubMed] [Google Scholar]
  92. Abou-Alfa GK, Letourneau R, Harker G, Modiano M, Hurwitz H, Tchekmedyian NS, et al. Randomized phase III study of exatecan and gemcitabine compared with gemcitabine alone in untreated advanced pancreatic cancer. J. Clin. Oncol. 2006;24:4441–4447. doi: 10.1200/JCO.2006.07.0201. [DOI] [PubMed] [Google Scholar]
  93. Heinemann V, Quietzsch D, Gieseler F, Gonnermann M, Schönekäs H, Rost A, et al. Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J. Clin. Oncol. 2006;24:3946–3952. doi: 10.1200/JCO.2005.05.1490. [DOI] [PubMed] [Google Scholar]
  94. Stathopoulos GP, Syrigos K, Aravantinos G, Polyzos A, Papakotoulas P, Fountzilas G, et al. A multicenter phase III trial comparing irinotecan-gemcitabine (IG) with gemcitabine (G) monotherapy as first-line treatment in patients with locally advanced or metastatic pancreatic cancer. Br. J. Cancer. 2006;95:587–592. doi: 10.1038/sj.bjc.6603301. [DOI] [PMC free article] [PubMed] [Google Scholar]
  95. Herrmann R, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schüller J, et al. Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group. J. Clin. Oncol. 2007;25:2212–2217. doi: 10.1200/JCO.2006.09.0886. [DOI] [PubMed] [Google Scholar]
  96. Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J. Clin. Oncol. 2007;25:1960–1966. doi: 10.1200/JCO.2006.07.9525. [DOI] [PubMed] [Google Scholar]
  97. Poplin E, Feng Y, Berlin J, Rothenberg ML, Hochster H, Mitchell E, et al. Phase III randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group. J. Clin. Oncol. 2009;27:3778–3785. doi: 10.1200/JCO.2008.20.9007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  98. Van Cutsem E, Vervenne WL, Bennouna J, Humblet Y, Gill S, Van Laethem JL, et al. Phase III trial of bevacizumab in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. J. Clin. Oncol. 2009;27:2231–2237. doi: 10.1200/JCO.2008.20.0238. [DOI] [PubMed] [Google Scholar]
  99. Kindler HL, Niedzwiecki D, Hollis D, Sutherland S, Schrag D, Hurwitz H, et al. Gemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic cancer: phase III trial of the Cancer and Leukemia Group B (CALGB 80303) J. Clin. Oncol. 2010;28:3617–3622. doi: 10.1200/JCO.2010.28.1386. [DOI] [PMC free article] [PubMed] [Google Scholar]
  100. Philip PA, Benedetti J, Corless CL, Wong R, O’Reilly EM, Flynn PJ, et al. Phase III study comparing gemcitabine plus cetuximab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: Southwest Oncology Group-directed intergroup trial S0205. J. Clin. Oncol. 2010;28:3605–3610. doi: 10.1200/JCO.2009.25.7550. [DOI] [PMC free article] [PubMed] [Google Scholar]
  101. Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N. Engl. J. Med. 2013;369:1691–1703. doi: 10.1056/NEJMoa1304369. [DOI] [PMC free article] [PubMed] [Google Scholar]

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