Copyright ©The Author(s) 2017.
World J Gastrointest Oncol. Dec 15, 2017; 9(12): 457-465
Published online Dec 15, 2017. doi: 10.4251/wjgo.v9.i12.457
Table 1 Operational definitions of resectability of pancreatic cancer
Classification of resectability of pancreatic cancerDefinition by AHPBA/SSO/SSATDefinition by MD Anderson Cancer Centre
ResectableThe tumor does not abut or encase any of the following vascular structures: the superior mesenteric vein or portal vein, superior mesenteric artery or common hepatic artery or celiac trunkThe tumor abuts or encases the superior mesenteric vein or portal vein without occluding the lumen. Absence of abutment or encasement of the superior mesenteric artery, common hepatic artery or celiac trunk
Borderline resectableAbutment, encasement or occlusion of the superior mesenteric vein or portal vein. Abutment of the superior mesenteric artery. Abutment or short segment encasement of the common hepatic artery. Absence or abutment or encasement of the celiac trunkTumor causing a short-segment occlusion of the superior mesenteric vein or portal vein. Presence of abutment of the superior mesenteric artery, abutment or encasement of a short segment of the common hepatic artery, absence of abutment or encasement of the celiac trunk
Locally advancedTumor located in the proximity of the superior mesenteric vein or portal vein and the superior mesenteric vein or portal vein are unable to be resected and reconstructed. Tumor encasing the superior mesenteric artery, or long-segment encasement of the common hepatic artery, or abutment of the celiac trunkTumor located in the proximity of the superior mesenteric vein or portal vein that are not reconstructible. Presence of tumor encasement of the superior mesenteric artery, long-segment encasement of the common hepatic artery and encasement of the celiac trunk
Table 2 Summary of the benefits and drawbacks of neo-adjuvant and adjuvant therapies for the treatment of patients with resectable pancreatic cancer
Neo-adjuvant therapyAdjuvant therapy

In comparison to the strategy of adjuvant chemotherapy or chemoradiation therapy where up to 50% of patients who undergo surgery cannot complete their therapy due to complications or decline of their function, neoadjuvant strategy has been shown to be well tolerated by the majority of patients and therefore a greater proportion receive systemic therapyNeoadjuvant therapy requires the placement of biliary stents to decompress the biliary obstruction prior to surgery of patients with jaundice. The placement of biliary stents before surgery increases the risk of infections in the perioperative periodOne of the advantages of surgery first approach is that patients have a short period of time between when they are diagnosed and when they undergo resections of their tumor. This might have some benefits on patients’ and their families’ anxietyAbout 20%-50% of patients will not be able to complete their postoperative therapy due to surgical complications or overall decline of their performance status
The use of neo-adjuvant therapy might sterilize the presence of small metastatic disease and reduce the size of the primary tumor. Downsizing the primary tumor might increase the likelihood of negative resection marginsPre-operative therapy delays surgery and increases the risk of progression of the disease to the point of becoming unresectableSince patients undergo surgery as soon as possible after their diagnosis, their risk of tumor progression is smaller than patients who wait a longer time before being operated onOne of the risk of undergoing surgery first for pancreatic cancer is that, some patients will undergo a major operation without the benefit of being cured as they might already have micrometastases
Treating patients before surgery, gives physicians some time to identify the tumors with poor prognosis that do not respond to the therapy. The identification of those patients who are likely to experience early metastases is very important because prevents them to undergo unnecessary surgeryThe use of neoadjuvant therapies might increase the risk of perioperative morbidity and mortality due to the side effects of chemotherapy or chemoradiationPatients who undergo surgery first do not routinely need the placement of biliary stents to release their jaundice before undergoing resectionPatients who undergo surgery first have a higher risk of positive resection margins
One of the advantages of using chemotherapy or chemoradiation therapy before surgery is that the blood supply to the pancreatic tumor is not compromised by the ligation of vessels. Therefore, chemotherapy agents can be delivered to the pancreatic tumor in higher concentrations
Table 3 Phase I and Phase II studies assessing the outcomes of patients with resectable pancreatic cancer treated with neoadjuvant therapies
Author (yr)/ journal/trial/institutionNo. of patientsClinical stage/ duration of neoadjuvant therapyStudy designChemotherapy/chemoradiationRadiological responseResection rate (%)Negative resection margins (%)Median overall survival (mo)
Hoffman (1998)/J Clin Oncol/ECOG53Resectable PC/2.8 moPhase II, prospective study, November 1991 to September 19935-FU (1000 mg/m2) per day + Mitomycin C (10 mg/m2) + RT (50 Gy)Partial response 8%; Stable disease 78%; Progression 16%456715 with surgery; without surgery 8; 10.9 for the entire cohort
PistersPister (2002)/J Clin Oncol/MD Anderson Cancer Centre35Resectable PC/1.8 moPhase II, prospective study, timeframe not specifiedPaclitaxel (60 mg/m2) weekly, RT (30 Gy)Partial response 4%; Stable disease 23%; Progression 20%576812 for the entire cohort; 19 with surgery; 10 without surgery
Joensuu (2004)/Int J Radiat Oncol Biol Phys/Helsinki University28Resectable PC/3.5 moPhase I-II prospective study, November 1999 to December 2001Gemcitabine (20 mg/m2vs 50 mg/m2vs 100 mg/m2) twice a week + RT (50 GY)NA71NA13.6 for the entire cohort
Talamonti (2006)/Ann Surg Oncol/Northwestern University20Resectable PC/3.8 moPhase II prospective, multi-institutional study, April 2002 to October 2003Gemcitabine (1000 mg/m2 weekly) + RT (36 Gy)Partial response 15%; Stable disease 80%; Progression 5%859426 mo with surgery
Palmer (2007)/Ann Surg Oncol/University of Birmingham24Resectable PC/4 moPhase II, prospective study, November 1999 to May 2003Gemcitabine (1000 mg/m2 weekly)Partial Response 0%; Stable Disease 29%; Progression 4%; Unable to measure 4%387528.4 with surgery; 9.9 for the entire cohort
Palmer (2007)/Ann Surg Oncol/University of Birmingham26Resectable PC/4 moPhase II, prospective study, November 1999 to May 2003Gemcitabine (1000 mg/m2 weekly) + Cisplatin (25 mg/m2)Partial Response 0%; Stable Disease 66%; Progression 21%; Unable to measure 4%707528.4 with surgery; 9.9 for the entire cohort
Le Scodan (2009)/Ann Oncol/SFRO-FFCD41Resectable PC/3 moPhase II, prospective study, January 1998 to March 2003RT (50 Gy) + 5-FU (300 mg/m2 daily) + Cisplatin (20 mg/m2)Partial response 10%; Stable Disease 65%; Progression 25%638111.7 with surgery; 9.4 for the entire cohort
Heinrich (2008)/Ann Surg/University Hospital of Zurich28Resectable PC/2 moPhase II, prospective study, August 2001 to April 2007Gemcitabine (1000 mg/m2 twice weekly) + Cisplatin (50 mg/m2)Partial response 4%; Stable Disease 61%; Progression 13%898019.1 mo with surgery
Evans (2008)/J Clin Oncol/MD Anderson Cancer Centre80Resectable PC/3 moPhase II, prospective study, July 1998 to October 2001Gemcitabine (400 mg/m2 weekly) + RT (30 Gy)NA858234 mo with surgery; 22.7 mo for the entire cohort; 7 mo without surgery
Varadhachari (2008)/J Clin Oncol/MD Anderson Cancer Centre90Resectable PC/4.3 moPhase II, prospective study, October 2002 to February 2006Gemcitabine (750 mg/m2 weekly) + Cisplatin (30 mg/m2) every 2 wk + RT (30 Gy)NA589631.0 mo with surgery; 17.4 mo for the entire cohort; 10.5 mo without surgery
Turrini (2009)/Oncology /University Mediterranean34Resectable PC/2.1 moPhase II, prospective study, May 2003 to July 2005Docetazel (30 mg/m2) weekly + RT (45 GY)Partial response 9%; Stable disease 59%; Progression 32%6810032 mo with surgery; 15.5 mo for entire cohort; 11 mo without surgery
Landry (2010)/J Surg Oncol/Emory University/Multicenter ECOG21Resectable PC/3 moPhase II, prospective two-arm study, October 2013 to June 2015Arm A: Gemcitabine (500 mg/m2) weekly + RT (50 Gy) Arm B: Gemcitabine (175 mg/m2) + Cisplatin (20 mg/m2) + 5-FU (600 mg/m2) + RT (50 Gy)Arm A: Partial response 10%, Arm B: Partial response 18.2%NANAArm A: Entire cohort 19.4 mo. Arm B: entire cohort 13.4 mo. 26.3 mo with surgery
Wo (2014)/Radiother Oncol/Multicentric10Resectable PCPhase I, prospective studyCapecitabine (1650 mg/m2) over 10 d + RT (30 Gy)NA80NANA
Shinoto (2013)/Cancer/Japan26Resetable PCPhase I, prospective study, April 2003 to December 2010RT (30 Gy)Partial response 3.8%; Stable disease 96.1%819018.6 mo for entire cohort; NA for patients who underwent surgery
O'Reilly (2014)/Ann Surg/Memorial Sloan Kettering Cancer Centre38Resectable PCPhase II, prospective study, July 2007 to December 2011Gemcitabine (1000 mg/m2) + Oxaliplatin (80 mg/m2) every 2 wkPartial response 10.5%; Stable disease 73.7%; Progression 7.9%; NA 7.9%777427.2 mo for the enire cohort; 22 mo progression free survival with surgery
Golcher (2015)/Strahlenther Onkol/Germany66 (33 patients allocated to surgery + 33 patients allocated to chemoradiation followed by surgery)Resectable PCPhase II, prospective randomized trial with two arms: Primary surgery vs preoperative chemoradiation followed by surgery. June 2003 to December 2009Gemcitabine (300 mg/m2) + Cisplatin (30 mg /m2) + RT (50.4 Gy) (Preoperative for patients enrolled in Arm A)NAPreoperative chemoradiation: 69% Surgery first: 57%Arm A (preoperative chemoradition): 48. Arm B (surgery first): 51Arm A (preoperative chemoradiation): 18.9 mo. Arm B (surgery first): 25.0 mo
Van Buren (2013)/Ann Surg Oncol/Multicenter/United States59Resectable PCPhase II, prospective study, February 2007 to February 2011Gemcitabine (1500 mg/m2) ever 2 wk + Bevacizumab (10 mg/kg) + RT (30 Gy)Partial response 8.4%; Stable disease 73.7%; Progression 7.9%748819.7 mo with surgery; 16.8 mo for the entire cohort
Table 4 List of ongoing phase II and phase III trials comparing neoadjuvant therapies vs adjuvant strategies for resectable pancreatic adenocarcinoma
StudyDesignNo. of patients neededTherapyPrimary outcome
NEOPAC (NCT01314027)Phase III Enrollment 2009-2014350Neoadjuvant gemcitabineoxaliplatin + adjuvant gemcitabine vs Adjuvant gemcitabineProgression free survival
NEOPAC (NCT01521702)Phase III Initiated in 2011310Preoperative FOLFIRINOX, followed by adjuvant gemcitabine after surgery vs adjuvant gemcitabine after resectionFive-year progression free survival
NCT01900327Phase III410Neoadjuvant gemcitabine-based chemoradiation therapy followed by adjuvant gemcitabine vs adjuvant gemcitabineThree-year overall survival
NCT01771146Phase II100Neoadjuvant FOLFIRINOXProgression free survival
NEONAX (NCT02047513)Randomized phase II166Neoadjuvant gemcitabine + nab-paclitaxel followed by adjuvant gemcitabine + nab-paclitaxel vs adjuvant gemcitabine + nab-paclitaxelDisease-free survival at 18 mo
NCT01150630Randomized phase II/III370Adjuvant PEXG vs adjuvant gemcitabine vs neoadjuvant PEXG - followed by surgery and then adjuvant PEXGOne year event-free survival
ACOSOG-Z5041 (NCT00733746)Phase II123Neoadjuvant gemcitabine + erlotinib (completed; results pending)Two-year overall survival
NCT00727441Phase II87Neoadjuvant GVAX +/- IV or oral cyclophosphamide followed by adjuvant gemcitabine + CRTSafety, feasibility, and immune response
NCT02178709Phase II48Neoadjuvant FOLFIRINOXPathologic complete response
GEMCAD1003 (NCT01389440)Phase II24Neoadjuvant gemcitabine + erlotinibR0 resection rate
NCT02562716Phase II Enrollment 2015-2019112Neoadjuvant and adjuvant mFOLFIRINOX vs neoadjuvant and adjuvant Nab-paclitaxel and gemcitabineOverall survival
NCT02243007Randomized phase II112Neoadjuvant FOLFIRINOX vs gemcitabine + nab-paclitaxel18-mo overall survival
NCT02030860Pilot15Neoadjuvant gemcitabine + nab-paclitaxel ± paricalcitolNumber of adverse events
NCT02305186Randomized phase Ib/II56Neoadjuvant capecitabine-based CRT ± pembrolizumab (MK-3745)Safety and immune response