Neoadjuvant therapy for resectable pancreatic cancer

Table 1 Operational definitions of resectability of pancreatic cancer

Classification of resectability of pancreatic cancer	Definition by AHPBA/SSO/SSAT	Definition by MD Anderson Cancer Centre
Resectable	The 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 trunk	The 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 resectable	Abutment, 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 trunk	Tumor 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 advanced	Tumor 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 trunk	Tumor 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

AHPBA: Americas Hepato-Pancreato-Biliary Association; SSO: Society of Surgical Oncology; SSAT: Society for Surgery of the Alimentary Tract.

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 therapy		Adjuvant therapy
Advantages	Disadvantages	Advantages	Disadvantages
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 therapy	Neoadjuvant 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 period	One 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’ anxiety	About 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 margins	Pre-operative therapy delays surgery and increases the risk of progression of the disease to the point of becoming unresectable	Since 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 on	One 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 surgery	The use of neoadjuvant therapies might increase the risk of perioperative morbidity and mortality due to the side effects of chemotherapy or chemoradiation	Patients who undergo surgery first do not routinely need the placement of biliary stents to release their jaundice before undergoing resection	Patients 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/institution	No. of patients	Clinical stage/ duration of neoadjuvant therapy	Study design	Chemotherapy/chemoradiation	Radiological response	Resection rate (%)	Negative resection margins (%)	Median overall survival (mo)
Hoffman (1998)/J Clin Oncol/ECOG	53	Resectable PC/2.8 mo	Phase II, prospective study, November 1991 to September 1993	5-FU (1000 mg/m2) per day + Mitomycin C (10 mg/m2) + RT (50 Gy)	Partial response 8%; Stable disease 78%; Progression 16%	45	67	15 with surgery; without surgery 8; 10.9 for the entire cohort
PistersPister (2002)/J Clin Oncol/MD Anderson Cancer Centre	35	Resectable PC/1.8 mo	Phase II, prospective study, timeframe not specified	Paclitaxel (60 mg/m2) weekly, RT (30 Gy)	Partial response 4%; Stable disease 23%; Progression 20%	57	68	12 for the entire cohort; 19 with surgery; 10 without surgery
Joensuu (2004)/Int J Radiat Oncol Biol Phys/Helsinki University	28	Resectable PC/3.5 mo	Phase I-II prospective study, November 1999 to December 2001	Gemcitabine (20 mg/m2vs 50 mg/m2vs 100 mg/m2) twice a week + RT (50 GY)	NA	71	NA	13.6 for the entire cohort
Talamonti (2006)/Ann Surg Oncol/Northwestern University	20	Resectable PC/3.8 mo	Phase II prospective, multi-institutional study, April 2002 to October 2003	Gemcitabine (1000 mg/m2 weekly) + RT (36 Gy)	Partial response 15%; Stable disease 80%; Progression 5%	85	94	26 mo with surgery
Palmer (2007)/Ann Surg Oncol/University of Birmingham	24	Resectable PC/4 mo	Phase II, prospective study, November 1999 to May 2003	Gemcitabine (1000 mg/m2 weekly)	Partial Response 0%; Stable Disease 29%; Progression 4%; Unable to measure 4%	38	75	28.4 with surgery; 9.9 for the entire cohort
Palmer (2007)/Ann Surg Oncol/University of Birmingham	26	Resectable PC/4 mo	Phase II, prospective study, November 1999 to May 2003	Gemcitabine (1000 mg/m2 weekly) + Cisplatin (25 mg/m2)	Partial Response 0%; Stable Disease 66%; Progression 21%; Unable to measure 4%	70	75	28.4 with surgery; 9.9 for the entire cohort
Le Scodan (2009)/Ann Oncol/SFRO-FFCD	41	Resectable PC/3 mo	Phase II, prospective study, January 1998 to March 2003	RT (50 Gy) + 5-FU (300 mg/m2 daily) + Cisplatin (20 mg/m2)	Partial response 10%; Stable Disease 65%; Progression 25%	63	81	11.7 with surgery; 9.4 for the entire cohort
Heinrich (2008)/Ann Surg/University Hospital of Zurich	28	Resectable PC/2 mo	Phase II, prospective study, August 2001 to April 2007	Gemcitabine (1000 mg/m2 twice weekly) + Cisplatin (50 mg/m2)	Partial response 4%; Stable Disease 61%; Progression 13%	89	80	19.1 mo with surgery
Evans (2008)/J Clin Oncol/MD Anderson Cancer Centre	80	Resectable PC/3 mo	Phase II, prospective study, July 1998 to October 2001	Gemcitabine (400 mg/m2 weekly) + RT (30 Gy)	NA	85	82	34 mo with surgery; 22.7 mo for the entire cohort; 7 mo without surgery
Varadhachari (2008)/J Clin Oncol/MD Anderson Cancer Centre	90	Resectable PC/4.3 mo	Phase II, prospective study, October 2002 to February 2006	Gemcitabine (750 mg/m2 weekly) + Cisplatin (30 mg/m2) every 2 wk + RT (30 Gy)	NA	58	96	31.0 mo with surgery; 17.4 mo for the entire cohort; 10.5 mo without surgery
Turrini (2009)/Oncology /University Mediterranean	34	Resectable PC/2.1 mo	Phase II, prospective study, May 2003 to July 2005	Docetazel (30 mg/m2) weekly + RT (45 GY)	Partial response 9%; Stable disease 59%; Progression 32%	68	100	32 mo with surgery; 15.5 mo for entire cohort; 11 mo without surgery
Landry (2010)/J Surg Oncol/Emory University/Multicenter ECOG	21	Resectable PC/3 mo	Phase II, prospective two-arm study, October 2013 to June 2015	Arm 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%	NA	NA	Arm A: Entire cohort 19.4 mo. Arm B: entire cohort 13.4 mo. 26.3 mo with surgery
Wo (2014)/Radiother Oncol/Multicentric	10	Resectable PC	Phase I, prospective study	Capecitabine (1650 mg/m2) over 10 d + RT (30 Gy)	NA	80	NA	NA
Shinoto (2013)/Cancer/Japan	26	Resetable PC	Phase I, prospective study, April 2003 to December 2010	RT (30 Gy)	Partial response 3.8%; Stable disease 96.1%	81	90	18.6 mo for entire cohort; NA for patients who underwent surgery
O'Reilly (2014)/Ann Surg/Memorial Sloan Kettering Cancer Centre	38	Resectable PC	Phase II, prospective study, July 2007 to December 2011	Gemcitabine (1000 mg/m2) + Oxaliplatin (80 mg/m2) every 2 wk	Partial response 10.5%; Stable disease 73.7%; Progression 7.9%; NA 7.9%	77	74	27.2 mo for the enire cohort; 22 mo progression free survival with surgery
Golcher (2015)/Strahlenther Onkol/Germany	66 (33 patients allocated to surgery + 33 patients allocated to chemoradiation followed by surgery)	Resectable PC	Phase II, prospective randomized trial with two arms: Primary surgery vs preoperative chemoradiation followed by surgery. June 2003 to December 2009	Gemcitabine (300 mg/m2) + Cisplatin (30 mg /m2) + RT (50.4 Gy) (Preoperative for patients enrolled in Arm A)	NA	Preoperative chemoradiation: 69% Surgery first: 57%	Arm A (preoperative chemoradition): 48. Arm B (surgery first): 51	Arm A (preoperative chemoradiation): 18.9 mo. Arm B (surgery first): 25.0 mo
Van Buren (2013)/Ann Surg Oncol/Multicenter/United States	59	Resectable PC	Phase II, prospective study, February 2007 to February 2011	Gemcitabine (1500 mg/m2) ever 2 wk + Bevacizumab (10 mg/kg) + RT (30 Gy)	Partial response 8.4%; Stable disease 73.7%; Progression 7.9%	74	88	19.7 mo with surgery; 16.8 mo for the entire cohort

NA: Not available.

Table 4 List of ongoing phase II and phase III trials comparing neoadjuvant therapies vs adjuvant strategies for resectable pancreatic adenocarcinoma

Study	Design	No. of patients needed	Therapy	Primary outcome
NEOPAC (NCT01314027)	Phase III Enrollment 2009-2014	350	Neoadjuvant gemcitabineoxaliplatin + adjuvant gemcitabine vs Adjuvant gemcitabine	Progression free survival
NEOPAC (NCT01521702)	Phase III Initiated in 2011	310	Preoperative FOLFIRINOX, followed by adjuvant gemcitabine after surgery vs adjuvant gemcitabine after resection	Five-year progression free survival
NCT01900327	Phase III	410	Neoadjuvant gemcitabine-based chemoradiation therapy followed by adjuvant gemcitabine vs adjuvant gemcitabine	Three-year overall survival
NCT01771146	Phase II	100	Neoadjuvant FOLFIRINOX	Progression free survival
NEONAX (NCT02047513)	Randomized phase II	166	Neoadjuvant gemcitabine + nab-paclitaxel followed by adjuvant gemcitabine + nab-paclitaxel vs adjuvant gemcitabine + nab-paclitaxel	Disease-free survival at 18 mo
NCT01150630	Randomized phase II/III	370	Adjuvant PEXG vs adjuvant gemcitabine vs neoadjuvant PEXG - followed by surgery and then adjuvant PEXG	One year event-free survival
ACOSOG-Z5041 (NCT00733746)	Phase II	123	Neoadjuvant gemcitabine + erlotinib (completed; results pending)	Two-year overall survival
NCT00727441	Phase II	87	Neoadjuvant GVAX +/- IV or oral cyclophosphamide followed by adjuvant gemcitabine + CRT	Safety, feasibility, and immune response
NCT02178709	Phase II	48	Neoadjuvant FOLFIRINOX	Pathologic complete response
GEMCAD1003 (NCT01389440)	Phase II	24	Neoadjuvant gemcitabine + erlotinib	R0 resection rate
NCT02562716	Phase II Enrollment 2015-2019	112	Neoadjuvant and adjuvant mFOLFIRINOX vs neoadjuvant and adjuvant Nab-paclitaxel and gemcitabine	Overall survival
NCT02243007	Randomized phase II	112	Neoadjuvant FOLFIRINOX vs gemcitabine + nab-paclitaxel	18-mo overall survival
NCT02030860	Pilot	15	Neoadjuvant gemcitabine + nab-paclitaxel ± paricalcitol	Number of adverse events
NCT02305186	Randomized phase Ib/II	56	Neoadjuvant capecitabine-based CRT ± pembrolizumab (MK-3745)	Safety and immune response

CRT: Chemoradiation therapy; GVAX: Granulocyte-macrophage colony-stimulating factor gene-transfected tumor cell vaccine; PEXG: Cisplatin, epirubicin, capecitabine, gemcitabine; R0: Margin-negative surgical resection.