Neoadjuvant therapy for pancreas cancer: Past lessons and future therapies

Table 1 Rationale for patient selection for neoadjuvant therapy in pancreatic cancer

Rationale in support of neoadjuvant therapy
Increasing the likelihood of margin-negative resection[4,20-25]
Increasing the likelihood of completion of multimodality therapy[5,26-29]
Increasing efficacy of radiotherapy[4,24]
Minimizing pancreatic leak (without increasing complications)[19,30-34]
Determination of indeterminant lesions[29,35]
Declaration of distant metastases[4,29]
Decreasing “open-and-close” rates[19]
Allowing a patient’s functional status to declare itself[36]
Improved cost-effectiveness[37]

Table 2 Recently published prospective neoadjuvant trials of multimodal therapy for pancreatic cancer n (%)

Ref.	Initial staging	Regimen		Resection	Survival	Notes
		Chemoradiation	Chemotherapy
Palmer et al[106], 2007	Resectable (n = 50)	N/A	Gem vs Gem + Cis	Overall: 27 (54); Gem: 9 (38), Gem + Cis: and 18 (70)	Gem: 42%, Gem + Cis: 62% (1 yr survival)	Randomized Phase II; No difference in surgical complcations
Le Scodan et al[41], 2008	Resectable (n = 41)	50 Gy + 5-FU + Cis	N/A	26 (63)	Overall: 9.4 mo, R: 11.7 mo (2 yr survival 32%) UR: 5.7 mo	Phase II; 67.5% were successfully treated with entire radiation dose and ≥ 75% chemotherapy dose; 81% achieved an R0 resection
Heinrich et al[107], 2008	Resectable (n = 28)	N/A	Gem + Cis	26 (93)	Overall: 26.5 mo; R: 19.1 mo	Phase II; 80% achieved an R0 resection
Evans et al[19], 2008	Resectable (n = 86)	30 Gy + Gem	N/A	64 (74)	Overall: 22.7 mo; R: 34 mo, UR: 7 mo (P < 0.001)	Phase II; 27% 5 yr OS, 36% vs 0% for resected vs unresected
Varadhachary et al[33], 2008	Resectable (n = 90)	30 Gy + Gem + Cis	Gem + Cis	52 (66)	Overall: 17.4 mo; R: 31 mo, UR: 10.5 mo	Phase II
Turrini et al[108], 2010	Resectable (n = 34)	45 Gy + Docetaxel	N/A	17 (50)	R: 32 mo	Phase II; 10% R0 resection; 5 yr survival resected 41%
Landry et al[109], 2010	Borderline	Arm A: 50.4 Gy + Gem (n = 10)	Arm B: Gem + Cis + 5-FU then 50.4 Gy + 5-FU (n = 11)	A: 3 (30) B: 2 (22)	R: 26.3 mo A: 19.4 mo B: 13.4 mo	Phase II; early termination due to poor accrual
Sahora et al[45], 2011	Unresectable (n = 18), borderline (n = 15)	N/A	Gem + Oxaliplatin	13 (39)	R: 22 mo UR: 12 mo (P = 0.046)	Phase II; 69% R0 resection
Sahora et al[46], 2011	Borderline (n = 12), Unresectable (n = 13)	N/A	Gem + Docetaxel	8 (32)	R: 16 mo, UR: 12 mo	Phase II; 87% R0 resection
Pipas et al[43], 2012	Resectable (n = 4), Borderline (n = 23), Unresectable (n = 6)	54 Gy + Cetuximab + Gem	N/A	25 (76)	R: 24.3 mo	Phase II; 92% R0 resection
Wo et al[51], 2013	Resectable (n = 10)	Short-course photon RT (3 Gy × 10, 5 Gy × 5 qod, 5 Gy × 5 qd) + Capecitabine	N/A	N/A	N/A	Phase I; closed early due to intraoperative complications (fibrosis)
Kim et al[44], 2013	Resectable (n = 23), Borderline (n = 39), Unresectable (n = 6)	30 Gy + Gem + Oxaliplatin	N/A	43 (63)	Overall: 18.2 mo; R:27.1 mo, UR: 10.9	Phase II, multi-institutional
Shinoto et al[52], 2013	Resectable (n = 26)	30.0-36.8 Gy E of Carbon-ion radiotherapy (CIRT)	N/A	21 (81)	Overall: 42%, R: 52% (5 yr survival)	Phase I; short course radiation

Gem: Gemcitabine, Cis: Cisplatin; 5-FU: Fluorouracil; Gy: Gray; R: Resected patients; UR: Unresected patients; N/A: Not available.

Table 3 Select clinically valuable pancreatic cancer biomarkers

Gene product	Target drug	Mechanism	Ref.
hENT1	Gemcitabine	Nucleoside inhibitor, prevents DNA synthesis in cancer cells	[59-64]
TS/DPD	5-FU/S-1	Suicide inhibitor of TS, prevents DNA synthesis in cancer cells	[65-71]
EGFR	Erlotinib	Tyrosine kinase inhibitor, prevents EGFR-mediated cell cycle progression and cellular proliferation	[72-79]
CA 19-9	N/A	N/A	[80-88]
SPARC	Nab-paclitaxel	Disruption of microtubule formation during mitosis	[12,89-94]
SMAD4	N/A	Tumor suppression, initiation, and metastasis	[95-99]

CA 19-9: Carbohydrate antigen 19-9; TS: Thymidylate synthase; hENT1: Human equilibrative nucleoside transporter-1; SPARC: Secreted protein acidic and rich in cysteine; EGFR: Epidermal growth factor receptor.