Current controversies and advances in the management of pancreatic adenocarcinoma

Table 1 Tumor-node-metastasis staging of pancreatic adenocarcinoma [American Joint Committee on Cancer Tumor-Node-Metastasis Staging of Pancreatic Cancer (8^th edition, 2017)]-T staging

T	Primary tumor
TX	Primary tumor cannot be assessed
T0	No evidence of primary tumor
Tis	Carcinoma in situ. This includes high-grade pancreatic intraepithelial neoplasia (PanIn-3), intraductal papillary mucinous neoplasm with high-grade dysplasia, intraductal tubulopapillary neoplasm with high-grade dysplasia, and mucinous cystic neoplasm with high-grade dysplasia
T1	Tumor ≤ 2 cm in greatest dimension
T1a	Tumor ≤ 0.5 cm in greatest dimension
T1b	Tumor > 0.5 cm and < 1 cm in greatest dimension
T1c	Tumor 1–2 cm in greatest dimension
T2	Tumor > 2 cm and ≤ 4 cm in greatest dimension
T3	Tumor > 4 cm in greatest dimension
T4	Tumor involves the celiac axis, superior mesenteric artery, and/or common hepatic artery, regardless of size

Table 2 Tumor-node-metastasis staging of pancreatic adenocarcinoma [American Joint Committee on Cancer Tumor-Node-Metastasis Staging of Pancreatic Cancer (8^th edition, 2017)]-N staging

N	Regional lymph nodes
NX	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastases
N1	Metastasis in one to three regional lymph nodes
N2	Metastasis in four or more regional lymph nodes

Table 3 Tumor-node-metastasis staging of pancreatic adenocarcinoma [American Joint Committee on Cancer Tumor-Node-Metastasis Staging of Pancreatic Cancer (8^th edition, 2017)]-M staging

M	Distant metastasis
M0	No distant metastasis
M1	Distant metastasis

Table 4 Tumor-node-metastasis staging of pancreatic adenocarcinoma [American Joint Committee on Cancer Tumor-Node-Metastasis Staging of Pancreatic Cancer (8^th edition, 2017)]-tumor-node-metastasis staging

Stages	T	N	M
Stage 0	Tis	N0	M0
Stage IA	T1	N0	M0
Stage IB	T2	N0	M0
Stage IIA	T3	N0	M0
Stage IIB	T1, T2, T3	N1	M0
Stage III	T1, T2, T3	N2	M0
	T4	Any N	M0
Stage IV	Any T	Any N	M1

Table 5 Criteria defining resectability status of pancreatic adenocarcinoma[30]

Resectability status	Arterial	Venous
Resectable	No arterial tumor contact (CA, SMA, or CHA)	No tumor contact with the SMV or PV or ≤ 180° contact without vein contour irregularity
Borderline resectable	Pancreatic head/uncinate process: Solid tumor contact with CHA without extension to CA or hepatic artery bifurcation. Solid tumor contact with the SMA of ≤ 180°; Solid tumor contact with variant arterial anatomy (ex: Accessory right hepatic artery, replaced right hepatic artery, replaced CHA, and the origin of replaced or accessory artery). Pancreatic body/tail: Solid tumor contact with the CA of ≤ 180°; Solid tumor contact with the CA of > 180° without involvement of the aorta and with intact and uninvolved gastroduodenal artery thereby permitting a modified Appleby procedure (controversial)	Solid tumor contact with the SMV or PV of > 180°, contact of ≤ 180° with contour irregularity of the vein or thrombosis of the vein but with suitable vessel proximal and distal to the site of involvement allowing for safe and complete resection and vein reconstruction. Solid tumor contact with the IVC
Locally advanced	Head/uncinate process: Solid tumor contact with SMA > 180°; Solid tumor contact with the CA > 180°. Pancreatic body/tail: Solid tumor contact of > 180° with the SMA or CA; Solid tumor contact with the CA and aortic involvement	Unreconstructible SMV/PV due to tumor involvement or occlusion (can be due to tumor or bland thrombus)

CA: Celiac axis; SMA: Superior mesenteric artery; CHA: Common hepatic artery; SMV: Superior mesenteric vein; PV: Portal vein; IVC: Inferior vena cava.

Table 6 Treatment protocols for pancreatic adenocarcinoma in adjuvant setting

Drug	Dose and route	Administration	Toxicity
Adjuvant gemcitabine (cycle length: 4 wk)[156]
Gemcitabine	1000 mg/m2 IV	Weekly (× 3 wk) followed by one week of rest	Myelotoxicity; Hepatotoxicity; Pulmonary toxicity; Thrombotic microangiopathy
Adjuvant gemcitabine plus capecitabine (GemCap; cycle length: 28 d)[157]
Gemcitabine	1000 mg/m2 IV	Given on days 1, 8, and 15	Myelotoxicity; Nonhematologic toxicity (including hepatoxicity); Pulmonary toxicity; Thrombotic microangiopathy
Capecitabine	830 mg/m2 per dose by mouth	Given on days 1 through 21
Modified FOLFIRINOX (cycle length: 14 d)[158-162]
Oxaliplatin	85 mg/m2 IV	Given on day 1	Myelotoxicity; Diarrhea; Mucositis or hand-foot syndrome; Pulmonary toxicity; Neurotoxicity; Cardiotoxicity
Leucovorin	400 mg/m2 IV	Given on day 1
Irinotecan	150 mg/m2 IV	Given on day 1
Fluorouracil	2400 mg/m2 IV	Given on day 1

Table 7 Treatment protocols for locally advanced/metastatic pancreatic adenocarcinoma

Drug	Dose and route	Administration	Toxicity
Gemcitabine monotherapy (cycle length: 8 wk for first cycle, then 4 wk)[163-166]
Gemcitabine	1000 mg/m2 IV	Weekly (× 7 wk) followed by one week of rest in the first cycle, then weekly (× 3 wk) followed by one week of rest in all subsequent cycles	Myelotoxicity; Hepatoxicity; Pulmonary toxicity; Thrombotic microangiopathy
Gemcitabine plus nanoparticle albumin-bound paclitaxel (nabpaclitaxel) (cycle length: 4 wk)[167,168]
Nabpaclitaxel	125 mg/m2 IV	Given on days 1, 8, and 15	Myelotoxicity; Sepsis; Thrombotic microangiopathy; Peripheral neuropathy; Hepatotoxicity; Pulmonary toxicity
Gemcitabine	1000 mg/m2 IV	Given on days 1, 8, and 15
Gemcitabine plus capecitabine (cycle length: 21 d)[157,169]
Gemcitabine	1000 mg/m2 IV	Given on days 1 and 8	Myelotoxicity; Nonhematologic toxicity (including hepatoxicity); Pulmonary toxicity; Thrombotic microangiopathy
Capecitabine	650 mg/m2 per dose by mouth	Given on days 1 through 14
Gemcitabine plus cisplatin (cycle length: 21 d)[170]
Cisplatin	25 mg/m2 IV daily	Given on days 1 and 8	Myelotoxicity; Thrombotic microangiopathy; Pulmonary toxicity; Hepatotoxicity; Neurotoxicity; Nephrotoxicity
Gemcitabine	1000 mg/m2 IV daily	Given on days 1 and 8
FOLFIRINOX (fluorouracil plus leucovorin, irinotecan, and oxaliplatin) (cycle length: 14 d)[160,161]
Oxaliplatin	85 mg/m2 IV	Given on day 1	Myelotoxicity; Diarrhea; Mucositis or hand-foot syndrome; Pulmonary toxicity; Neurotoxicity; Cardiotoxicity
Leucovorin	400 mg/m2 IV	Given on day 1
Irinotecan	180 mg/m2 IV	Given on day 1
Fluorouracil	400 mg/m2 IV bolus	Given on day 1
FU	2400 mg/m2 IV	Given on day 1
Modified FOLFIRINOX (cycle length: 14 d)[158,159,161]
Oxaliplatin	85 mg/m2 IV	Given on day 1	Myelotoxicity; Diarrhea; Mucositis or hand-foot syndrome; Pulmonary toxicity; Neurotoxicity; Cardiotoxicity
Leucovorin	400 mg/m2 IV	Given on day 1
Irinotecan	150 mg/m2 IV	Given on day 1
Fluorouracil	2400 mg/m2 IV	Given on day 1
Modified FOLFOX6 (fluorouracil plus leucovorin and oxaliplatin) (cycle length: 14 d)[160,171,172]
Oxaliplatin	85 mg/m2 IV	Given on day 1	Myelotoxicity; Neurotoxicity; Diarrhea; Cardiopulmonary toxicity
Leucovorin	400 mg/m2 IV	Given on day 1
Fluorouracil	400 mg/m2 IV bolus	Given on day 1
FU	2400 mg/m2 IV	Given on day 1
Liposomal irinotecan and fluorouracil (cycle length: 14 d)[173]
Liposomal irinotecan	70 mg/m2 IV	Given on day 1	Myelotoxicity; Diarrhea; Neurotoxicity; Cardiotoxicity
Leucovorin	400 mg/m2 IV	Given on day 1
Fluorouracil	2400 mg/m2 IV	Given on day 1
Pembrolizumab monotherapy for microsatellite-unstable (mismatch repair-deficient) advanced cancer (cycle length: q3 weeks or q6 weeks)[174,175]
Pembrolizumab	200 mg IV	Given on day 1, every 3 wk	Pulmonary toxicity; Hepatotoxicity; Neurotoxicity; Dermatologic toxicityCardiotoxicity
OR
Pembrolizumab	400 mg IV	Given on day 1, every 6 wk