Current and emerging therapies for the treatment of pancreatic cancer

Figures & data

Figure 1 Survival of patients with pancreatic cancer categorized by the receipt of curative intent surgery. Copyright © 2007. Reproduced with permission from Shaib Y, Davila J, Naumann C, EI-Serag H. The impact of curative intent surgery on the survival of pancreatic cancer patients: a U.S. Population-based study. Am J Gastroenterol. 2007;102(7):1377–1382.

Table 1 Randomized control trials of adjuvant chemotherapy and CRT

Study	Year	Chemo	RT	No. of patients	MOS	2-yr survival rate, %	P value
GITSG Kalser^Citation15	1985	5-FURT→5-FU	40 Gy	21	20	42	0.035
		Observation		22	11	15
Bakkevold et al^Citation119	1993	AMF		30	23	43	0.009
		Observation		31	11	32
EORTC Klinkenbijl et al^Citation16	1999	5-FURT	60 Gy	60	17.1	37	0.099
		Observation		54	12.6	23
ESPAC-1 Neoptolemos et al^Citation18	2004	5-FURT	40 Gy	145	15.9	29	0.053
		Observation		144	17.9	41
		5-FU/LV		147	20.1	40	0.009
		Observation		142	15.5	30
ROTG 9704 Regine et al^Citation39	2006	All patients
		GEM→5-FURT→GEM	50.4 Gy	221	18.8		0.15
		5-FU→5-FURT→5-FU		221	16.9
		Pancreas head
		GEM→5-FURT→GEM	50.4 Gy	187	20.6		0.033
		5-FU→5-FURT→5-FU		194	16.9
Kosuge et al^Citation21	2006	5-FU/CDDP		45	12.5		0.94
		Observation		44	15.8
CONKO-001 Oettle et al^Citation22	2007	GEM		179	22.1	47.5	0.06
		Observation		175	20.2	42
Kosuge et al^Citation21/Ueno et al^Citation23 (abstract)	2007	GEM		58	22.3	48.3	0.29
		Observation		60	18.4	39.8
ESPAC-3 Neoptolemos et al^Citation24	2009	5-FU/LV		551	23.0
		GEM		537	23.6

Abbreviations: AMF, adriamycin/mitomycin CRT, chemoradiation; RT, radiation therapy; MOS, median survival overall; GITSG, Gastrointestinal Tumor Study Group; 5-FURT, fluorouracil and radiation; CDDP, cisplatin; EORTC, European Organization for Research and Treatment of Cancer; ESPAC, Europen Study Group For Pancreatic Cancer; 5-FU, fluorouracil; GEM, gemcitabine; LV, leucovorin; RTOG, Radiation Therapy Oncology Group; CONKO, German Study Group for Pancreatic Cancer.

Figure 2 Downstaging with neoadjuvant therapy: 59-year-old man with a 2.2 × 1.8 cm pancreatic head mass found to be pancreatic adenocarcinoma on biopsy A) Pretreatment scan. Note severe SMV impingement, which fits criteria for borderline resectable disease B) Post-treatment scan. The patient was reated with neoadjuvant capecitabine 1500 mg po bid and concurrent radiation. The SMV is less confined; the pancreas mass remains similar in size. C) Post-operative scan. The patient underwent pancreaticoduodenectomy with jugular SMV reconstruction.

Table 2 Criteria for defining resectability status^25,26

	Resectable	Borderline resectable	Unresectable
Venous	Patent SMV and portal vein	Severe SMV impingement or reconstructable SMV occlusion	Unreconstructable SMV/portal occlusion Greater than 180° SMA encasement
Arterial	Clear fat plane around celiac A and SMA	Less than 180° abutment of SMA, reconstructable encasement of SMA Reconstructable abutment or encasement of hepatic artery	Greater than 180° SMA encasement Unreconstructable SMA involvement Any celiac abutment (head mass) Greater than 180° SMA encasement (body mass)
Aorta			Aortic invasion or encasement
Mets	No distant metastases		Distant metastases Metastases to LN beyond field of resection

Table 3 Summary of studies for locally advanced pancreatic cancer

Study	Year	Chemo	Radiation	No. of patients	Resection rate, %	Borderline	Borderline resection rate	Median survival unresected	Median survival resected (borderline)
Weese et al^Citation32	1990	5-FU, MIT	50.4	15	67			7
Jessup et al^Citation29	1993	5-FU	>45	16	13			8	20
Yeung et al^Citation120	1993	5-FU, MIT	50.4	26	38			8
Kamthan et al^Citation121	1997	5-FU, CDDP, STZ	54	35	14			15	31
White et al^Citation122	1999	5-FU, MIT or CDDP	45	25	20			10
Bajetta et al^Citation123	1999	5-FU, Leu	50	32	16			10 overall
Wanebo et al^Citation124	2000	5-FU, CDDP	45	14	64 (3 refused)			9	19
Kim et al^Citation125	2002	5-FU/GEM		87	1 (n = 1)			11	18
Rau et al^Citation126	2002	5-FU, CDDP	45	26	42			10
Crane et al^Citation114	2002	5-FU or GEM	30	114	2 vs 9			9 vs 10
Aristu et al^Citation127	2003	5-FU or CDDP	45	47	19			10	23
Ammori et al^Citation28	2003	GEM	39.6	6 7	13	18	33%	12	18
Wilkowski et al^Citation128	2004	GEM, CDDP	45–50	47	42 (R0 27)			11	24 (for R0)
Sa Cunha et al^Citation129	2005	5-FU, CDDP	45	61	21			11	28
Delpero^Citation130	2006	5-FU, CDDP	45	26	58			21	Not reached
Adhoute et al^Citation131	2006	5-FU CDDP	45–50.4	33	24			16
Massuco et al^Citation33	2006	GEM	45	28	29%			10	721
Marti et al^Citation41	2007	GEM, CDDP		26	15	3	100%	13	(12–62)
Budiharto et al^Citation113	2008	GEM	45 or 54	5 vs 6	60 vs 33			20
Brown et al^Citation34	2008	Various 5-FU, cap/bev, or GEM	50.4			13	100		(69% OS at 2 yrs)
Chauffert et al^Citation42	2008	5-FU/CDDP + GEM	60 Gy	59
Tinkl et al^Citation132	2009	GEM, CDDP or 5-FU, MIT	3D55.8	120	32			25	52 (for R0)
Small et al^Citation38	2008	GEM	36	9.14	33%		7%*	3	33%

Notes:

* One patient deemed unresectable underwent surgery after neoadjuvant treatment.

Abbreviations: 5-FU, fluorouracil; CDDP, cisplatin; GEM, gemcitabine; cap/bev, capecitabine/bevacizumab; MIT, mitomycin C treatment.

Figure 3 A) CT image after injection of a small volume of dilute contrast agent through both needles, confirming correct distribution of injected contrast around the celiac axis (arrows) prior to alcohol injection. B) After injection of alcohol, darkened region (arrow) shows its distribution in the vicinity of the celiac plexus. Copyright © 2007. Reproduced with permission from Arellano RS. Image-guided pain management, Part 1: celiac plexus block for palliative pain relief. Radiology Rounds, Vol 5. Boston, MA: Massachusetts General Hospital; 2007.

Table 4 Phase III studies comparing addition to gemcitabine therapy

Study	Chemo	Year	No. of patients	RR, %	PFS, mo	OS, mo	1-year survival, %
E2297 Berlin et al^Citation133	GEM	2002	322	5.6	2.2	5.4	14
	GEM + 5-FU			6.9	3.4 (P = 0.022)	6.7 (P = 0.09)	20
Reiss et al^Citation134	GEM	2005	466			6.2	22
	GEM + 5-FU/leuk					5.85 (P = 0.68)	21 (P = 0.68)
Herrmann et al^Citation86	GEM	2007	319	7.8		7.2	30
	GEM + cap			10.0		8.4 (P = 0.234)	32
Cunningham et al^Citation135	GEM	2005	533	7		6.0	19
	GEM + cap			14 (P = 0.008)		7.4 (P = 0.26)	26
Heinemann et al^Citation136	GEM	2006	190	8.2	3.1	6.0
	GEM + cis			10.2	5.3 (P = 0.053)	7.5 (P = 0.15)
E6201 Poplin et al^Citation74	GEM	2009	824	6	2.6	4.9	16
	FDR GEM			10 (P = 0.11)	3.5 (P = 0.04)	6.2 (P = 0.04)	22
	GEM Ox			9	2.7 (P = 0.1)	5.7 (P = 0.22)	21
GERCOR/GISCAD	GEM	2005	313	17.3	3.7	7.1	27.8
Louvet et al^Citation76	GEM Ox			26.8	5.8 (P = 0.04)	9.0 (P = 0.13)	34.7 (P = 0.22)
Rocha Lima et al^Citation117	GEM	2004	342	4.4	3.0	6.6 (P = 0.789)
	GEM + iri			16.1 (P < 0.001)	3.5 (P = 0.352)	6.3 (P = 0.789)	20
Strathopoulos et al^Citation137	GEM	2006	130	10	2.9	6.5	21.8
	GEM + iri			15 (P = 0.387)	2.8	6.4 (P = 0.97)	24.3 (P = 0.666)
Abou-Alfa et al^Citation138	GEM	2006	349	5.1	3.8	6.2	21
	GEM + exa			6.8	3.7	6.7 (P = 0.52)	23 (P = 0.52)
Reni et al^Citation139	GEM	2005	104	8.5	3.3		21.3
	PEFG			38.5	5.4 (P = 0.0033)		38.5 (P = 0.11)
Oettle et al^Citation140	GEM	2005	565	7.1	3.3	6.3	20.1
	GEM + pemetrexed			14.8 (P = 0.004)	3.9 (P = 0.11)	6.2 (P = 0.85)	21.4

Abbreviations: RR, response rate; PFS, progression-free survival; OS, overall survival; GEM, gemcitabine; 5-FU, fluorouracil; Leuk, leukemia; cap, capecitabine; cis, cisplatin; FDR, fixed dose rate; GERCOR, French Multidisciplinary Clinical Research Group in Oncology; GISCAD, Italian Group for the Study of Gastrointestinal Tract Cancer; GEMOx, gemcitabine plus oxaliplatin; iri, irinotecan; exa, exatecan.

Table 5 Phase III trials of molecularly targeted agents for advanced and metastatic pancreatic cancer

Author	Chemo	Year	No. of patients	RR, %	PFS (mo)	OS (mo)	1-year survival (%)
Bramhall et al^Citation141	Marimastat	2001	414	3	2.9	4	14–20
	GEM			26	4.9 (P = 0.0001)	5.6 (P = 0.19)	19
Bramhall et al^Citation142	GEM	2002	239	16	3.2	5.5	17
	GEM + marimastat			11	3.1 (P = 0.68)	5.4 (P = 0.95)	18
Moore et al^Citation143	Talomastat	2003	277	1	1.68	3.74	10
	GEM			5	3.5 (P < 0.001)	6.59	25
Van Cutsem et al^Citation144	GEM	2007	688	8	3.6 (P = 0.72)	6.1	24
	GEM + tafarnib			6	3.7	6.4 (P = 0.75)	27
Philip^Citation93 S0205	Cetuximab	2007		7	3.5	6.5
				7	3 (P = 0.058)	6.0 (P = 0.14)
Kindler et al^Citation96 CALGB 8030	Bevacizumab	2007		11	4.7	5.8
				10	4.9 (P = 0.99)	6.1 (P = 0.78)

Abbreviations: RR, response rate; PFS, progression-free survival; OS, overall survival; GEM, gemcitabine.

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