Neoadjuvant treatment in resectable pancreatic cancer: Why is upfront surgery so hard to be beaten?

Table 1 Studies based on Gemcitabine for adjuvant treatment of resectable pancreatic adenocarcinoma

Ref.	Year	Trial Design	Age (range), years	Intervention	n	Median OS (95%CI), months	OS P value	Median DFS (95%CI), months	DFS P value	R0 rates (%)
CONKO-001[10]	2007	Ph3	62 (34-82)	Gem	179	22.1 (NS)	0.06	13.4 (11.4-15.3)	< 0.01	81
			61 (36-81)	Observation	175	20.2 (NS)		6.9 (6.1-7.8)		85
ESPAC-1[11]	2004	Two-by-two factorial design	62 (52-68)	5-FU+RDT	145	15.9 (13.7-19.9)	0.05	10.7 (8.8-15.5)1	0.04	812
			61 (55-66)	No RDT	144	17.9 (14.8-23.6)		15.2 (9.8-22.2)1		842
			61 (54-67)	5-FU	147	20.1 (16.5-22.7)	0.009	15.3 (10.5-19.2)1	0.02	812
			61 (54-67)	No 5-FU	142	15.5 (13.0-17.7)		9.4 (8.4-15.2)1		842
ESPAC-4[12]	2017	Ph3	65 (37-80)	Gem	366	25.5 (22.7–27.9)	0.03	13.1 (11.6–15.3)3	0.08	402
			65 (39-81)	Gem, Cap	364	28.0 (23.5–31.5)		13.9 (12.1–16.6)3		392
PRODIGE-24[13]	2018	Ph3	63 (30-79)	mFFX	247	54.4 (41.8-NR)	0.003	30.4 (21.7-NR)	< 0.001	59.9
			64 (30-81)	Gem	246	35 (28.7-43.9)		17.7 (14.2-21.5)		54.5
APACT[14]	2023	Ph3	64 (34-83)	Gem, Nab-Pac	432	41.8 (35.5- 47.2)	0.02	16.6 (14.5-19.2)	0.02	76
			64 (38-86)	Gem	434	37.7 (31.1-40.5)		13.7 (11.2-16.0)		77
JASPAC-1[15]	2016	Ph3	66 (59–73)	Gem	190	25.5 (22.5-29.6)	< 0.0001	11.3 (9.7-13.6)	0.0001	86
			66 (60–73)	S-1	187	46.5 (37.8-63.7)		22.9 (17.4–30.6)		88

¹Time-to-tumor recurrence.

²Negative margins.

³Relapse-free survival.

Ph3: Phase 3; Gem: Gemcitabine; 5-FU: Fluorouracil; RDT: Radiotherapy; mFFX: Modified FOLFIRINOX; NR: Not-reached; Nab-Pac: Nab-paclitaxel; NS: No specified.

Table 2 Randomized Clinical trials of neoadjuvant treatment for resectable pancreatic adenocarcinoma

Ref.	Year	Trial design	Age (range), years	Regimen	Intervention	n	Median OS (95%CI), months	OS HR (95%CI)	Median DFS (95%CI), months	DFS HR (95%CI)	R0 rates,%
Casadei et al[22]; Di Marco et al[23]	2015	Ph2	71.5 (51-78)	Neoadjuvant	GEM + RDT -> surgery -> GEM	18	24.3 (8.0-40.6)	P = 0.17	18.03 (2.58-33.48)	P = 0.24	38.9
			67.5 (48-79)	Adjuvant	Surgery -> GEM	20	21.1 (8.3-33.9)		8.53 (4.47-12.59)		25
Golcher et al[24]	2015	Ph2	62.5 (33-76)	Neoadjuvant	GEM, CDDP + RDT -> surgery > GEM	33	17.4	P = 0.96	—	—	52
			65.1 (46-73)	Adjuvant	Surgery -> GEM	33	14.4		—		48
Reni et al[25]	2018	Ph2	64 (39-75)	Neoadjuvant	PEXG -> Surgery -> PEXG	32	38.2 (27.3-49.1)	—	16.9 (3.7-28.7)	—	63
			68 (49-75)	Adjuvant	Surgery -> PEXG	30	26.4 (15.8-26.7)		12.4 (5.4-19.4)		37
			65 (37-74)	Adjuvant	Surgery > GEM	26	20.4 (14.6-25.8)		4.7 (0.9-8.9)		27
Satoi[26]	2019	Ph3	Not presented	Neoadjuvant	GEM + S1 -> surgery- > S1	182	36.7 (28.6-43.3)	P = 0.01	—	—	—
				Adjuvant	Surgery -> S1	180	26.6 (21-31.3)		—		—
Versteijne et al[7]	2022	Ph3	66 (59-71)	Neoadjuvant	GEM + RDT -> surgery -> GEM	65	14.6 (NS)	P = 0.83	9.2	0.88 (0.60-1.28), P = 0.52	66
			67 (60-73)	Adjuvant	Surgery -> GEM	68	15.6 (NS)		9.3		59
Labori et al[20]	2024	Ph2	68 (60-72)	Neoadjuvant	FFX-> Surgery-> Gem, Cap or FFX	77	25.1 (17.2-34.9)	P = 0.05	11.9 (9.3-15.7)	P = 0.22	56
			66 (57-72)	Adjuvant	Surgery -> Gem, Cap or FFX	63	38.5 (27.6-NR)		16.2 (10.8-21)		39
PREOPANC-2[23]	2023	Ph3	66 (NS)	Neoadjuvant	FFX-> surgery	185	21.9 (17.7-27)	P = 0.28	NS	-	61
			68 (NS)	Neoadjuvant	GEM+RDT-> Surgery-> GEM	184	21.3 (16.8-25.5)		NS		67
Seufferlein et al[18]	2023	Ph2	Not presented	Neoadjuvant	GEM + NAB-PACL > surgery	59	25.2 (NS)	HR: 1.26 (0.80-1.97)	11.5	1.31 (0.86-1.99)	87.8
				Adjuvant	Surgery > GEM + NAB-PACL	59	16.7 (NS)		5.9		67.4

Ph3: Phase 3; Ph2: Phase 2; Gem: Gemcitabine; 5-FU: Fluorouracil; RDT: Radiotherapy; mFFX: Modified FOLFIRINOX; NR: Not-reached; Nab-Pac: Nab-paclitaxel; NS: No specified; CDDP: Cisplatin; PEXG: Cisplatin, epirubicin, capecitabine, gemcitabine.

Table 3 Rational regarding putative pros cons of neoadjuvant treatment for both resectable and borderline pancreatic adenocarcinoma

Advantages	Disadvantages
Delivery of systemic therapy	Complications of pre-treatment procedures (biopsy, stents, etc.)
Increased efficacy of radiation	Occasional limiting toxicity due the treatment delaying surgical treatment
Removal of irradiated tissues	Occasional drop out due to either limiting toxicity or tumor progression
Increasing in R0 rates	No proven benefit for resectable lesions in randomized clinical trials
Decreasing of fistula rates