Advances in neoadjuvant therapy for pancreatic cancer: Current trends and future directions

Table 1 Neoadjuvant therapy in resectable pancreatic cancer

Ref.	Type of study	Year	Treated with radiotherapy	Total (n)	Stage of disease	Treatment regimen	Resection rate (%)	R0 resection rate (%)	Median OS (months)	Other outcome measure	Median DFS (months)
Ahmad et al[64]	Clinical trial	2020	No	55	RPC	mFOLFIRINOX	87	85	22.4	2-year OS rate: 41.60%	10.9
			No	47	RPC	Gemcitabine/nab-paclitaxel	77	85	23.6	48.80%	14.2
Motoi et al[65]	Clinical trial	2019	No	182	RPC	Gemcitabine + S1	NR	NR	36.7	NR	NR
			No	180	RPC	Upfront surgery	NR	NR	26.6	NR	NR
Versteijne et al[66]	Clinical trial	2020	Yes	65	RPC	Gemcitabine + radiotherapy	68	66	14.6	NR	9.2
			No	68	RPC	Upfront surgery	79	59	15.6	NR	9.3
Golcher et al[67]	Clinical trial	2015	Yes	33	RPC	Gemcitabine + cisplatin + radiotherapy	58	89	17.4	NR	NR
			No	33	RPC	Upfront surgery	70	70	14.4	NR	NR
Cucchetti et al[68]	Clinical Trial	2022	Yes	182	RPC	Gemcitabine + S1	NR	NR	36.7	NR	NR
Heinrich et al[69]	Clinical Trial	2019	Yes	102	RPC, BRPC, LAPC	Gemcitabine + radiotherapy	79	70	26.8	Improved resectability and surgical outcomes	12.1
Fujii et al[70]	Observational study	2017	Yes	40	RPC	5-FU + oteracil + gimeracil + S-1 + radiotherapy	92	97	24.9	NR	NR
			No	233	RPC	Upfront surgery	88	70	23.5	NR	NR
			No	56	RPC	Upfront surgery	87.5	56.5	NR	NR	NR
Casadei et al[71]	Randomized controlled trial	2015	Yes	18	RPC	Gemcitabine + radiotherapy	61.1	38.9	22.4	NR	NR
			No	20	RPC	Upfront surgery	75	25	19.5	NR	NR
Tzeng et al[72]	Retrospective study	2014	Yes	115	RPC	Gemcitabine and cisplatin + radiotherapy	83	89.5	28	NR	NR
			No	52	RPC	Upfront surgery	92.3	81.3	25.3	NR	NR
Ielpo et al[73]	Retrospective study	2017	Yes	19	RPC	Gemcitabine and nab-paclitaxel + radiotherapy	78.9	NR	22.1	NR	21
			No	17	RPC	Upfront surgery	100	NR	24.8	NR	14
Hoffman[74]	Review article	2010	No	N/A	RPC	FOLFIRINOX, gemcitabine-based therapies	NR	NR	NR	Enhanced R0 resection and downstaging in advanced cases	NR
Gillen et al[18]	Systematic review	2010	No	720	RPC	Multiple regimens	68.5	73	25.3	Improved tumor response and resection rates	NR

Table 1 provides a detailed summary of clinical trials and studies evaluating the efficacy of various neoadjuvant therapy (NAT) regimens in patients with resectable pancreatic cancer (RPC). The table includes data on study type, references, treatment regimens, resection rates, margin-negative (R0) resection rates (indicating margin-negative resection), median overall survival, and disease-free survival, where available. This provides a comprehensive view of the benefits and challenges associated with various neoadjuvant regimens in improving surgical outcomes. These metrics highlight the outcomes of different approaches, including chemotherapy, chemoradiation, and combinations of targeted agents. By presenting these key parameters, Table 1 underscores the significant improvements in resectability and survival outcomes achieved through NAT, compared with upfront surgery. Notably, regimens such as modified fluorouracil, leucovorin, irinotecan, and oxaliplatin and gemcitabine-based therapies demonstrate the highest R0 resection rates, affirming the pivotal role of NAT in enhancing surgical outcomes. The table serves as a valuable resource for understanding the therapeutic potential and challenges associated with various NAT protocols in the management of RPC. RPC: Resectable pancreatic cancer; R0: Margin-negative resection; OS: Overall survival; DFS: Disease-free survival; mFOLFIRINOX: Modified fluorouracil, leucovorin, irinotecan, and oxaliplatin; 5-FU: 5-fluorouracil; N/A: Not applicable; NR: Not report; BRPC: Borderline resectable pancreatic cancer; LAPC: Locally advanced pancreatic cancer.

Table 2 Neoadjuvant therapy in borderline resectable pancreatic cancer

Ref.	Type of study	Year	Treated with radiotherapy	Total (n)	Stage of disease	Treatment regimen	Resection rate (%)	R0 resection rate (%)	Median OS (months)	Median DFS (months)
Tran et al[75]	Clinical trial	2020	Yes	25	BRPC	FOLFIRINOX + radiotherapy + gemcitabine	52	100	24.4	NR
Springett et al[76]	Clinical trial	2008	Yes	130	BRPC	Gemcitabine + chemoradiation	Improved resectability	NR	NR	NR
Okada et al[77]	Clinical trial	2016	No	10	BRPC	mFOLFIRINOX	70	71.4	NR	NR
Chaudhari et al[78]	Clinical trial	2022	Yes	70	BRPC	Gemcitabine + radiotherapy + surgery	62.5	80.2	28.4	NR
Katz et al[79]	Clinical trial	2016	Yes	22	BRPC	mFOLFIRINOX + capecitabine + radiotherapy	68.2	93.3	21.7	NR
Murphy et al[80]	Clinical trial	2018	Yes	48	BRPC	FOLFIRINOX + radiotherapy	66.7	96.9	37.3	NR
Peng et al[81]	Clinical trial	2019	No	85	BRPC	Pathologic tumor response to NAT correlated with node-negative disease	NR	NR	No significant OS benefit	NR
Masui et al[82]	Clinical trial	2016	No	18	BRPC	Gemcitabine + S1	83.3	80	21.7	NR
			No	19	BRPC	Upfront surgery	100	52.6	21.1	NR
Heinrich et al[83]	Clinical trial	2019	Yes	100	BRPC	Total neoadjuvant therapy	Improved pathologic response	NR	Improved OS in pCR patients	NR
Javed et al[84]	Retrospective study	2019	Yes	151	BRPC	Fluorouracil-based + radiotherapy	63.6	77.1	23.7	NR
Patel et al[85]	Retrospective study	2011	Yes	14	BRPC	Gemcitabine + docetaxel + capecitabine + 5-FU + radiotherapy	64.3	88.9	15.64	10.48
Kim et al[86]	Retrospective study	2017	Yes	40	BRPC	Gemcitabine-based + radiotherapy	85	76.5	20	NR
Barnes et al[87]	Retrospective study	2019	Yes	185	BRPC	FOLFIRINOX + radiotherapy	62.2	96.5	20	19
Ielpo et al[73]	Retrospective study	2017	Yes	26	BRPC	Gemcitabine and nab-paclitaxel + radiotherapy	61.5	NR	18.9	NR
			No	19	BRPC	Upfront surgery	100	NR	13.5	NR

To provide a clearer understanding of the impact of neoadjuvant therapy (NAT) on borderline resectable pancreatic cancer (BRPC), Table 2 provides a comprehensive summary of clinical trials and retrospective studies evaluating NAT in patients with borderline BRPC. This table highlights key metrics, including treatment regimens, whether radiotherapy was used, resection rates, margin-negative (R0) resection rates, median overall survival, and disease-free survival. The data underscore the critical role of NAT in enhancing surgical outcomes for BRPC patients by increasing resection rates and achieving R0 resections, which are pivotal for long-term survival. Table 2 illustrates the efficacy of different NAT strategies in managing the unique challenges posed by BRPC, offering valuable insights for optimizing treatment protocols and advancing clinical management of this subset of pancreatic cancer. RPC: Resectable pancreatic cancer; BRPC: Borderline resectable pancreatic cancer; NAT: Neoadjuvant therapy; R0: Margin-negative resection; OS: Overall survival; DFS: Disease-free survival; FOLFIRINOX: Fluorouracil, leucovorin, irinotecan, and oxaliplatin; NR: Not reported.

Table 3 Neoadjuvant therapy in locally advanced pancreatic cancer

Ref.	Type of Study	Year	Treated with radiotherapy	Total (n)	Stage of disease	Treatment regimen	Resection rate (%)	R0 resection rate (%)	Median OS (months)	Median DFS (months)
Murphy et al[88]	Clinical trial	2019	Yes	49	LAPC	FOLFIRINOX + losartan + radiotherapy	80.9	88.2	31.4	NR
Stein et al[89]	Clinical trial	2016	Yes	31	LAPC	mFOLFIRINOX + radiotherapy	41.9	100	26.6	17.8
Pross et al[90]	Clinical trial	2015	Yes	120	LAPC	Multiple regimens + radiotherapy	Improved R0 resection	NR	Improved survival	NR
Ou et al[91]	Clinical trial	2020	Yes	85	LAPC	Gemcitabine-based regimen + radiotherapy	77.1	84.5	30.1	12.2
Boone et al[92]	Retrospective study	2013	Yes	13	LAPC	FOLFIRINOX + radiotherapy	20	50	NR	NR
Sadot et al[93]	Retrospective study	2015	Yes	101	LAPC	FOLFIRINOX and gemcitabine + radiotherapy	30.7	51.6	25	NR
Wo et al[94]	Retrospective study	2018	Yes	74	LAPC	FOLFIRINOX and gemcitabine + radiotherapy	39.2	NR	18.1	14.9
Hackert et al[95]	Retrospective study	2016	Yes	575	LAPC	FOLFIRINOX + radiotherapy	60.8	NR	16	NR
			Yes	575	LAPC	Gemcitabine + radiotherapy	46.6	NR	16.5	NR
			Yes	575	LAPC	Other regimens	51.6	NR	14	NR
Marthey et al[96]	Observational study	2015	Yes	77	LAPC	FOLFIRINOX + radiotherapy	36.4	89.3	22	NR
Gillen et al[18]	Systematic review	2010	Yes	860	LAPC	Various chemoradiation regimens	Improved R0 resection	NR	Prolonged survival	NR
Hyung et al[97]	Narrative review	2022	Nr	N/A	LAPC, BRPC	Overview of neoadjuvant chemotherapy and chemoradiation approaches	NR	NR	NR	NR

To further illustrate the impact of neoadjuvant therapy (NAT) on locally advanced pancreatic cancer (LAPC), Table 3 provides a detailed overview of studies evaluating the efficacy of NAT in patients with LAPC. The table highlights a range of clinical trials, retrospective studies, observational studies, and reviews, focusing on treatment regimens, the use of radiotherapy, resection rates, margin-negative (R0) resection rates, median overall survival, and disease-free survival. The data underscore the transformative potential of NAT in LAPC, demonstrating its ability to convert unresectable tumors into resectable ones, improve R0 resection rates, and extend survival outcomes. Specific regimens, such as fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) combined with radiotherapy, are prominently featured for their superior performance in improving resectability and survival. The integration of innovative approaches, such as losartan with FOLFIRINOX, further highlights the emerging strategies to enhance tumor response. Table 3 serves as a critical reference for understanding the clinical impact of various NAT protocols and emphasizes the role of multimodal approaches in addressing the challenges of LAPC management. LAPC: Locally advanced pancreatic cancer; BRPC: Borderline resectable pancreatic cancer; NAT: Neoadjuvant therapy; R0: Margin-negative resection; OS: Overall survival; DFS: Disease-free survival; FOLFIRINOX: Fluorouracil, leucovorin, irinotecan, and oxaliplatin; mFOLFIRINOX: Modified fluorouracil, leucovorin, irinotecan, and oxaliplatin; NR: Not reported.