Are we used the appropriate therapy regimens on advanced pancreatic cancer?

A B S T R A C T

Even through numerous combinations of chemotherapy regimens are used to treat on the advanced pancreatic cancer, APC; however, the survival rate (overall survival and progress free survival) and treatment-related toxicity remain challenge. Here we provided neutral and failed outcomes that treat the APC in clinical trials, this need us to think twice whether we were used the appropriate therapy regimens, to enlarge the survival rate and to reduce the treatment-related toxicity. Evidences of treatment on APC are need indeed to assistant our physician decision making correctly.

Keywords

Advanced Pancreatic Cancer,chemotherapy regimens,treatment-related toxicity

Background of advanced pancreatic cancer

Advanced Pancreatic Cancer (APC) is characteristic with high mortality, increasing incidence, relative survival rate presents 20% in one-year and 8% in five-year during all APC stages [1-3]. APC may occur when the pancreas cells grow exponentially and uncontrollably, they will be dividing and spreading rapidly, forming malignant tumors. The treatment timing window of APC depends on the stage or extent of the cancer, the treatment options include surgery, ablative treatments to destroy the tumor, radiation, and chemotherapy [4]. In the advanced stage of pancreatic cancer, oral or injectable drugs usually kill cancer cells, but in fact only control the growth of cancer cells. The drugs used mainly include gemcitabine with nab-paclitaxel and FOLFIRINOX (a cocktail of oxaliplatin, irinotecan, 5FU, and leucovorin), which can increase the overall survival by several months [5].

Our previous meta-analysis study [6] disclosed that there are not less than 20 therapy regimens. Even through many combinations of drugs birthed, combined with frontline drug gemcitabine, such as “gemcitabine+X”. Unfortunately, the overall survival and progress free survival of APC patients were not improved significantly. There is big question worth us thinking twice, there are too much choices for frontline in clinic, however the evidence-based medicine of them remains challenge. Are we used the appropriate therapy regimens on APC? Namely, are there any drug abuses during the treatment on APC?

In order to clarify this question, we have collected the clinical trial data from http://Clinicaltrail.gov, searching with the key words “advanced pancreatic cancer”, and then selected filter with “has results” and “has publication”. We selected the results that authors stated failed or neutral in the publications. There are 14 articles reported failed in the clinical trials and 3 publications stated neutral result. Generally, we kept the first author, published year, sample size, drugs, overall survival (OS), progress free survival (PFS) and drug against biomarker. Details please see (Table 1 and 2).

OS and PFS comparison in failed and neutral results on APC

Generally, there ware 14 studies ranged from 2011 to 2018, recruited 2448 APC patients (1385 male and 1063 female) to conduct the clinical trials, details please see (table 1). Averagely the OS was 8.25 months and PFS was 4.39 months in failed studies. It is noteworthy that Faivre in 2017 tested sunitinib malate to treat APC and achieved 38.6 months of OS and 12.6 months of PFS. However, Wolpin reported that hydroxychloroquine to cure APC, unfortunately, there were 1.8 months both in OS and PFS. Even through many combination tests, however, the benefit for APC patients are still remains low extremely.

Table 1: Clinical trial failed outcome on pancreatic cancer
Year	Author	N	M	F	Drug	OS	PFS	Biomarkers
2011	Kindler HL[7]	314	191	123	Gemcitabine; AG-013736	8.5	4.4	vascular endothelial growth factor (VEGF)
		316	188	128	Gemcitabine; Placebo	8.3	4.4
2012	Ko AH[8]	29	18	11	Cetuximab; Bevacizumab; Gemcitabine	5.41	4.17	epidermal growth factor receptor (EGFR); vascular endothelial growth factor (VEGF)
		29	14	15	Cetuximab; Bevacizumab	3.55	1.91
2013	Rougier P[9]	275	157	118	Placebo; Gemcitabine	7.8	3.7	Vascular endothelial growth factor (VEGF)
		271	160	111	Aflibercept; Gemcitabine	6.5	3.7
2013	Wu C[10]	30	16	14	Etanercept; Gemcitabine	5.43	0.3	tumor necrosis factor α (TNF-α)
		8	3	5	Gemcitabine	8.1	1.8
2014	Propper D [11]	104	59	45	Erlotinib	4.0	1.5	epidermal growth factor receptor (EGFR)
		103	59	44	Placebo	3.1	1.5
2014	Infante JR[12]	80	39	41	Gemcitabine; GSK1120212	8.4	16.1	circulating free DNA (cfDNA)
		80	46	34	Placebo; Gemcitabine	6.7	15.1
2014	Wolpin BM [13]	10	5	5	Hydroxychloroquine 400mg	1.8	1.8	LC3-II
		10	6	4	Hydroxychloroquine 600mg	3.0	1.6
2015	Catenacci DV[14]	53	27	26	Gemcitabine hydrochloride; hydrocortisone/placebo	6.1	2.5	hedgehog (Hh) pathway；Sonic hedgehog (SHH)
		53	31	22	Gemcitabine hydrochloride; Vismodegib	6.9	4.0
2016	Noonan AM[15]	36	22	14	Wild-type reovirus; Carboplatin; paclitaxel	7.31	4.94	vascular endothelial growth factor (VEGF)；normal T cell expressed and secreted (RANTES); IL-6, IL-8
		37	19	18	Carboplatin; Paclitaxel	8.77	5.2
2017	Chung V[16]	62	22	40	Fluorouracil; Oxaliplatin	6.7	2.0	KRAS protein
		58	35	23	MK2206; Selumetinib	3.9	1.9
2017	Faivre S[17]	86	42	44	Sunitinib malate	38.6	12.6	vascular endothelial growth factor receptors (VEGFRs)；platelet-derived growth factor receptors (PDGFRs)
		85	40	45	Placebo	29.1	5.8
2017	Ko AH[18]	66	38	28	OGX-427	6.9	3.8	heat shock protein 27 (Hsp27)
		66	37	29	Placebo	5.3	2.7
2017	Laquente B[19]	65	42	23	LY2603618; Gemcitabine	7.8	3.5	Checkpoint kinase 1 (CHK1)
		34	20	14	Gemcitabine	8.3	5.6
2018	Van Cutsem E[20]	44	22	22	Gemcitabine; Placebo	7.6	2.8	MEK1/2-dependent effector proteins (ERK 1/2)
		44	27	17	Gemcitabine; Pimasertib	7.3	3.7
Note：OS, overall survival; PFS, progress free survival; M: male; F: female.

Furthermore, there were 3 studies clarified neutral results in OS and PFS result, ranged from 2008 to 2016, totally recruited 229 APC patients (121 male and 108 female), details please see (Table 2). Averagely the OS was 16.6 months and PFS was 9 months in neutral studies. For example, Spano in 2008 reported gemcitabine plus AG-013736 achieved better OS and PFS (6.9 and 4.2) than gemcitabine single used.

Perspective

With respecting the drug abuse in cure on APC, this is an open question. The current evidence uncovered that APC patients benefit less on OS or PFS. Unfortunately, the treatment-related toxicities accompany with therapy, patients did not only endure the pain from the cancer, but also need to be tolerant of the side reactions. Evidence medicine on APC treatment are need to be strength to balance the benefit and lost in vast degree from patients’ perspective.

Funding

This work was supported by Chengdu Medical College nature science foundation (CYZ18-08, CYZ18-20, CYZ18-33).

Authors’ contribution

XF summarized the general idea and draft the manuscript, DYX and YLQ performed the data collection and table construction, YS conducted the quality control, LFF drafted the concept photograph.

Conflict of Interest

The authors declare that they have no competing interests

Article Info

Article Type

Research Article

Publication history

Received: Fri 17, May 2019
Accepted: Thu 13, Jun 2019
Published: Tue 23, Jul 2019

Copyright

© 2023 Fan Xu. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Hosting by Science Repository.
DOI: 10.31487/j.DDA.2019.01.01

Author Info

Liqiong YANG Fan Xu Fangfang LIU Shu YANG Yuxi DUAN

Corresponding Author

Fan Xu
Department of Public Health, Chengdu Medical College, Sichuan, China, 610500

Figures & Tables

Figure 1: Difficult to make the decision.

Table 1: Clinical trial failed outcome on pancreatic cancer
Year	Author	N	M	F	Drug	OS	PFS	Biomarkers
2011	Kindler HL[7]	314	191	123	Gemcitabine; AG-013736	8.5	4.4	vascular endothelial growth factor (VEGF)
		316	188	128	Gemcitabine; Placebo	8.3	4.4
2012	Ko AH[8]	29	18	11	Cetuximab; Bevacizumab; Gemcitabine	5.41	4.17	epidermal growth factor receptor (EGFR); vascular endothelial growth factor (VEGF)
		29	14	15	Cetuximab; Bevacizumab	3.55	1.91
2013	Rougier P[9]	275	157	118	Placebo; Gemcitabine	7.8	3.7	Vascular endothelial growth factor (VEGF)
		271	160	111	Aflibercept; Gemcitabine	6.5	3.7
2013	Wu C[10]	30	16	14	Etanercept; Gemcitabine	5.43	0.3	tumor necrosis factor α (TNF-α)
		8	3	5	Gemcitabine	8.1	1.8
2014	Propper D [11]	104	59	45	Erlotinib	4.0	1.5	epidermal growth factor receptor (EGFR)
		103	59	44	Placebo	3.1	1.5
2014	Infante JR[12]	80	39	41	Gemcitabine; GSK1120212	8.4	16.1	circulating free DNA (cfDNA)
		80	46	34	Placebo; Gemcitabine	6.7	15.1
2014	Wolpin BM [13]	10	5	5	Hydroxychloroquine 400mg	1.8	1.8	LC3-II
		10	6	4	Hydroxychloroquine 600mg	3.0	1.6
2015	Catenacci DV[14]	53	27	26	Gemcitabine hydrochloride; hydrocortisone/placebo	6.1	2.5	hedgehog (Hh) pathway；Sonic hedgehog (SHH)
		53	31	22	Gemcitabine hydrochloride; Vismodegib	6.9	4.0
2016	Noonan AM[15]	36	22	14	Wild-type reovirus; Carboplatin; paclitaxel	7.31	4.94	vascular endothelial growth factor (VEGF)；normal T cell expressed and secreted (RANTES); IL-6, IL-8
		37	19	18	Carboplatin; Paclitaxel	8.77	5.2
2017	Chung V[16]	62	22	40	Fluorouracil; Oxaliplatin	6.7	2.0	KRAS protein
		58	35	23	MK2206; Selumetinib	3.9	1.9
2017	Faivre S[17]	86	42	44	Sunitinib malate	38.6	12.6	vascular endothelial growth factor receptors (VEGFRs)；platelet-derived growth factor receptors (PDGFRs)
		85	40	45	Placebo	29.1	5.8
2017	Ko AH[18]	66	38	28	OGX-427	6.9	3.8	heat shock protein 27 (Hsp27)
		66	37	29	Placebo	5.3	2.7
2017	Laquente B[19]	65	42	23	LY2603618; Gemcitabine	7.8	3.5	Checkpoint kinase 1 (CHK1)
		34	20	14	Gemcitabine	8.3	5.6
2018	Van Cutsem E[20]	44	22	22	Gemcitabine; Placebo	7.6	2.8	MEK1/2-dependent effector proteins (ERK 1/2)
		44	27	17	Gemcitabine; Pimasertib	7.3	3.7
Note：OS, overall survival; PFS, progress free survival; M: male; F: female.

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