Treatment for Postoperative Recurrence of Pancreatic Cancer

A Narrative Review

Takuji Okusaka

Chin Clin Oncol. 2022;11(3):19

Abstract and Introduction

Abstract

Background and Objective: Patients with pancreatic cancer frequently develop postoperative disease recurrence, even after surgical resection with curative intent. Because of the heterogeneity of this patient population, phase III trials have never been conducted to establish a standard therapy for patients with post-surgical recurrence, and no uniform consensus based on high-level evidence exists as to which intervention might be the most appropriate. The aim of this review is to introduce globally popular treatment strategies for pancreatic cancer patients with postoperative recurrences.

Methods: This is a narrative review, summarising the contemporary evidence and emerging studies with treatment for postoperative recurrence of pancreatic cancer.

Key and Content and Findings: For patients with local recurrence alone, various therapeutic strategies have been attempted, including repeat surgical resection, chemoradiotherapy, and chemotherapy alone. Several studies have examined the outcomes of these therapies, but most are retrospective analyses of a small number of patients and statistically too underpowered to allow any solid recommendations to be made. Therefore, with the exception that there appears to be a potential benefit of repeat resection for isolated recurrences in the pancreatic remnant in a selected subgroup of patients, the patient outcomes remain dismal. In regard to the management of patients with distant recurrences, postoperative distant recurrences are generally not considered as being distinct from primary metastatic disease, and most patients with distant recurrence(s) with/without local tumor recurrence receive systemic chemotherapy as the standard therapy for metastatic disease; some studies have demonstrated a trend toward better survival outcomes in patients with a history of surgical resection than in those without a history of surgical resection.

Conclusions: Although no uniform consensus based on high-level evidence exists, systemic chemotherapy has been used as the main treatment option, and some regimens have been demonstrated to offer a survival benefit. There is an urgent need for prospective trials to establish the most appropriate treatment strategies for this patients' population.

Introduction

Pancreatic cancer remains one of the most challenging malignancies to treat. Of all the modalities available for the treatment of pancreatic cancer, only resection offers an opportunity for cure. However, even among patients with resectable disease, the long-term outcomes remain unsatisfactory, with 5-year survival rates remaining a dismal 10–40%, because most patients develop recurrence even after resection with curative intent.^[1–10] It is speculated that the major reasons for these poor outcomes are the presence of occult systemic tumor spread (which are responsible for distant metastasis) even at the time of diagnosis, and the microscopic persistence of malignant cells around the resection area (which are responsible for local recurrence) after a macroscopically curative tumor resection.

This review focuses on the management of local and distant recurrences developing after surgical resection in patients with pancreatic cancer. No phase III trials have ever been conducted in this patient population, and literature on this topic remains limited. While it has therefore been difficult to establish standard management strategies for this category of patients, globally popular treatment strategies for pancreatic cancer patients with postoperative recurrences and future perspectives in this field are introduced in this article. I present the following article in accordance with the Narrative Review reporting checklist (available at https://cco.amegroups.com/article/view/10.21037/cco-21-87/rc).

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Abstract and Introduction
Methods
Discussion
Conclusions
References

Table 1. The search strategy summary
Items	Specification
Date of search (specified to date, month and year)	01 June 2021
Databases and other sources searched	Medline, PubMed, NCCN Clinical Practice Guidelines in Oncology, ESMO Clinical Practice Guidelines
Search terms used (including MeSH and free text search terms and filters)	Pancreatic cancer, pancreatic resection, recurrence, treatment, re-resection, chemoradiotherapy, chemotherapy
Timeframe	Between July 1990 and September 2021
Inclusion and exclusion criteria (study type, language restrictions, etc.)	Included in the review were retrospective or prospective clinical studies published in English
Selection process (who conducted the selection, whether it was conducted independently, how consensus was obtained, etc.)	The author conducted the selection
Any additional considerations, if applicable	Additional data have been included under the revision

NCCN, National Comprehensive Cancer Network; ESMO, European Society for Medical Oncology.

Table 2. Rates and patterns of recurrence in recent randomized trials of adjuvant therapy after pancreatic cancer resection
Treatment (modality)	Author, year (ref)	Study name	Regimen	Follow-up period (months), median [range]	Recurrence rate, % (n/N)	Recurrence pattern (%)			DFS (months), median
Treatment (modality)	Author, year (ref)	Study name	Regimen	Follow-up period (months), median [range]	Recurrence rate, % (n/N)	L	L + D	D	DFS (months), median
Surgery alone	Klinkenbijl JH, 1999 (3)	EORTC	Surgery alone	NA	66 (68/103)	22	32	43	16.0
	Oettle H, 2007 (4)	CONKO-001	Surgery alone	53 [9–96]	92 (161/175)	41		49	6.9
	Ueno H, 2009 (5)	JSAP 02	Surgery alone	60.4 [40.6–77.1]	88 (53/60)	32	NA	66	5.0
Surgery + adjuvant CRT	Klinkenbijl JH, 1999 (3)	EORTC	CRT	NA	65 (67/104)	22	28	48	17.4
	Regine WF, 2011 (6)	RTOG 9704	CRT + 5-FU	1.48 [0.1–9.1] years	89 (205/230)	30	NA	70	NA
	Regine WF, 2011 (6)	RTOG 9704	CRT + gemcitabine	1.48 [0.1–9.1] years	88 (195/221)	25	NA	78	NA
–	Neoptolemos JP, 2004 (7)	ESPAC-1	All groups*	42 [33–62]	55 (158/289)	35	27	34	NA
Surgery + adjuvant chemotherapy	Oettle H, 2007 (4)	CONKO-001	Gemcitabine	53 [9–96]	74 (133/179)	34		56	13.4
	Ueno H, 2009 (5)	JSAP 02	Gemcitabine	60.4 [40.6–77.1]	76 (544/58)	23	NA	75	11.4
	Neoptolemos JP, 2004 (7)	ESPAC-3	5-FU + FA	34.2 [27.1–43.4]	63 (688/1,088)	NA	15.1
	Neoptolemos JP, 2004 (7)	ESPAC-3	Gemcitabine	34.2 [27.1–43.4]	63 (688/1,088)	NA	14.3
	Uesaka K, 2016 (8)	JASPAC01	S-1	79.3 [72.0–89.0]**	66 (123/187)	19	NA	NA	22.9
	Uesaka K, 2016 (8)	JASPAC01	Gemcitabine	82.3 [71.8–88.5]**	78 (149/190)	26	NA	NA	11.3
	Neoptolemos JP, 2017 (9)	ESPAC-4	Gemcitabine + capecitabine	43.2 [39.7–45.5]***	65 (236/364)	46	NA	NA	13.9
	Neoptolemos JP, 2017 (9)	ESPAC-4	Gemcitabine	43.2 [39.7–45.5]***	66 (243/366)	53	NA	NA	13.1
	Conroy T, 2018 (10)	PRODIGE 24-ACCORD 24/CCTG PA 6	Modified FOLFIRINOX	33.6 [30.3–36.0]***	54.2 (134/247)	25	18	52	21.6
	Conroy T, 2018 (10)	PRODIGE 24-ACCORD 24/CCTG PA 6	Gemcitabine	33.6 [30.3–36.0]***	73.2 (180/246)	24	23	46	12.8

*, all groups include the CRT group, 5-FU + leucovorin group, CRT + 5-FU + leucovorin group, and surgery-alone group in the ESPAC-1 trial; **, interquartile range; ***, 95% CI. CRT, chemoradiotherapy; 5-FU, 5-fluorouracil; FA, folinic acid; FOLFIRINOX, fluorouracil, leucovorin, irinotecan, and oxaliplatin; NA, not available; L, locoregional; L + D, locoregional plus distant recurrence; D, distant recurrence; DFS, disease-free survival; CI, confidence interval.

Table 3. Recurrence patterns and survival periods in retrospective studies
Author, year (ref)	Number of patients with recurrences	Pattern of initial recurrence (%)			Time to recurrence (months), median			Survival after recurrence (months), median
Author, year (ref)	Number of patients with recurrences	L	L + D	D	L	L + D	D	L	L + D	D
Griffin JF, 1990 (11)	26	27	43	30	NA	NA	NA	NA	NA	NA
Westerdahl J, 1993 (12)	74	8	78	14	15	6	4	23	9	7
Sperti C, 1997 (13)	78	33	40	27	9.5	6.0^a	9.0^b	7.0	3.0^c
Van den Broeck A, 2009 (14)	110	17	23	60	NA	NA	NA	NA	NA	NA
Zhang Y, 2012 (15)	72	31	24	46	9.3	7	7.5	10.4	5.5	5.8
Kolbeinsson H, 2021 (16)	221	17	67	16	11.0^d	NA	5.0–11.0^e	3.0^d	NA	4.0–19.0^e

^a, locoregional and hepatic recurrence; ^b, hepatic recurrence; ^c, hepatic recurrence or locoregional and hepatic recurrence; ^d, local and peritoneal recurrence; ^e, liver and lung recurrence. L, locoregional; L + D, locoregional plus distant recurrence; D, distant recurrence; NA, not available.

Table 4. Surgical treatment for recurrence of pancreatic cancer
Author, year (ref)	N	Type of recurrence		Median overall survival (months)	Median survival after recurrence (months)
Author, year (ref)	N	Local	Distant	Median overall survival (months)	Median survival after recurrence (months)
Kleeff J, 2007 (21)	15	15	0	17	NA
Strobel O, 2013 (24)	41	41	0	NR	26
Miyazaki M, 2014 (25)	11	11	0	78.2	25
Shima Y, 2015 (27)	6	6	0	49	27.5
Chang SC, 2016 (28)	14	14	0	57.8	14.1
Nakayama Y, 2018 (30)	11	11	0	70	44
Yamada S, 2018 (31)	90	90	0	NR	26
Arnaoutakis GJ, 2011 (22)	9	0	9**	51	18.6
Yasukawa M, 2017 (29)	12	0	12**	121	47
Groot VP, 2019 (32)	19	0	19**	68.9	35
Thomas RM, 2012 (23)	21	7	14***	81.1	36
Boone BA, 2014 (26)	22*	10	12****	60.6	28.1
Kim YI, 2019 (33)	48	15	33*****	40.4	23.6

*, 6 patients with ampullary cancer were included; **, all patients had isolated pulmonary recurrence; ***, 7 patients had lung, 9 had liver, 1 had brain, and 1 had abdominal-wall metastasis; ****, 5 patients had lung, 6 had liver, and 1 had ovarian metastasis; *****, 15 patients had lung, 13 had liver, and 5 had other-organ metastasis. NR, not reported.