Treatment for postoperative recurrence of pancreatic cancer: a narrative review
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).
Medline, PubMed, and various international evidence-based guidelines [like National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology] were searched for the current status of treatment for postoperative recurrence of pancreatic cancer (Table 1). Included in the review were English, retrospective or prospective clinical studies published between July 1990 and September 2021.
|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.
Rates and sites of recurrence after pancreatic resection
Most pancreatic cancer patients develop recurrence after surgery, even after surgical resection with curative intent. According to most recent clinical trials and retrospective series, the median time to recurrence is between 5 and 23 months in (3-16). This period has been gradually extended with the introduction of adjuvant chemotherapies or chemoradiotherapies established on the basis of well-designed, randomized, controlled trials, although their impact still remains limited (3-10) (Table 2). Several randomized studies have demonstrated that extended lymphadenectomy had no impact on either the recurrence rate or the pattern of recurrence (17-19).
|Treatment (modality)||Author, year (ref)||Study name||Regimen||Follow-up period (months), median [range]||Recurrence rate, % (n/N)||Recurrence pattern (%)||DFS (months), median|
|L||L + D||D|
|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|
|CRT + gemcitabine||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|
|Uesaka K, 2016 (8)||JASPAC01||S-1||79.3 [72.0–89.0]**||66 (123/187)||19||NA||NA||22.9|
|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|
|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|
*, 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.
Locoregional recurrence is the major pattern of recurrence after pancreatic cancer resection: 8–53% of cases present with only local recurrence as the initial recurrence, without evidence of distant recurrence. The incidence of postoperative local recurrence has apparently remained fairly unchanged even after the introduction of adjuvant local therapies such as postoperative chemoradiotherapy, although available data are limited (3,6). The time to diagnosis of local recurrence in this population is almost the same as the time to diagnosis of distant recurrence; according to several reports, the median interval from resection until recurrence is around 9–11 months, for both local recurrence and distant recurrence (11-16) (Table 3).
|Author, year (ref)||Number of patients with recurrences||Pattern of initial recurrence (%)||Time to recurrence (months), median||Survival after recurrence (months), median|
|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||6.0a||9.0b||7.0||3.0c|
|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||11.0d||NA||5.0–11.0e||3.0d||NA||4.0–19.0e|
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.
On the other hand, distant recurrence is another major pattern of recurrence after pancreatic surgery; 14–78% of patients present with only extra-pancreatic recurrence as the initial recurrence, while 18–78% patients present with combined locoregional and distant recurrence. The most common sites of distant recurrence are the liver, lymph node, and peritoneum, followed in frequency by the lung, bone, and other distant sites, including the brain (14-16,20). Distant recurrence is serious, not only because it is the major pattern of recurrence, but also because it indicates systemic tumor spread. The median survival period after diagnosis of a distant recurrence is 3.0–19.0 months, although a more favorable outcome has been reported in patients with isolated pulmonary metastases (12,13,15,16).
Management of local recurrence
Among patients diagnosed as having recurrence after resection for pancreatic cancer, 8–53% exhibit local recurrence without distant metastases (3,5-16). Various therapeutic strategies have been attempted, although no uniform consensus based on high-level evidence exists as to which intervention might be the most appropriate for this subset of patients.
Surgery for local recurrence
Repeat surgical resection is one of the therapeutic options for patients with pancreatic adenocarcinoma presenting with an isolated recurrence, including local recurrence (21-34) (Table 4). A local recurrence is usually defined as a recurrent lesion localized to the resection bed, the pancreatic remnant, or the mesenteric root: the site of recurrence is usually diagnosed by preoperative imaging, intraoperative gross examination, and postoperative histopathological findings in case of operable recurrence, although a definitive diagnosis is sometimes difficult. Repeat surgical resection may be beneficial for a selected subgroup of patients with isolated local recurrence, for example, patients with a good performance status, with recurrence localized only in the remnant pancreas, with no major vessel invasion, and with no active neural invasion, because complete resection with a negative surgical margin at the second resection is relatively more likely to be achieved in such cases. The median survival time after repeat surgical resection appears to be relatively more favorable (25–44 months) in patients with recurrence localized to the pancreatic remnant (25,27,30,31).
|Author, year (ref)||N||Type of recurrence||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.
Serafini et al. performed a systematic review/meta-analysis to determine the outcomes of repeat surgical resection in pancreatic cancer patients with isolated postoperative local recurrence (35). Six studies involving 431 patients with recurrent pancreatic cancer were included in the analysis, including 176 who had undergone repeat surgery and 255 who had undergone non-surgical treatments. After surgery for local recurrence, the reported mortality rate was 1.1% (2/176 patients) (24,33); the morbidity rate ranged from 6% (33) to 33% (31). The overall survival and post-recurrence survival were significantly longer in the repeat resection group, with a median overall survival period of 28.7 months. They concluded that resection for isolated pancreatic cancer recurrence is safe and feasible and may offer survival benefit. Miyasaka et al. reviewed the developmental mechanisms, predictive factors, and treatments of high-risk lesions (HRLs), including high-grade pancreatic intraepithelial neoplasia (PanIN), pancreatic ductal adenocarcinoma, high-grade intraductal papillary mucinous neoplasm (IPMN), and IPMN with associated invasive carcinoma in the remnant pancreas after partial pancreatic resection for pancreatic cancer or IPMN (36). They suggested that HRLs in the remnant pancreas may occur even long after the initial operation, and that life-long surveillance may be necessary in patients undergoing partial pancreatic resection for pancreatic cancer or IPMN.
The most common surgical procedure employed for local recurrence in the remnant pancreas is total remnant pancreatectomy, although partial pancreatectomy is performed some cases (25,37). Laparoscopic and robotic resection for postoperative pancreatic cancer recurrence are still uncommon as alternative approaches to open surgery, although several surgeons have reported favorable results of these surgical procedures for postoperative local recurrence of pancreatic cancer (38-41).
Chemotherapy and/or radiotherapy for local recurrence
While surgical resection offers the only opportunity for cure, it is extremely difficult to achieve complete resection of the disease by repeat resection in patients with local recurrence of pancreatic cancer, and the prognosis of most patients undergoing repeat resection remains dismal. Therefore, repeat surgical resection, with its low success rate, may be too invasive for patients expected to have a poor prognosis, and should be exclusively proposed to patients who are eligible for potential R0 resection. Effective non-surgical treatments are needed as alternatives to repeat resection in patients who are not suitable candidates for repeat resection, or as induction therapies before repeat resection: chemoradiotherapy could be useful as combined local plus systemic therapy with the potential to surpass the benefit of resection in terms of the lower degree of invasiveness and satisfactory tumor control potential.
Data on chemoradiotherapy for postoperative local recurrences of pancreatic cancer after surgical resection are limited (42,43). However, recently, some prospective studies have either been planned or conducted to assess the efficacy/safety of combined chemoradiotherapy. A randomized controlled trial is being planned to evaluate the usefulness of stereotactic body radiotherapy (SBRT) in addition to the standard of care in patients with postoperative local recurrence as compared to the standard of care alone, with regard to both survival and quality of life outcomes (NCT04881487). Another randomized controlled phase II trial conducted to evaluate the usefulness of SBRT plus pembrolizumab and trametinib as compared to SBRT plus gemcitabine in locally recurrent pancreatic cancer patients with mutant KRAS and positive tumor immunohistochemical staining for PD-L1 (44) reported a median overall survival of 24.9 months in the SBRT plus pembrolizumab and trametinib arm, and 22.4 months in the SBRT plus gemcitabine arm (hazard ratio: 0.60; P=0.0012). The authors concluded that the results of this study need to be validated by a phase III study.
Groot et al. conducted a systematic review of treatments employed for isolated local recurrence after pancreatic resection (45), including repeat surgical resection (8 studies, 100 patients), chemoradiotherapy (7 studies, 153 patients), and stereotactic body radiation therapy (SBRT) (4 studies, 60 patients). The reported morbidity and mortality rates were 29% and 1% for repeat surgical resection, 54% and 0% for chemoradiotherapy, and 3% and 1% for SBRT, respectively. The reported median survival periods after treatment of isolated local recurrence were 32 months for re-resection, 19 months for chemoradiotherapy, and 16 months for SBRT. They suggested that the above treatments for isolated postoperative local recurrence of pancreatic cancer seem to be safe and feasible and to be associated with relatively good survivals in selected patients.
Management of distant recurrences
Chemotherapy for distant recurrences
In regard to the management of patients with distant metastases, recurrent disease is, in general, not considered as being distinct from primary metastatic disease, and most patients with distant recurrence, with or without local tumor recurrence, receive systemic chemotherapy as the standard therapy for metastatic disease. Most current guidelines recommend FOLFIRINOX therapy or combined gemcitabine plus nab-paclitaxel therapy as the first-line treatment for pancreatic cancer patients with distant metastases and a good performance status, olaparib for those with germline BRCA mutations, pembrolizumab for those with microsatellite instability (MSI)-high, entrectinib or larotrectinib for those with NTRK gene mutations, and combined nanoliposomal irinotecan plus 5-fluorouracil (5-FU) and leucovorin therapy as maintenance or second-line treatment. However, no global consensus exists in regard to the most suitable chemotherapy regimens for postoperative disease recurrence in patients who have already received postoperative adjuvant chemotherapy. For patients in whom the interval from completion of postoperative adjuvant therapy to detection of postoperative recurrence is less than 6 months, the NCCN guidelines recommend administration of an alternative chemotherapy regimen (46); on the other hand, for patients in whom this interval is 6 months or longer, they recommend an alternative regimen or the same regimen as that used for the postoperative adjuvant therapy.
We retrospectively reviewed the clinical data of 41 patients with distant recurrence who had received postoperative adjuvant chemotherapy (47). We divided the patients into two groups according to the interval from completion of adjuvant chemotherapy with gemcitabine to diagnosis of recurrence (<6 vs. ≥6 months, as per the recommendation in the NCCN guidelines): ADJ-Rec <6 months (n=25) and ADJ-Rec ≥6 months (n=16). The disease control rate, progression-free survival period after completion of treatment for recurrence, and the overall survival after recurrence in the two groups were 68% and 94% (P=0.066), 5.5 and 8.2 months (P=0.186), and 13.7 and 19.8 months (P=0.009), respectively. Then, we further subdivided the patient group with ADJ-Rec <6 months into two groups: a group in which the recurrent disease was treated with gemcitabine for (n=6) and a group in which the recurrent disease was treated with alternative regimens, including fluoropyrimidine-containing regimens (n=19). In our analysis, the results revealed that the outcomes were better in the patients treated with alternative regimens than in those treated with gemcitabine. Thus, we concluded that use of alternative chemotherapy regimens may be a reasonable strategy for recurrent disease detected within a short period after completion of adjuvant chemotherapy, although additional analyses may be needed in this era of use of FOLFIRINOX and gemcitabine plus nab-paclitaxel.
Surgery for distant recurrences
Recent rapid advances in imaging technologies such as computed tomography (CT) and magnetic resonance imaging (MRI) have facilitated identification of small-volume metastatic recurrences after resection in cancer patients, and the concept and clinical significance of oligometastases has been established recently in patients with certain cancers, including pancreatic cancer. Damanakis et al. proposed defining oligometastatic disease in pancreatic cancer as a limited disease with ≤4 metastases in the liver or lung, together with baseline CA 19-9 levels of <1,000 U/mL, and a treatment response of complete/partial response or stable disease to first-line chemotherapy (48). They reviewed the data of 128 patients with metastatic pancreatic cancer who had never undergone surgery for either the primary tumor or metastases, and identified 10 (7.8%) patients who fulfilled the criteria of oligometastatic disease. All these 10 patients survived for significantly longer periods than the remaining patients; the median overall survival was 19.4 months in this small subgroup vs. 7.2 months in the remaining patients [95% confidence interval (CI): 5.7–9.8; P=0.009], and they concluded that patients fulfilling the criteria for oligometastatic disease could potentially benefit from surgical resection.
Recent reports suggest more favorable outcomes in pancreatic cancer patients with isolated pulmonary metastases than in patients with metastases in other locations, although the precise reason for this difference remains unclear. Guerra et al. conducted a systematic review/meta-analysis to evaluate the outcomes in pancreatic cancer patients with isolated pulmonary vs. non-pulmonary metastasis (49). The analysis included the data of 11,916 pancreatic cancer patients with isolated distant metastases from 15 primary reports. Of the 11,916 patients, 2,619 patients (22%) had developed recurrence following resection and the remaining 7,884 patients with single-site distant metastasis had not undergone resection. In the setting of single-organ dissemination, patients with isolated lung metastasis showed significantly better survival than those with hepatic, locoregional, or peritoneal recurrence. In particular, patients who developed isolated recurrence in the lung after pancreatectomy showed significantly better outcomes than those who developed isolated locoregional, hepatic or peritoneal relapse after pancreatectomy, in terms of the disease-free survival (15.9 months in patients with isolated pulmonary metastasis vs. 12.3, 7.3, and 8.5 months, respectively, in patients with locoregional, hepatic and peritoneal recurrence), survival after recurrence (16.5 vs. 9.7, 8, and 5.5 months, respectively), as well as overall survival (34.7 vs. 23.6, 11.3, and 17.9 months, respectively). Zheng et al. reported that lung metastasis as the initial site of recurrence after pancreatic resection was associated with an earlier tumor stage, lower histologic grade, lower frequency of vascular invasion, and lower residual tumor volume as compared to liver metastasis (50). Recent basic studies conducted to examine the evolution of pancreatic cancer at the genetic level have shown that the clonal complexity of metastatic pancreatic cancer is already existent within the primary tumors, and that organ-specific metastases are derived from different tumor subclones (51,52). The NCCN guidelines include preliminary data to suggest that pulmonary metastasectomy may be advantageous in pancreatic cancer patients presenting with isolated pulmonary metastases after primary resection, although they also state that more data are needed before any definitive recommendations can be made in regard to the management of pancreatic cancer patients with isolated pulmonary metastases.
Despite the recent improvements in surgical techniques and introduction of potentially effective adjuvant treatments for patients with resectable pancreatic cancer, most patients still develop locoregional and/or systemic recurrence after surgery. Although no uniform consensus based on high-level evidence exists as to which intervention might be the most appropriate for such patients, systemic chemotherapy has been used as the main treatment option for patients with distant recurrences, and more recently, even for patients with local recurrence alone, and some regimens have been clearly demonstrated to offer a survival benefit in patients with recurrent pancreatic cancer. For patients with local recurrences alone, local therapies, such as repeat surgical resection and combined chemoradiotherapy have been attempted, although the prognosis of these patients remains dismal and any significant benefits of these therapeutic strategies have yet to be confirmed. Therefore, it is important to consider the patient’s quality of life while selecting the appropriate treatment strategy for recurrent pancreatic cancer.
Finally, I would like to emphasize that recently, attempts have been made to establish neoadjuvant therapies to improve the outcomes after surgery, and if successful, could lead to a radical change in the therapeutic strategy for pancreatic cancer (53,54). Although no global standard has been established yet, the potential advantages of neoadjuvant therapy are that it could (I) improve the chances of curative resection by shrinking the primary lesion, (II) exert therapeutic effect against microscopic distant metastases that are difficult to detect by imaging, and (III) allow better selection of patients for curative resection by allowing those showing rapid tumor progression or worsening of the general condition during neoadjuvant therapy to be excluded.
Thus, there is an urgent need for prospective trials to establish the most appropriate perioperative treatment strategies for patients with pancreatic cancer.
Provenance and Peer Review: This article was commissioned by the Guest Editor (Yoji Kishi) for the series “Pre- and Post-operative Treatment for Pancreatic Cancer” published in Chinese Clinical Oncology. The article has undergone external peer review.
Reporting Checklist: The author has completed the Narrative Review reporting checklist. Available at https://cco.amegroups.com/article/view/10.21037/cco-21-87/rc
Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-21-87/coif). The series “Pre- and Post-operative Treatment for Pancreatic Cancer” was commissioned by the editorial office without any funding or sponsorship. The author has received research grants from Novartis Pharma K.K., Pfizer Japan Inc., Ono Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Dainippon Sumitomo Pharma Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., AstraZeneca K.K., Chugai Pharmaceutical Co., Ltd., Bristol-Myers K.K., MSD K.K., Syneos Health, Nano Carrier Co., Ltd., Baxter, and Taiho Pharmaceutical Co., Ltd.; consulting fees from Meiji Seika Pharma, Nippon Shinyaku Co., Ltd., Nihon Servier, Taiho Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Dainippon Sumitomo Pharma Co., Ltd., Bristol-Myers K.K., AstraZeneca K.K., and Eisai Co., Ltd.; honoraria from AstraZeneca K.K., AbbVie Inc., Eisai Co., Ltd., Ono Pharmaceutical Co., Ltd., Yakult Honsha Co., Ltd., Daiichi Sankyo Co., Ltd., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Teijin Pharma Ltd., Eli Lilly Japan K.K., Nihon Servier Co., Ltd., and Novartis Pharma K.K.; and fees for participation on a data safety monitoring board or advisory board from Shire, AstraZeneca K.K., Incyte Corporation, Eisai Co., Ltd., Ono Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Takara Bio Inc., Takeda Pharmaceutical Co., Ltd, Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Nihon Servier Co., Ltd., Novartis Pharma K.K., Bayer Yakuhin, Ltd., Pfizer Japan Inc., Bristol-Myers K.K., and Mundipharma K.K. The author has no other conflicts of interest to declare.
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