Current update of treatment strategies for borderline resectable pancreatic cancer: a narrative review

Introduction

Pancreatic cancer was estimated to be the 12th most common newly diagnosed cancer and the 7th leading cause of cancer-related deaths worldwide in 2020 (1,2). The prognosis of pancreatic cancer is still poor, and the 5-year survival rate is reported to be 2–9% (3). The only potentially curative treatment for pancreatic cancer is surgical resection. However, since many patients with pancreatic cancer exhibit tumor invasion in the surrounding organs or develop distant metastasis at the time of initial diagnosis, only less than 20% of them are eligible for surgery (4). Non-metastatic pancreatic cancer is divided into three levels based on its resectability status: resectable, borderline resectable, and locally advanced. Among them, borderline resectable pancreatic cancer (BRPC) consists of a group of diseases in which the tumor invades the major blood vessels, such as the portal vein and superior mesenteric artery, and it is difficult to determine whether the tumor is resectable. However, there is no uniform definition of BRPC, and the degree of venous and arterial involvement varies with each definition. BRPC is currently defined based on the international criteria of the following: the National Comprehensive Cancer Network (NCCN) (5), a research by MD Anderson (6), American Hepato Pancreato-Biliary Association/Society of Surgical Oncology/Society for Surgery of the Alimentary Tract (AHPBA/SSO/SSAT) consensus (7), and the International Association of Pancreatology consensus (8). The existence of these multiple definitions and the fact that the diagnosis of this condition based on imaging results is not easy is related to the difficulty in assessing the therapeutic outcome of BRPC. The main treatment options for BRPC are upfront surgery, neoadjuvant chemotherapy (NACT) followed by surgery, and neoadjuvant chemoradiation therapy (NACRT) followed by surgery. To date, there has been no confirmed treatment strategy for BRPC. Previous studies on BRPC only included a small number of cases or performed analyses of patients in whom surgery were performed, resulting in a limited number of clinical studies with a high level of evidence. However, high-level studies, such as those using the intention-to-treat analysis, have recently been published. The intention-to-treat analysis studies included patients who did not undergo surgery, thus reducing potential bias in the treatment effects.

This review aimed to investigate the current status of treatment strategies for BRPC. To conduct a fair comparison, we investigated studies that performed an intention-to-treat analysis. We present the following article in accordance with the Narrative Review reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-21-829/rc).

Methods

Table 1 shows the search strategy summary. In this review, the PubMed and Web of Science databases were searched. Eligible articles were screened by two authors (AO and YM). The focused keywords were “borderline resectable pancreatic cancer”, “neoadjuvant chemotherapy”, “neoadjuvant chemoradiation therapy”, and “upfront surgery”. The reference lists of relevant articles were manually searched. Studies conducted in patients with BRPC, either treated with upfront surgery or neoadjuvant therapy, or those that reported the median overall survival (OS) were included. Studies conducted in patients with either resectable cancer or BRPC and in those with either BRPC or locally advanced cancer were also included if the data on these patients with BRPC could be extracted. We selected studies that mentioned conducting or those that we judged to have conducted an intention-to-treat analysis. The articles were limited to full-text publications in English. Data on the study design, treatment details, number of cases, resection rate, R0 resection rate, median OS, and number of cases with treatment-related mortality were extracted. The R0 resection rate in patients who underwent pancreatic cancer resection was calculated.

Discussion

Overview of the literature extracted

An overview of 22 studies (9-30) extracted for this review is shown in Table 2: 10 phase II studies, 1 phase II/III study, 1 phase III study, and 10 retrospective studies. Twelve articles were prospective studies, and a high number of prospective studies were found in articles with recent reporting years. Among the 10 retrospective studies, a propensity score-matched analysis was performed in one (10).

The diagnosis of BRPC was made by a multidisciplinary team in nine studies, a central review team in three studies, and multiple radiologists in three studies. No specific description was provided for the diagnosis in seven studies. For the definition of BRPC, 13 studies used the NCCN guidelines, two studies used the modified NCCN guidelines, and seven studies used other criteria. Dholakia et al. (19) reclassified 50 BRPC patients classified by their institutional definition using the AHPBA/SSO/SSAT criteria. The results showed that 40 patients (80%) were classified as BRPC and ten patients (20%) as locally advanced pancreatic cancer using the AHPBA/SSO/SSAT criteria. Takahashi et al. (29) performed a multicenter, phase II study of patients with BRPC. In this study, 52 patients were eligible for BRPC. However, 41 were classified as BRPC by a central review, while the remaining 11 patients as locally advanced cancer. Thus, the imaging diagnosis of BRPC remains not an easy task. Although the NCCN definition tends to be used as the diagnostic criteria for BRPC, we still recognize many reports that use each institution’s definition. In addition, the NCCN guidelines have been revised and updated over time. These may lead to bias in the assessment of treatment outcomes in patients with BRPC. Hence, it is important to establish the diagnostic criteria for BRPC. In addition, the diagnosis of BRPC should be made by a multidisciplinary team in single-center studies and by a central review in multicenter studies.

Upfront surgery versus neoadjuvant therapy (Table 3)

Six studies compared neoadjuvant therapy with upfront surgery (9-14). The neoadjuvant therapy group had a significantly higher R0 resection rate than the upfront surgery group as reported in five articles (9-13), while this information was not reported in one article (14). OS was significantly longer in the neoadjuvant therapy group than in the upfront surgery group as reported in all articles (9-14). The multicenter phase II/III trial by Jang et al. (11) compared the upfront surgery group and the NACRT group, which received 54 Gy of irradiation delivered in 30 fractions combined with gemcitabine as a treatment for BRPC. The median OS was significantly better in the NACRT group than in the upfront surgery group [P=0.028, hazard ratio (HR): 1.97, 95% confidence interval (CI): 1.07–3.36]. The R0 resection rate was also significantly higher in the NACRT group than in the upfront surgery group (P=0.004). The safety monitoring committee decided to discontinue the study early as the neoadjuvant treatment efficacy showed statistical significance. The multicenter phase III PREOPANC trial by Versteijne et al. (13) compared the upfront surgery group and the NACRT group, which received 36 Gy of irradiation delivered in 15 fractions combined with gemcitabine for resectable pancreatic cancer and BRPC. In this study, the analysis of all patients did not show any OS benefit in the NACRT group; in the subgroup analysis of BRPC patients, the NACRT group had significantly better OS than the upfront surgery group (P=0.029, HR: 0.62; 95% CI: 0.40–0.95), and the R0 resection rate was also high [P<0.001, odds ratio (OR): 24.20, 95% CI: 6.57–89.12]. Two retrospective studies compared the efficacy of upfront surgery and NACT. Inoue et al. (12) compared the efficacy of NACT with gemcitabine and nanoparticle albumin-bound paclitaxel (nab-paclitaxel) with that of upfront surgery. The NACT group showed a significantly high R0 resection rate (P=0.004) and a long median OS (P=0.014, HR: 0.61). Murakami et al. (9) compared the outcomes of upfront surgery and NACT with gemcitabine and S-1 for BRPC with arterial involvement (BR-A) cases. Results showed that the NACT group had a significantly higher R0 resection rate (P<0.001) and longer median OS (P=0.003) than the upfront surgery group. Fujii et al. (10) used the propensity score-matched analysis to compare the results of upfront surgery and NACRT (50.4 Gy of irradiation delivered in 28 fractions combined with oral S-1) in three groups: resectable, BRPC with portal vein involvement (BR-PV), and BR-A. Results showed that NACRT significantly prolonged the median survival in BR-PV (P=0.044, HR: 0.451, 95% CI: 0.19–0.91) and BR-A patients (P=0.046, HR: 0.626, 95% CI: 0.27–0.95) but not in patients with resectable cancer (P=0.960, HR: 0.984, 95% CI: 0.48–2.02). In the NACRT group, the incidence of positive pathological margins was significantly reduced in both BR-PV and BR-A patients (P=0.01, OR: 0.06 and P=0.016, OR: 0.072, respectively). Kimura et al. (14) retrospectively compared the results of upfront surgery and neoadjuvant therapy in patients with BR-PV and BR-A. This study included various chemotherapeutic regimens and chemoradiation as neoadjuvant therapies. Results showed that neoadjuvant therapy significantly prolonged the median survival in both BR-PV (P=0.004, HR: 0.38, 95% CI: 0.19–0.75) and BR-A patients (P<0.001, HR: 0.36, 95% CI: 0.21–0.63). Five (9-13) of the six articles described the postoperative complications of upfront surgery and neoadjuvant treatment, and none of them reported statistical differences between the two.

As noted above, both the R0 resection rate and median OS in patients who underwent upfront surgery were significantly worse than those who underwent neoadjuvant treatment in all studies that investigated the overall BRPC cases, BR-PV and BR-A cases separately, and BR-A cases. In the 2020 annual meeting of an American Society of Clinical Oncology Group, the results of the ESPAC-5F trial (31), a four-arm, multicenter, randomized phase II trial that compared the efficacy of upfront surgery with that of neoadjuvant gemcitabine plus capecitabine or fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) or chemoradiation therapy as a treatment for BRPC, was opened. In this study, neoadjuvant therapy significantly improved survival compared with upfront surgery (P<0.001, HR: 0.27, 95% CI: 0.13–0.55). At this moment, neoadjuvant therapy should be considered for patients with BRPC.

Neoadjuvant therapy

Neoadjuvant chemotherapy

Table 4 shows the six studies reporting the results of NACT followed by surgery for BRPC. Neoadjuvant gemcitabine plus S-1 was investigated in three studies conducted by Masui et al. (15), Murakami et al. (9), and Motoi et al. (18). The R0 resection rates were 80%, 72.3%, and 81%, respectively, and the median OS rates were 21.7, 27.1, and 21.1 months, respectively. Miyasaka et al. (17) and Inoue et al. (12) investigated the efficacy of neoadjuvant gemcitabine plus nab-paclitaxel. The R0 resection rates were 100% and 93%, respectively, while the median OS rates were 27.9 months and 31.9 months, respectively. Yoo et al. (16) investigated the use of neoadjuvant FOLFIRINOX. The R0 resection rate was 75%, while the median OS was 21.2 months. Treatment-related mortality was not observed in any of the studies.

The development of systemic chemotherapy for pancreatic cancer has traditionally focused on treating unresectable pancreatic cancer. Randomized controlled trials of gemcitabine in patients with unresectable pancreatic cancer, including those with locally advanced cases, have reported that gemcitabine is more effective than fluorouracil in prolonging survival and relieving the symptoms (32) and has been used as a first-line treatment for unresectable pancreatic cancer. Since then, many randomized controlled trials have been conducted using gemcitabine as a control. The results of the Prodige4-ACCORD11 (33) and MPACT (34) trials showed that FOLFIRINOX and gemcitabine plus nab-paclitaxel were associated with a higher incidence of adverse events compared to gemcitabine; however, survival benefits were also observed in patients administered with these drugs. According to the NCCN guidelines (5), the preferred regimens for locally advanced disease consist of FOLFIRINOX and gemcitabine plus nab-paclitaxel for patients with good performance status (PS), and gemcitabine, capecitabine, and continuous infusion of 5-Fluorouracil for patients with poor PS. The efficacy of S-1 monotherapy and multi-drug combination therapy, including S-1, has been investigated mainly in Japan. The GEST study was a phase III trial on locally advanced pancreatic cancer aimed to evaluate the non-inferiority of S-1 over gemcitabine and the superiority of gemcitabine plus S-1. Results of this study showed that S-1 was non-inferior in terms of OS. On the contrary, the combination of gemcitabine and S-1 showed a significant improvement in progression-free survival but no superiority over gemcitabine in improving OS (35). It was difficult to determine which regimen is superior to the others at the time of this review. Recently, Kunzmann et al. (36) reported the results of the NEOLAP-AIO-PAK-0113 multicenter, randomized, phase II trial comparing nab-paclitaxel plus gemcitabine with nab-paclitaxel plus gemcitabine followed by FOLFIRINOX for locally advanced pancreatic cancer. No difference was found in OS and R0 resection rates. However, both showed significantly high surgical conversion rates: 35.9% in the nab-paclitaxel group and 43.9% in the sequential FORFIRINOX group. The sequential FORFIRINOX group showed a higher rate of histopathological downstaging in evaluable resection specimens than in the nab-paclitaxel group. In addition, the JCOG1407 randomized phase II trial of modified FOLFIRINOX versus gemcitabine plus nab-paclitaxel for locally advanced pancreatic cancer is still ongoing (37). A randomized phase II trial (PDAC-GS/GA-rP2, CSGO-HBP-015 trial) comparing neoadjuvant gemcitabine plus nab-paclitaxel with neoadjuvant gemcitabine plus S-1 in patients with resectable pancreatic cancer and BRPC is also underway (38).

Based on our review, the NACT regimens included FOLFILINOX in one study (16), gemcitabine plus nab-paclitaxel in two studies (12,17), and gemcitabine plus S-1 in three studies (9,15,18). These regimens have been shown to be useful in locally advanced pancreatic cancer; no studies have compared the efficacy of these NACT regimens in BRPC, and no definitive NACT regimen exists. However, the accumulation of evidence supporting the efficacy of chemotherapy regimens for locally advanced pancreatic cancer and their introduction into BRPC may lead to high resection and survival rates.

Neoadjuvant chemoradiation therapy

Table 5 shows the 15 studies reporting the results of NACRT followed by surgery for BRPC. Five prospective phase II studies investigating NACRT with induction chemotherapy followed by concurrent chemoradiation therapy were conducted (23,25-27,30). Among them, the induction chemotherapy regimen used was using FOLFIRINOX in three studies (23,27,30) and gemcitabine in two studies (25,26). Katz et al. (23) reported the results of the ALLIANCE trial, which was a prospective, multicenter, single-arm trial aimed to determine the feasibility of induction of modified FOLFIRINOX followed by external-beam irradiation (50.4 Gy in 28 fractions) concurrent with capecitabine prior to pancreatectomy for BRPC. This study showed a resection rate of 68%, an R0 resection rate of 93%, and a median OS of 21.7 months (95% CI: 15.7, not reached). The phase II trial by Murphy et al. (27) evaluated the efficacy of FOLFIRINOX followed by individualized chemoradiation therapy concurrent with capecitabine. Radiation therapy in this study included short-course proton therapy (25 GyE in 5 fractions) or intensity-modulated radiotherapy (IMRT) (30 Gy in 10 fractions) and long-course IMRT (58.8 Gy in 28 fractions). This study showed that the R0 resection rate was 97%, while the median OS was 37.7 months (95% CI: 19.4, not reached). Tran et al. (30) reported a phase II trial showing the results of induction FOLFIRINOX followed by IMRT (50 Gy in 25 fractions) with gemcitabine. This study showed that the R0 resection rate was 100%, while the median OS was 24.4 months (95% CI: 12.6–40.0). Nagakawa et al. (25) reported the results of a phase II study of a previous administration of gemcitabine followed by concurrent IMRT (50.4 Gy in 28 fractions) with gemcitabine and S-1 for BR-A patients. This study showed that the R0 resection rate was 94.7%, while the median OS was 22.4 months (95% CI: not reported). Masui et al. (26) reported the results of a phase II study of a previous administration of gemcitabine followed by concurrent chemoradiation therapy with gemcitabine for BR-A patients. This study showed that the R0 resection rate was 94.7%, and the median OS was 22.4 months (95% CI: not reported). This study also compared the survival benefit of IMRT (42–45 Gy in 14–15 fractions) with that of 3DCRT (39 Gy in 13 fractions), and the IMRT group showed a significantly higher OS rate than the 3DCRT group (P=0.027). However, only the cumulative dose of S-1 was a significant factor in the multivariate analysis. So, caution may be exercised when interpreting these results.

Studies have been conducted to improve the resection rate using radiation therapy methods. Seven studies (19,21,23,25-27,30) used or allowed IMRT, and one study (27) used proton therapy. With regard to the irradiation dose, nine studies (10,11,19,23,25,27-30) used conventional fractionated doses of 1.8–2.0 Gy, while the other six studies (13,20-22,24,26) used an increased fractional dose. Three studies (20,22,24) investigated induction chemotherapy followed by planned stereotactic body radiation therapy (SBRT) as the radiotherapy method; all of them were retrospective studies. In all of the studies, chemotherapy was administered as induction chemotherapy and not concurrently with SBRT. Chuong et al. (20) adopted the volumetric modulated arc therapy technique using the simultaneous integrated boost method for SBRT, delivering 35 to 50 Gy to vessel abutment/encasement and 25 to 30 Gy to the remainder of the tumor in 5 fractions. The resection and R0 resection rates were 56.1% and 96.9%, respectively, while the median OS was 16.4 months. Mellon et al. (22) used a similar method, delivering 40 Gy to tumor-vessel interfaces and 30 Gy to the remainder of the tumor in 5 fractions. The resection and R0 resection rates were 51% and 96%, respectively, while the median OS was 19.2 months. Rashid et al. (24) reported the results of induction chemotherapy with gemcitabine, docetaxel, and capecitabine followed by SBRT. In this study, an irradiation dose of 30–40 Gy delivered in 5 fractions was used; however, the details of the SBRT method were not stated. The resection and R0 resection rates were 54.5% and 96.4%, respectively, while the median OS was 17 months (95% CI: 14.0–20.0 months).

Fujii et al. (10) retrospectively evaluated the outcomes of NACRT using an irradiation dose of 50.4 Gy delivered in 30 fractions concurrent with S-1 in patients with BR-PV and BR-A. The resection rates in the BR-PV and BR-A patients were 93% and 67%, respectively, while the R0 resection rates were 96% and 71%, respectively. The median OS by propensity score matching analysis were 28.4 months in the BR-PV patients and 18.1 months in the BR-A group. Although no statistical comparison was made, the outcomes of BR-A patients were worse than those of BR-PV patients.

In the 15 NACRT-related studies selected for this review, a wide range of methods was used, and it was difficult to determine the optimal NACRT in terms of the treatment outcome and safety. However, BRPC might lead to a prolonged prognosis if the resection rate and R0 resection rate are improved by treating the infiltrated areas of the major vessels with high-intensity radiation. Therefore, further research on multidisciplinary treatment using the latest high-precision radiation therapy is needed.

On the contrary, in NACRT, unlike NACT and upfront surgery, concerns have been raised regarding the risk of gastrointestinal toxicity due to irradiation. Chakraborty et al. (21) conducted a phase II study evaluating the efficacy of capecitabine combined with a fractionated dose of 2.5 Gy and a total dose of 50 Gy. However, this study was discontinued before a planned interim analysis as two cases of severe (grades 4 and 5) gastric ulcerations were reported. Mellon et al. (22) showed that gastrointestinal bleeding from the duodenum or stomach (grade 3 or higher) was the most common toxic effect. The avoidance of severe gastrointestinal toxicity must also be considered in the development of optimal NACRT for BRPC.

Neoadjuvant chemotherapy versus neoadjuvant chemoradiation therapy

In the studies extracted for this review, the R0 resection rate ranged from 72.3% to 100% in the NACT group and from 71% to 100% in the NACRT group. The median OS ranged from 21.1 to 31.9 months in the NACT group and from 13.8 to 37.7 months in the NACRT group. This suggests that there is no clear difference in treatment results between NACT and NACRT. At present, the results of comparative studies between NACT and NACRT for BRPC have not been reported, and the superiority of the two regimens remains unclear.

Future prospective

Ongoing studies of neoadjuvant therapy

There are several ongoing comparative studies investigating the superiority of NACT to NACRT (Table 6). The PREOPANC-2 trial (39) is a multicenter phase III randomized controlled trial conducted by the Dutch Pancreatic Cancer Group. This trial compared neoadjuvant FOLFIRINOX followed by surgery without adjuvant therapy with neoadjuvant gemcitabine combined with hypofractionated radiotherapy followed by surgery and adjuvant gemcitabine for resectable pancreatic cancer and BRPC. The BRPCNCC-1 trial (40) is a prospective, randomized phase II trial that compared and evaluated the efficacy of neoadjuvant gemcitabine plus nab-paclitaxel with that of gemcitabine plus nab-paclitaxel with SBRT versus S-1 plus nab-paclitaxel with SBRT for BRPC. The GABARNANCE trial (41) is a phase II/III randomized trial that compared the efficacy of gemcitabine and nab-paclitaxel with that of S-1 and concurrent irradiation as neoadjuvant therapy for BRPC. The ALLIANCE trial A021501 (42) is a randomized phase II trial that compared the efficacy of preoperative modified FOLFIRINOX with that of modified FOLFIRINOX followed by SBRT (33–40 Gy in 5 fractions) for BRPC of the head of the pancreas. The results of these ongoing clinical trials may provide a direction for a neoadjuvant treatment of patients with BRPC.

Molecular targeted therapy and immunotherapy

Studies on molecular-targeted therapy for pancreatic cancer has not shown promising results (43,44). Recently, Golan et al. reported that the common founder germline BRCA1 or BRCA2 mutation-positive (gBRCAm) patients with BRPC have an advantage in terms of pathologic complete response rate and long-term survival when treated with neoadjuvant FOLFIRINOX (45). In their study, the pathologic complete response rates were 44.4% for gBRCAm patients and 10% for BRCA non-carriers (P=0.009). The median disease-free survival was not reached for the gBRCAm patients and was 7 months for the BRCA non-carriers (P=0.03).

Pancreatic cancer is less likely to respond to immune checkpoint inhibitors because it mildly expresses programmed death-ligand 1 and tumor-specific neoantigens (46). Recently, the results of the KEYNOTE-158 study (47) have been reported. This multicenter phase II study evaluated the efficacy and safety of pembrolizumab in previously treated patients with advanced high levels of microsatellite instability (MSI-H)/mismatch repair deficiency (dMMR) solid tumors in 27 cancer types other than colorectal cancer. A total of 233 patients were enrolled, 22 of whom had pancreatic cancer. The response rate for pancreatic cancer was 18.2% (95% CI: 5.2–40.3), while the median duration of response was 13.4 months (95% CI: 8.1–16.0), showing promising results. Although the frequency of MSI-H/dMMR in pancreatic cancer is not high, a treatment incorporating immunotherapy should be developed.

Limitations

Our review had several limitations. The regimens for both NACT and NACRT were diverse. Furthermore, the number of cases in BRPC studies was limited, and the diagnostic criteria for BRPC used were not uniform. The quality of the evidence was limited in some studies, with few phase III trials. Some studies analyzed all cases of BRPC, while some analyzed BR-PV and BR-A cases separately, and some only included BR-A cases. Therefore, we considered it difficult to aggregate the data of NACT and NACRT and compare between them. For this reason, we adopted the style of narrative review in this paper. Despite these limitations, the present review provides the most reliable data reported for BRPC patients using an intention-to-treat analysis.

Conclusions

The current standard of care in the treatment of BRPC includes neoadjuvant therapy followed by the determination of resectability and, if possible, surgery. Although optimal neoadjuvant therapy for BRPC has not yet been determined, several clinical trials are being conducted to address this issue. A multidisciplinary treatment incorporating high-precision radiotherapy should be developed to increase the R0 resection rate.

Acknowledgments

We would like to thank Editage (www.editage.com) for English language editing.

Funding: An internship program at the International Atomic Energy Agency (IAEA; Vienna, Austria) was supported by the Hiroshima International Council for Health Care of Radiation-exposed and IAEA.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-21-829/rc

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-21-829/coif). Abdel-Wahab M reports that she is the chair of the international committee of the American society for radiation oncology. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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