Surgery based on resectability status of pancreatic cancer: a narrative review.

Introduction
At present, surgical resection is the only curative treatment option for patients with pancreatic ductal adenocarcinoma (PDAC), who often have poor prognoses [1]. Currently, we determine the treatment plan based on the resectability status, which is classified into: resectable (R), borderline resectable (BR), and unresectable (UR), according to the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology, Pancreatic Adenocarcinoma [2]. Pancreatic cancer treatments have been undergoing significant changes, including the dissemination of new drug treatments, and advances in diagnostic imaging and endoscopic diagnosis. R patients are now receiving neoadjuvant therapy, and some BR and UR patients at the initial diagnosis may subsequently be downstaged following chemotherapy. In this article, we review the surgical strategy after multidisciplinary treatment based on the resectability classification, and present current problems that need to be overcome and possible solutions.

Methods

How articles were selected in this review
This is a narrative review, written based on the resectability of PDAC. We cite only published articles, not just presentations. A literature search of PubMed was conducted during 5th–15th January 2025 (carried out again in 25th–31th May 2025), with the aim of identifying the most recent English literature since 1st January 2010. Regarding the search strategy, search terms were: “pancreatic cancer”, “pancreatic ductal adenocarcinoma”, and “pancreatic adenocarcinoma”. This strategy was subsequently extended with the following terms: “neoadjuvant therapy”, “induction therapy”, “preoperative chemotherapy”, “chemoradiotherapy”, “preoperative chemoradiotherapy”, “adjuvant chemotherapy”, “adjuvant chemoradiotherapy”, “resectable”, “borderline resectable”, “unresectable”, “locally advanced”, and “resection”. Articles were sorted by resectability classification and included according to the following criteria: For R, we selected papers reporting results of representative prospective trials involving adjuvant therapy, and introduced representative prospective trials assessing preoperative chemotherapy and chemoradiotherapy. For BR, “the definition of BR” and “treatment strategy for BR” involved the introduction of representative retrospective and multicenter studies, and in “prospective clinical trials for BR”, we presented prospective studies. For UR, strategies were divided into “UR-LA” and “UR-M”, and we introduced representative retrospective studies. Based on this, we cite original articles that we consider to be clinically important and cutting-edge efforts.

The definition of conversion surgery
Conversion surgery (CS) refers to surgical resection performed for initially “unresectable” cancer that has become resectable after chemotherapy or chemoradiotherapy [3–5].

Resectable
In the pancreatic cancer registry of the Japan Pancreatic Society report from 1981 to 2004, the 5-year survival rate of patients with primary pancreatic cancer after complete resection failed to reach 15% [6]. Efforts have been made to develop better adjuvant therapies to improve the prognosis of R patients [7–11]. Regarding R patients initially considered to be R on imaging, surgeons often identify distant metastases during laparotomy, resulting in them becoming UR due to local progression in a short period. In addition, some patients show early recurrence after curative resection. These findings suggest that the clinical diagnosis of R is not always accurate, and preoperative treatment may be useful to estimate the tumor aggressiveness and avoid unnecessary surgery.

Chemoradiotherapy
In the PREOPANC trial, patients classified as R or BR were randomly assigned to receive either preoperative chemoradiotherapy (gemcitabine: 1000 mg/m2, 3 times) with 15 fractions of 2.4-Gy radiotherapy, followed by surgery, and four courses of adjuvant gemcitabine as adjuvant chemotherapy or upfront surgery with 6 courses of adjuvant gemcitabine. Preoperative chemoradiotherapy did not lead to a significant overall survival (OS) benefit compared with upfront surgery (16.0 vs. 14.3 months, respectively, P = .096) [12]. The JASPAC 04 trial compared the efficacy of neoadjuvant treatment: neoadjuvant chemoradiotherapy (NAC-RT) with S-1 or neoadjuvant chemotherapy (NAC) with gemcitabine and S-1 (NAC-GS). The primary endpoint was the 2-year progression-free survival rate. This rate was not significantly different between them (P = .35: 45.0, and 54.9% in NAC-RT and NAC-GS groups, respectively) [13]. The clinical PREOPANC-2 trial is currently undergoing, comparing total neoadjuvant FOLFIRINOX versus neoadjuvant gemcitabine-based chemoradiotherapy and adjuvant gemcitabine for R and BR patients [14].

Chemotherapy
A review of selected trials for patients with localized pancreatic cancer suggested a benefit of neoadjuvant chemotherapy [15,16]. NAC-GS was feasible and actively prolonged survival following planned resection (PREP-01) [17]. Based on this trial, a randomized, controlled trial was conducted to compare NAC-GS with upfront surgery for patients planned to undergo resection of pancreatic cancer (PREP02/JSAP05) [18,19]. Outcomes of the NAC-GS group were superior to those of the upfront surgery group, with a hazard ratio of 0.72 (P = .015) for OS. Based on these results, the Prep02/JSAP05 protocol is currently the standard treatment for R patients in Japan (Fig. 1). To date, clinical trials have led to perioperative regimes becoming more intensive: PANACHE01 FRENCH08 PRODIGE 48 study [20], NORPACT-1 [21], RCT, CSGO-HBP-015 [22], NEONAX [23], and extending the duration of NAC [24]; however, there has been no consequent survival benefit.

Elderly patients
One of the difficulties associated with pancreatic cancer treatment is that target patients are often elderly. Such patients have many problems compared with younger ones, such as a short life expectancy, multiple comorbidities, taking many types of medication, declines in physiological functions due to aging, and possibly limited cognitive function; thus, treatment plans need to be carefully considered. For patients aged 80 years or older with R-PDAC, it is necessary to make individual decisions about whether to carry out surgery, chemotherapy, or best supportive care (BSC). First, in terms of treatment options, the prognosis of patients aged 80 years or older with R or BR PDAC who underwent surgery, chemotherapy, or BSC was examined. The results showed that the survival time was significantly better in the surgery group than chemotherapy or BSC group (median survival times: 20.6, 18.6, and 8.8 months in each group, respectively). In the surgery group, lymph node metastasis, tumor size, and BMI were significant independent prognostic factors. In the chemotherapy group, tumor diameter, second-line chemotherapy, nutrition, and patient condition (such as serum albumin level, American Society of Anesthesiologists classification, body mass index, and modified Glasgow prognostic score) were significant independent prognostic factors [25]. Regarding surgery for PDAC, it has been reported that elderly patients have higher rates of complications and perioperative mortality after pancreatic resection compared with younger ones [26–28]. However, by determining operability for pancreatic resection based on the performance status (PS) and American Society of Anesthesiologists physical status, no significant differences were noted between patients aged 80 years or older and those younger than 80 in terms of the length of hospital stay, complications, and perioperative mortality rate after pancreatic resection, and it has also been reported that long-term outcomes were equivalent to those of younger patients [29–32]. Based on the above, indications for pancreatic resection in elderly patients should not be determined solely by age; patient selection should be based on the physical condition and nutritional assessment.

Further questions regarding R
What is the appropriate intensity and duration of preoperative treatment?

For breast cancer, the National Surgical Adjuvant Breast and Bowel Project B-18 study compared OS and disease-free survival (DFS) between patients pre- and postoperatively receiving four cycles of doxorubicin/cyclophosphamide. The results showed that there were no significant overall differences in survival or DFS between the groups [33]. For pancreatic cancer patients, it is difficult to administer strong postoperative adjuvant therapy such as modified FOLFIRINOX (mFOLFIRINOX) (completion rate: 66%) [10] because the necessary surgical procedures are highly invasive. At present, comparisons of perioperative mFOLFIRINOX clinical trials of PREOPANC-3 [34] and ALLIANCE A021806 [35], involving eight cycles of NAC FOLFIRINOX followed by surgery and four cycles of adjuvant mFOLFIRINOX versus surgery followed by 12 cycles of adjuvant mFOLFIRINOX, respectively, are undergoing. Although the response rates to anticancer drugs and surgery differ between breast and pancreatic cancer patients, in view of the results, new clinical questions arise about the duration and intensity of NAC. To answer such questions, it might be necessary to consider the optimal dosage by changing NAC and adjuvant chemotherapy regimens and cycles.

The definition and treatment strategy for biological BR

Among R patients, clinicians often encounter cases associated with early recurrence and a poor prognosis after surgery. Even if these are anatomically R, they are considered to have biological and conditional factors associated with a poor prognosis. Biological factors include potential R disease based on anatomic criteria but with clinical findings suggesting (but unproven) distant metastases, such as carbohydrate antigen (CA) 19-9 level over 500 units/mL, a large tumor size, or regional lymph node metastases diagnosed by biopsy or positron emission tomography-computed tomography (PET-CT). Conditional factors include patients with Eastern Cooperative Oncology Group (ECOG) PS of two or more. It was proposed that it is important to comprehensively evaluate biological and conditional factors, and, in such cases, we need to consider performing multidisciplinary treatment instead of early resection to extend OS [36]. Oba et al. reported that CA19-9 is the most useful biological marker, CEA, CA125, and DUPAN-2 may be useful as tumor biology markers in Lewis antigen-negative populations, PET-CT maximum standardized uptake values (SUVmax) of the primary tumor may be good biology markers [37], and that to obtain more accurate information in order to appropriately determine resectability, it is important to detect clinical factors from endoscopic ultrasound-guided fine-needle aspiration biopsy (EUS-FNA) specimens and circulating biomarkers in blood samples [38]. To be widely accepted, it is desirable to have a standard that is easy to understand and use, such as CT-based resectability.

Borderline resectable

The definition of borderline resectable
BR is based on tumor extension of venous and arterial involvement without distant metastasis [39]. Definitions of BR are as follows: BR-PV (SMV/PV invasion alone): Tumor contact of 180° or greater or invasion of SMV/PV, and not exceeding the inferior border of the duodenum; Japanese classification of pancreatic carcinoma by the Japan Pancreas Society: Eighth edition [39] added this statement to the NCCN Guidelines [2]; BR-A (arterial invasion): Tumor contact with SMA and/or CA less than 180° without showing stenosis or deformity. Tumor abutment of CHA without showing tumor contact with the proper hepatic artery and/or CA. Currently, to improve patient outcomes, new multidisciplinary treatments and surgical techniques are being developed. Additionally, in recent years, there has been a trend to designate biological BR, involving consideration of biological and conditional factors for R.

Treatment strategy for borderline resectable
By introducing preoperative treatment, clinicians can evaluate tumor malignancy, and potentially improve the prognosis of selected patients who respond well to treatment and can undergo surgery. An observational multicenter study of pancreatic head carcinoma patients who were treated with upfront surgery was performed to evaluate the validity of the preoperative resectability status. As the results, OS of BR-PV and BR-A groups was significantly poorer than that of the R group. In addition, BR-PV and BR-A were independent prognostic factors of OS [40]. Furthermore, in most other retrospective studies, outcomes of the preoperative treatment group were significantly better than those of the upfront surgery group [41–48]. For these reasons, standard therapy for BR is preoperative treatment followed by surgery, if possible.

Prospective clinical trials for borderline resectable
Clinical trials of NAC or NAC-RT are planned for BR-classified pancreatic cancer patients. Jang et al. reported a multicenter randomized controlled trial in which patients were randomly assigned to receive radiation (54 Gy) with gemcitabine-based NAC-RT treatment followed by surgery or upfront surgery followed by chemoradiation treatment (CRT). The 2-year and median survival rates were significantly better in the NAC-RT than upfront surgery group (40.7%, 21 months vs. 26.1%, 12 months, respectively, P = .028). Also, the NAC-RT group showed a high R0 resection rate compared with the upfront surgery group (51.8 vs. 26.1%, respectively, P = .004) [49]. In Japan, the JASPAC05 study, a multicenter, single-arm, phase II study, showed that S-1 (40 mg/m2 twice daily on the day of irradiation: total of 50.4 Gy in 28 fractions) before surgery may be feasible and effective for increasing the R0 resection rate (52%), with a 2-year OS rate and median OS duration of 58% and 30.8 months, respectively [50]. Kondo et al. evaluated NAC, including gemcitabine, nab-paclitaxel, and S-1 (GAS), for BR-A patients. The results showed that the GAS regimen was associated with a high R0 resection rate (85%) and more favorable BR-A patient survival, with a 2-year OS rate and median OS time of 70.1% and 41.0 months, respectively [51]. Yamaguchi et al. reported NUPAT-01, a randomized phase II trial, in which patients with BR pancreatic cancer were enrolled and randomly assigned to receive NAC with either FOLFIRINOX or gemcitabine with nab-paclitaxel (GnP). After the completion of chemotherapy, the resection rate was 84.3%, and the R0 resection rate was 73% in the FOLFIRINOX group and 56% in the GnP group. The 3-year OS rate was 55% in the FOLFIRINOX group and 54% in the GnP group. No significant difference in OS was observed between the FOLFIRINOX and GnP groups (P = .351) [52]. Katz et al. compared treatment with neoadjuvant mFOLFIRINOX with or without radiation therapy. The median OS of evaluable patients without and with radiation was 29.8 and 17.1 months, respectively [53]. Ghaneh et al. compared three neoadjuvant treatments: gemcitabine and capecitabine, FOLFIRINOX, and capecitabine-based CRT, with upfront surgery. The results were: 1-year OS of 39% for upfront surgery, 78% for gemcitabine plus capecitabine, 84% for FOLFIRINOX, and 60% for capecitabine-based chemoradiotherapy (P = .0028) [54]. Okada et al. showed the effectiveness of NAC with GnP. The resection rate was 73.8% and R0 resection rate was 63.9%, with median OS of 25.2 months [55] (Table 1).
All clinical trials comparing upfront surgery with preoperative treatment have shown a better prognosis with the latter. We still need to explore preoperative treatment strategies associated with higher efficacy, improved R0 resection rates, and a better prognosis. For preoperative treatment of BR patients, clinical trials of NAC and NACRT are currently being conducted. Although radiation therapy is a good way to perform R0 surgery, it is questionable whether it is necessary for all BR patients. There might be a greater risk of radiation therapy reducing the strength of anticancer drugs or shortening the period of systemic treatment [53,54]. Clinical trials of the GABARNANCE study and PANDAS/PRODIGE 44 trial are currently underway [56,57]. The GABARNANCE study is a randomized phase II/III study of GnP versus S-1 and concurrent radiotherapy as neoadjuvant treatment for BR. The PANDAS/PRODIGE 44 study is evaluating the effectiveness of adding CRT to neoadjuvant mFOLFIRINOX for patients with BR.

Further questions regarding BR
The appropriate preoperative treatment period

In clinical trials, surgery is performed after preoperative treatment for a certain period. Although the prognosis is better than that associated with upfront surgery, the optimal administration period and regimen have yet to be determined. Based on the present review, although radiation therapy aims to increase the R0 rate, the problem with such therapy for BR is that when it is performed after systemic chemotherapy, the administration period of systemic chemotherapy is shortened, and when it is performed in combination with systemic chemotherapy, the amount of systemic chemotherapy administered is reduced. As in the new concept of biological BR, BR is basically a systemic disease associated with a poor prognosis, and questions remain about the short-term preoperative treatment policy. Clinical trials comparing longer and shorter preoperative chemotherapy periods are needed to determine the optimal duration of preoperative chemotherapy.

What are the indications for surgery in BR patients?

In clinical trials, preoperative treatment is performed for BR patients, but not all are suitable for surgery. For example, there are some reports that the value of CA19-9 after preoperative treatment is associated with postoperative survival [58–60]. We eagerly anticipate reports on the kind of surgery facilitating a favorable prognosis based on sub-analysis in future prospective clinical trials.

Should BR-PV and BR-A be treated with the same strategy?

Regarding BR, the question remains as to whether treatment strategies for BR-PV and BR-A should be separate. Many prospective studies have involved the treatment of BR-PV and BR-A together. However, the R0 rate differs between them; furthermore, the prognosis associated with BR-A is poorer than that of BR-PV [40,61]. There are also reports that applying total neoadjuvant therapy (TNT: usually upfront systemic chemotherapy is followed by preoperative chemoradiotherapy in a neoadjuvant setting) to BR-A improves the prognosis [62–65]. We await future reports on whether TNT is useful for BR-PV.

Unresectable
The history of CS for UR patients is based on the results of the Japanese Society of Hepato-Biliary-Pancreatic Surgery to assess the role of CS in a multi-institutional retrospective study, showing that the OS rate following initial treatment is high, especially in patients receiving systemic chemotherapy for over 8 months [66]. Since this result, the view that the optimal preoperative treatment period is at least 8 months has become widespread. However, at this time, FOLFIRINOX [67] and GnP [68] regimens have yet to become available, and there is an opinion that clinicians need to reconsider the optimal preoperative treatment period. Recently, response rates have been increasing, and we have been encountering more potential CS cases. A more recent and extensive study by Okano et al. reported a median preoperative chemotherapy duration of 6.9 months, with CS showing an improved prognosis regardless of the chemotherapy duration compared with unresected cases [5]. Clinical trials are needed to evaluate appropriate treatment methods and durations for UR patients.

UR-locally advanced
When surgeons perform CS for UR-locally advanced (UR-LA) patients, the main problem is whether R0 resection can be realized. To realize radical surgery for such patients, the concept of TNT, which uses CRT to regulate tumor invasion, is becoming widespread [62–65]. Truly et al. achieved a high R0 rate (94%) in a study of locally advanced pancreatic cancer patients treated with FOLFIRINOX or GnP therapy followed by CRT [64]. Similarly, there are reports that adding CRT improves the prognosis [69], Igarashi et al. revealed that the use of systemic chemotherapy until surgery is more significant than achievement of R0 resection and adjuvant chemotherapy [70]. At present, there is no consensus regarding radiotherapy before CS for UR-LA. In the event that patients respond favorably to FOLFIRINOX or GnP, CS becomes associated with a better prognosis than chemotherapy alone [5]. A randomized phase II study compared the regimes of four cycles GnP with two cycles GnP followed by four cycles FOLFIRINOX in UR-LA. Conversion rates were 35.9% and 43.9% in the GnP and sequential FOLFIRINOX groups, respectively. Median OS times were 18.5 and 20.7 months in the GnP and sequential FOLFIRINOX groups, respectively [71].
One of the major problems of CS for UR-LA is that the recurrence rate after CS is very high. Seelen et al. reported that the recurrence rate after CS for UR-LA was 70.2% that a preoperative predictor for early recurrence, within 6 months, was post-induction therapy CA19-9 ≥100 U/mL, and that postoperative predictors were: poor tumor differentiation and the absence of adjuvant chemotherapy [72]. Nagai et al. reported that a CS group of UR-LA in which CEA, CA19-9, and DUPAN-2 markers were normal had a better prognosis than a group in which one or more markers were elevated [73].
Another problem of CS for UR-LA is that surgeons often need to perform difficult surgeries that require high-level techniques. In our experience of CS for UR, portal vein and arterial resections were performed in 53% [1]. Arterial resection for pancreatic cancer, excluding distal pancreatectomy with celiac axis resection [74–77], leads to a high rate of serious complications associated with the resection and reconstruction of major arteries, such as thrombosis and post-operative bleeding, re-operation rates, incidence of visceral ischemia, and low survival rate after surgery [78]; there have been many opinions against aggressive application of this procedure [79]. Recently, retrospective studies reported relatively good short- and long-term outcomes in patients with combined arterial resection after preoperative treatment [80–82]. However, problems with combined arterial resection include high perioperative morbidity and mortality rates (2015–2018: morbidity, 25%–89%; mortality, 0%–18.4%) [81]. The surgical technique of arterial resection is demanding and should be performed at a facility with extensive experience and the ability to perform it safely. Loos et al. reported that periadventitial dissection after neoadjuvant treatment was safer than arterial resection [83] (Table 2).

UR-metastatic
Most oncologists regard UR-M (metastatic) as a systemic disease, and perform systemic chemotherapy first. In UR-M, there are some patients in whom metastatic spread is limited to the liver, lung, and peritoneum with small volumes, so-called oligometastases. In a small number of oligometastatic patients, we sometimes perform CS after systemic chemotherapy, possibly followed by resection. In liver metastasis, Hamad et al. reported that liver-only metastatic pancreatic adenocarcinoma patients who received CS after systemic chemotherapy had a longer median OS (15.6 vs. 8.1 months, respectively) compared with those who received chemotherapy alone (P < .001) [84]. Takeda et al. reported that CS after a favorable response to chemotherapy for highly selected patients resulted in an unexpectedly long median OS of 54.6 months [85]. Other retrospective studies also reported many favorable opinions on CS after chemotherapy [86]. Regarding lung metastasis, some studies reported that in selected patients, surgical resection showed good efficacy regarding survival [87,88]. Homma et al. performed a multicenter retrospective study on metachronous lung metastasis, and reported that surgical resection is a favorable option for selected patients with a solitary lung lesion and for whom adjuvant chemotherapy can be performed [89]. Ilmer assessed the perioperative and long-term outcomes following pulmonary resection in patients with metachronous lung metastasis, reported that DFS and OS after surgery were 18 and 26 months, respectively, and that patients who developed lung metastasis more than 17 months after primary surgery showed better OS compared with those who developed it before 17 months (32.2 vs. 14.8 months, respectively, P = .025) [90]. Survival in the presence of peritoneal dissemination is very poor, but the survival-promoting effect of intraperitoneal chemotherapy with paclitaxel was very promising in patients with peritoneal dissemination [91]. Currently, a randomized phase-III trial to assess the superiority of intravenous and intraperitoneal paclitaxel with S-1 relative to gemcitabine plus nab-PTX is being conducted [92]. In a retrospective multicenter study by Okano et al., the surgical group had a better prognosis than the control group (34.4 vs. 19.8 months, respectively), but the recurrence rate was still high (median RFS: 13.6 months) [5].

Further questions regarding UR
Is CS necessary for UR-LA patients?

To achieve R0 resection for UR-LA, extensive surgical resection, including PVR and arterial resection, may be required. In our experience of CS in a UR group, PVR and arterial resection were performed in 53%. The R0 rate was 67%, and postoperative mortality was limited to one patient [1]. Some patients developed refractory diarrhea, malabsorption, weight loss, fatty liver disease, and osteoporosis after arterial resection [78]. In a multicenter retrospective study by Okano et al., the surgical group had a better prognosis than the control group (34.4 vs 19.8 months), but the recurrence rate was still high (median RFS 13.6 months) [5]. Concerning radiation therapy, technical advances have made it possible to increase the dose relatively safely. Carbon-ion radiotherapy is expected to improve the prognosis associated with UR-LA [93–95]. It may be necessary to conduct a clinical trial to compare CS and radiotherapy.

To increase the conversion rate

Anticancer drugs include cytotoxic anticancer drugs, molecular-targeted therapy, and immune checkpoint inhibitors; now, in our daily practice, we mainly use cytotoxic anticancer drugs, and molecular-targeted drugs such as PARP inhibitors, Olaparib for germline BRCA-mutated PDAC patients [96], and the KRAS inhibitors sotorasib and adagrasib [97]. If new anticancer drugs or regimens [98] with marked therapeutic effects are developed, such as Atezolizumab and FOLFIRINOX combined with personalized RNA neoantigen vaccines [99], it is expected that the number of CS cases will increase even further, and this may improve the prognosis of UR patients. Ideally, as is the case with breast cancer [100–102], it may be possible to classify the cancer into subtypes based on treatment at the time of diagnosis. It is desirable to use anticancer drugs based on the predicted chemotherapeutic efficacy using samples taken at the time of diagnosis.
Based on these contents, we present the current treatments and problems with surgery for each resectability status (Fig. 2).

Conclusion
Pancreatic cancer is associated with a poor prognosis, so NAC followed by surgical resection rather than upfront surgery should be the standard treatment for R patients. Patients with BR and UR can be cured only by surgery following systemic chemotherapy with or without radiation. While the development of new anticancer drugs associated with higher response rates is awaited, it is important to realize that the establishment of multidisciplinary treatments based on resectability will improve the prognosis.