1) Adjuvant chemotherapy

Even with microscopically complete (R0) resections, recurrence rates are very high in pancreatic cancer. Therefore, additional adjuvant therapy is required for all patients with resected pancreatic adenocarcinoma. From early 1980s, there are several milestone studies for adjuvant chemotherapy of resected pancreatic cancer (Table 1) [11-19]. Especially, the European Study Group for Pancreatic Cancer (ESPAC-1) and CONKO (Charité Onkologie)-001 trial proved the benefit of adjuvant chemotherapy with gemcitabine or 5-fluorouracil (5-FU) plus leucovorin after curative surgery [13,14]. In 2004, final data of ESPAC-1 was reported [13]. They used 2×2 factorial design to randomize 289 patients to either chemotherapy with 5-FU/leucovorin or no chemotherapy, and chemoradiotherapy with 20 Gy dose in 10 daily fractions plus 5-FU or no chemoradiation. The overall survival of chemotherapy with 5-FU/leucovorin group was significantly better than no chemotherapy group (HR 0.71; 95% CI 0.55–0.92; p=0.009). With this study, adjuvant chemotherapy was turned out to be effective and beneficial. In 2007, Oettle et al. [14] reported a randomized controlled trial-CONKO-001 with gemcitabine monotherapy versus observation after curative surgery. In this study, disease free survival was significantly longer in gemcitabine monotherapy group compared to observation group (13.4 vs. 6.9 months). However, median overall survival was comparable in both group (22.1 vs. 20.2 months). Based on this study, gemcitabine monotherapy has been regarded as one of standard adjuvant chemotherapy.

Table 1.

Summary of clinical trials of adjuvant chemotherapy for pancreatic cancer

With the above data, adjuvant chemotherapy for pancreatic cancer was justified. There are still debates for what is the best regimen or a drug as adjuvant setting. In 2016, adjuvant S-1, an oral fluorouracil prodrug was evaluated for adjuvant chemotherapy with Japanese patients [16]. In this study, S-1 showed remarkable superiority to gemcitabine monotherapy in overall survival (46.5 vs. 25.5 months, HR 0.57; 95% CI 0.44–0.72; p<0.001). Even though the authors concluded that S-1 rather than gemcitabine should be the standard adjuvant chemotherapy after surgery of pancreatic cancer, it should be validated for ethnic difference to S-1 in future. In 2017, the final data of ESPAC-04 trial was published. In this study, a total of 730 patients were randomized to adjuvant chemotherapy with gemcitabine ± capecitabine [17,18]. The overall survival of gemcitabine/capecitabine group was 28.0 months and 25.5 months in gemcitabine monotherapy group (HR 0.82; 95% CI 0.68–0.98; p=0.032). More recently, the results from the multicenter, randomized PRODIGE24/CCTGPA.6 French-Canadian trial was reported. At a median follow-up of 34 months, disease free survival was significantly better with mFOLFIRINOX (21.6 vs. 12.8 months, HR 0.58; 95% CI 0.46–0.73; p<0.001), as was overall survival (54.4 vs. 35 months, HR 0.64; 95% CI 0.48–0.86; p=0.003) [19].

Based upon currently available data, gemcitabine ± capecitabine or mFOLFIRINOX can be considered as the first choice of adjuvant chemotherapy for the patients of resected pancreatic cancer. However, there is still a large proportion of patients with poor response to the above chemotherapy. So, pretreatment response prediction models for personalized treatment such as patient derived tumor organoids or conditionally reprogrammed cell culture should be more investigated [20].

2) Neoadjuvant chemotherapy

As already mentioned, pancreatic cancer is notorious for high risk of recurrence after surgery even in cases of very early staged cancer. Furthermore, the potential risk of complications with relatively aggressive surgery such as Whipple’s operation frequently prevent the patient from receiving adjuvant chemotherapy. These situations are the reason why neoadjuvant therapy should be considered in specific situations of pancreatic cancer. However, because powered randomized trials are insufficient, long-term outcome of neoadjuvant therapy was found through phase II trials and retrospective database analyses (Table 2).

Table 2.

Summary of clinical trials on neoadjuvant therapy with resectable pancreatic cancer

In resectable disease, it is examined, an observational retrospective study analyzed by propensity score matching in 15,237 patients with resected pancreatic cancer. It showed that those who received neoadjuvant therapy had better overall survival than those who received upfront resection (median survival 26 months vs. 21 months, respectively; HR, 0.72; 95% CI 0.68–0.78; p<0.01) [21]. Recently, SWOG S1505 trial is under way, which is a randomized phase II study intended to choose the most promising perioperative regimen (mFOLFIRINOX vs. gemcitabine/nab-paclitaxel [GnP]) for resectable pancreatic cancer [22]. From 2015 to 2018, 147 patients were enrolled, but 42/147 (29%) were ineligible at central radiology review. Follow up for overall survival is ongoing.

In borderline resectable disease, whether neoadjuvant therapy is better than upfront surgery plus adjuvant chemotherapy, and what is the best regimens to use in the borderline neoadjuvant setting are debated topics. But several studies suggest that neoadjuvant therapy with FOLFIRINOX are an auspicious approach in patients with borderline resectable disease [23-25].

3) Palliative chemotherapy

About more than half of the pancreatic cancer patients are diagnosed with metastatic disease. Consider unresectable status of locally advanced pancreatic cancer, more than two third of all pancreatic cancer patients should be treated with systemic anti-cancer therapies with palliative aims. But pancreatic cancer is one of the most resistant cancers to chemotherapy. It makes most novel drugs ineffective in so many clinical trials for pancreatic cancer. In real world, there are some auspicious signs for advanced pancreatic cancer such as introduction of relatively effective chemotherapeutic regimens or drug.

1) Targeted therapies

Because of the heterogeneous environment of pancreatic cancer and complexity of stromal interactions, few targeted therapies succeed in clinical trials compared to standard treatment. As already mentioned, erlotinib plus gemcitabine was the only exception that showed statistically significant (2 weeks) improvement in overall survival [27]. Although, most of the studies on targeted therapies failed during phase II/III trials, numerous phase I/Ib studies are still ongoing.

2) Immunotherapy including cell therapy, immune check point inhibitor

Immune-checkpoint-inhibitor antibodies is a new treatment option, which inhibit the interactions between immune cells and antigen presenting cells, including tumor cells [35]. One of immune-checkpoint–inhibitor antibodies, pembrolizumab, which blockades PD-1, may be susceptible in tumors with mismatch repair deficiency [36]. Pembrolizumab, anti-PD-1 receptor antibody, blocks the interaction with its ligands, PD-L1 and PD-L2 [36]. And then, pembrolizumab improves antitumor immune response [36]. It is showed that ORR was 62% among 6 pancreatic cancer patients in a phase II study in patients with 12 different mismatch repair deficiency advanced cancers, including pancreatic cancer [37]. Even, 2 had complete response. Two major approaches affect to increase the impact of immunotherapy in pancreatic cancer, which are usually combined with chemotherapy. First, multitargeted strategies to stimulate antitumor T-cell responses are being studied. For example, in an ongoing clinical trial it is studied, a multi-drug regimen consisting of chemotherapy (e.g., GnP), CD40 agonist and anti-PD-1 (Table 3). In other strategies, the focus is on combining PD-1/PDL1 blockade with drugs that inhibit immunosuppressive mechanisms mediated by fibroblasts (e.g., FAK), matrix proteins (e.g., hyaluronidase), and myeloid cells (e.g., CSF1R, BTK CCR2, CXCR2) (Table 3). Second, immune based strategies are focused to enhanced responsiveness to chemotherapy. For example, CCR2 inhibitor which interrupts the immune-cell recruitment to tumors in the situation of cytotoxic stress, has shown effective activity in patients with locally advanced pancreatic cancer [38].

Table 3.

Select immunotherapy trials in pancreatic cancer [64]

As an immunostimulatory strategy for cancer therapy, radiation is combined with immunotherapy in pancreatic cancer (Table 3). Radiation has also affect increased expression of MHC class I on tumor cells and synergy with anti-CD40, anti-PD-1, and anti-CTLA-4 [39,40].

1) Adjuvant chemoradiation

After resection, adjuvant RT may be considered in patients with a high likelihood of local recurrence (e.g., positive resection margins, lymph nodes) [41,43]. The role of radiation has not yet been clarified, and remains at studies [41]. Updated 2020 guidelines from the NCCN suggest chemotherapy alone (FOLFIRINOX, Gemcitabine + nab-paclitaxel) as the preferred regimen for adjuvant therapy, but they include induction chemotherapy followed by chemoradiotherapy as an option for adjuvant therapy [41]. The Gastrointestinal Tumor Study Group has shown an advantage to adjuvant chemoradiation over observation after resection, but European Organization for Research and Treatment of Cancer reported no statistically significant differences between adjuvant RT and 5-FU versus observation, at median follow-up of 11.7 years [44]. ESPAC-1 trial showed that adding radiation to adjuvant 5-FU chemotherapy may be rather harmful (Table 4) [13,41].

Table 4.

Randomized clinical trial of adjuvant chemoradiation therapy

2) Neoadjuvant chemoradiation

Retrospective analyses found that neoadjuvant chemoradiation is better than neoadjuvant chemotherapy in local control, but not in survival [45]. In resectable disease, although there is an evidence that neoadjuvant therapy may make a better chance of margin-negative resection [46], there are still few randomized trials. So, some randomized trials (SWOG 1505 trial [NCT02562716], or [NCT01389440]) are ongoing. Only patients, who have poor prognostic factors (e.g., significantly elevated CA 19-9; huge primary tumors; large regional lymph nodes; excessive weight loss; extreme pain) but appear resectable, can consider neoadjuvant therapy after biopsy confirmation [41].

Recently, various kinds of radiation therapy were introduced. In RT modalities, there are stereotactic body radiation therapy (SBRT), intensity-modulated radiation therapy (IMRT), proton beam radiation therapy, charged particle therapy, and so on. First, SBRT, deriving from Gamma-knife, is advanced technique that increase dose to target while reducing exposure to surrounding healthy tissue [47-54]. SBRT uses a variety of motion management techniques to account for tumor and normal tissue motion, permitting higher doses than conventional RT to the tumor while minimizing the risk of injury to adjacent organs. Retrospective study in the patients with locally advanced pancreatic cancer (n=998) represented that patients with SBRT compared to patients with conventionally fractionated RT had better median overall survival (13.9 vs. 11.6 months, respectively; p<0.001) and 2-year overall survival (21.7% vs. 16.5%, respectively; p=0.001) [55]. Also, IMRT, developed from 3-dimensional conformal radiotherapy (3D-CRT), is increasingly applied for treatment of locally advanced pancreatic cancer. In recent systematic review, IMRT was not superior to 3D-CRT at survival outcomes [56], but in IMRT, toxicities grade 3 or greater were fewer than in 3D-CRT (p=0.017). Besides, Proton beam radiation thearpy is one of external beam radiation therapy, using not X-rays but proton beams. Proton radiotherapy can reach the optimal dose to targets while significantly normal-tissue sparing [57]. Charged particle therapy is one of the most advanced technologies in radiation therapy [58]. Charged particle therapy deposits more energy selectively, maximizing the effect on cancer and minimizing the damage from surrounding healthy tissue. And then, it can reduce complications and improve recovery rapidly after treatment [59].