Neoadjuvant and Adjuvant Treatments for Resectable and Borderline Resectable Pancreatic Ductal Adenocarcinoma: The Current Status of Pancreatic Ductal Adenocarcinoma Treatment in Japan

Abstract

Resection is the only curative treatment for pancreatic ductal adenocarcinoma (PDAC). Although the outcome of technically resectable PDAC has improved with advances in surgery and adjuvant therapy, the 5-year survival rate remains low at 20% to 40%. More effective therapy is needed. Almost 15 years ago, the National Comprehensive Cancer Network guidelines proposed a resectability classification of PDAC based on preoperative imaging. Since then, treatment strategies for PDAC have been devised based on resectability. The standard of care for resectable PDAC is adjuvant chemotherapy after R0 resection, as shown by the results of pivotal clinical trials. With regard to neoadjuvant treatment, several recent clinical trials comparing neoadjuvant treatment with upfront resection have been conducted on resectable PDAC and borderline resectable PDAC, and the benefits and efficacy of neoadjuvant treatment for pancreatic cancer has become clearer. The significance of neoadjuvant treatment for resectable PDAC remains controversial, but in borderline resectable PDAC the efficacy of neoadjuvant treatment has been further recognised, although the standard of care has not yet been established. Several promising clinical trials for PDAC are ongoing. This review presents previous and ongoing trials of perioperative treatment for resectable and borderline resectable PDAC, focusing on the difference between Asian and Western countries.

INTRODUCTION

Pancreatic ductal adenocarcinoma (PDAC) frequently recurs after resection even if radical resection is performed. Perioperative treatment such as neoadjuvant or adjuvant therapy is essential to improve the prognosis of PDAC. The 5-year survival rate after pancreatic resection without any perioperative treatment for PDAC is approximately 10%,^1,2 whereas that with adjuvant therapy has improved to 20% to 40% in the last two decades. This study reviewed previous pivotal studies of perioperative treatment for PDAC to reconfirm the evolution of the standard treatment to date and also highlighted the interesting ongoing trials to discuss future development trends of perioperative treatment for PDAC.

When planning treatment strategies for PDAC, the resectability status is critically important alongside the staging classification (TNM classification) to determine the possibility of curative resection, prognosis, and tumor progression patterns. The National Comprehensive Cancer Network guidelines³ have classified resectability since 2006, and the Japanese Clinical Practice Guidelines for Pancreatic Cancer (7th edition)⁴ also defines resectability classification (Table 1). Both classifications define the resectability status as resectable (R), borderline resectable (BR), or unresectable (UR). Either R-PDAC or BR-PDAC is technically resectable; however, the tumor stage including local extension and lymph node metastasis is more advanced in BR-PDAC than that in R-PDAC. The risk of local and distant BR-PDAC progression is higher than that of R-PDAC.^5-7 Thus, perioperative treatment strategies for BR-PDAC and R-PDAC should be different. Therefore, this review separately examined the perioperative treatment development for R-PDAC and BR-PDAC.

Table 1.

Criteria Defining Resectability Status in Japan Pancreas Society Classification 7th Edition (2016)

Resectable: R SMV/PV: no tumor contact or contact of <180° without occlusion SMA, CA, CHA: no tumor contact/invasion

Borderline resectable: BR (subclassified according to SMV/PV invasion alone or arterial invasion)

BR-PV (SMV/PV invasion alone) SMV/PV: tumor contact/invasion of ≥180°/occlusion, not exceeding the inferior border of the duodenum SMA, CA, CHA: no tumor contact/invasion

BR-A (arterial invasion) SMA, CA: tumor contact/invasion of <180° without deformity or narrowing CHA: tumor contact/invasion without showing tumor contact/invasion of the PHA and/or CA (cases of contact/invasion of both PV and peripancreatic arteries are considered BR-A)

Unresectable: UR (subclassified according to the presence or absence of distant metastases)

UR-LA (locally advanced) SMV/PV: tumor contact/invasion of ≥180°/occlusion, exceeding the inferior border of the duodenum SMA, CA: tumor contact/invasion of ≥180° CHA: tumor contact/invasion showing tumor contact/invasion of the PHA and/or CA AO: tumor contact or invasion

UR-M (metastasis) Distant metastasis including non-regional lymph node metastasis.

SMV, superior mesenteric vein; PV, portal vein; SMA, superior mesenteric artery; CA, celiac artery; CHA, common hepatic artery; PHA, proper hepatic artery; AO, aorta.

This review also focuses on the uniqueness of perioperative treatment development in Asia, including Japan, and compares it with that in Europe and United States.

ADJUVANT THERAPY FOR R-PDAC

1. Establishment of adjuvant gemcitabine therapy

Randomized controlled trials (RCTs) comparing postoperative adjuvant chemotherapy with resection alone for PDAC have been conducted since the 1990s; however, the development of effective treatments had not yet been established until the ESPAC-1 trial⁸ in 2004, which demonstrated a significant survival benefit of postoperative 5-fluorouracil+leucovorin (5-FU+LV) therapy over resection alone, and results of this trial had made postoperative 5-FU+LV therapy the standard of care for R-PDAC in Europe. However, the complex study design using a 2×2 factorial design was controversial and had not been implemented as the standard therapy in the United States and Japan.

Subsequently, the CONKO-001 trial^2,9 was conducted mainly in Germany, in which 354 patients after PDAC resection were randomized to the adjuvant chemotherapy group with gemcitabine (GEM) and resection-alone group, showing a significant prolongation of recurrence-free survival with the adjuvant chemotherapy group (13.4 months vs 6.9 months, p<0.001). Initially, adjuvant chemotherapy did not show a significant increase in the overall survival (OS) (p=0.06); however, current long-term follow-up studies reported a significant increase not only in recurrence-free survival but also in the median OS (22.8 months vs 20.2 months, p=0.01).²

At about the same time, the JSAP-02 trial¹⁰ was conducted in Japan, which randomized 118 patients after PDAC resection to adjuvant chemotherapy with GEM and resection alone, and reported a significantly prolonged recurrence-free survival with postoperative GEM, a finding similar to the initial report of the CONKO-001 trial. As a result, GEM therapy was considered one of the standard treatments in addition to 5-FU+LV therapy.

European Study Group for Pancreatic Cancer (ESPAC) subsequently conducted the ESPAC-3 trial,¹¹ in which 1,088 patients with resected PDAC were randomly allocated to the postoperative GEM or 5-FU+LV treatment groups, and reported no significant difference in the OS between the two groups (23.6 months vs 23.0 months: hazard ratio [HR], 0.94; 95% confidential interval [CI], 0.81 to 1.08; p=0.39). However, serious adverse events were significantly lower in the GEM group than in the 5-FU+LV group, and due to its safety profile, GEM therapy was preferentially selected as the standard of care not only in Japan but also worldwide. Subsequently, postoperative GEM became the standard regimen for the control group in many phase III trials for R-PDAC (Table 2).^2,8-16

Table 2.

Pivotal Trial on Adjuvant Chemotherapy for Pancreatic Cancer after Radical Resection

Trial	Year	Adjuvant treatment	No. of patients	Primary outcome	Median	HR (95% CI)	p-value
ESPAC-18	2004	5-FU+LV treated arm in 2×2 factorial design	147	2-yr survival rate	40%	0.71 (0.55–0.92)	<0.01
		5-FU+LV non-treated arm in 2×2 factorial design	142		30%
CONKO-0012,9	2007	GEM	186	DFS	13.4 mo	0.55 (0.44–0.69)	<0.01
		Surgery alone	182		6.7 mo
JSAP-0210	2009	GEM	58	OS	22.3 mo	0.77 (0.51–1.14)	0.19
		Surgery alone	60		18.4 mo
ESPAC-311	2010	GEM	478	OS	23.6 mo	0.94 (0.81–1.08)	0.39
		5-FU+LV	486		23.0 mo
JASPAC-0112	2013	S-1	187	OS	46.5 mo	0.57 (0.44–0.72)	<0.01
		GEM	190		25.5 mo
ESPAC-413	2016	GEM+capecitabine	364	OS	28.0 mo	0.82 (0.68–0.98)	0.03
		GEM	366		25.5 mo
PRODIGE24/ ACCORD2414	2018	mFOLFIRINOX	247	DFS	21.6 mo	0.58 (0.46–0.73)	<0.01
		GEM	246		12.8 mo
APACT15 (ASCO)	2019	GEM+nab-PTX	432	DFS	19.4 mo	0.88 (0.73–1.06)	0.18
		GEM	434		18.8 mo
JSAP-0416	On going	GEM+S-1	-	OS/DFS	-	-	-
		GEM	-		-

HR, hazard ratio; CI, confidence interval; 5-FU+LV, 5-fluorouracil+leucovorin; GEM, gemcitabine; DFS, disease-free survival; OS, overall survival; mFOLFIRINOX, modified FOLFIRINOX; nab-PTX, nab-paclitaxel.

The use of 5-FU+LV therapy was recommended for patients who could not be safely administered with GEM, such as those with a history of interstitial pneumonia^17,18 or hemolytic uremic syndrome^19,20 in the Japanese Clinical Practice Guidelines for Pancreatic Cancer.

2. Development of postoperative adjuvant therapy superior to adjuvant GEM

In Europe, ESPAC conducted the ESPAC-4 trial¹³ involving 730 patients who underwent PDAC resection randomly allocated to the postoperative GEM and GEM+capecitabine (Cape) groups. The results showed that the OS was more significantly improved in the postoperative GEM+Cape group than in the GEM group (28.0 months vs 25.5 months: HR, 0.82; 95% CI, 0.68 to 0.98; p=0.032), and the study results led to the replacement of GEM therapy with GEM+Cape therapy as the standard postoperative adjuvant treatment.

Studies in France and Canada reported the results of a multicenter RCT (PRODIGE 24-ACCORD 24/CCTG PA 6)¹⁴ comparing postoperative modified FOLFIRINOX (mFOLFIRINOX) with GEM alone. This study used mFOLFIRINOX therapy considering the toxicity of FOLFIRINOX therapy, in which rapid administration of 5-FU was omitted and the irinotecan dose was reduced. The median disease-free survival, the primary endpoint, was 21.6 and 12.8 months in the mFOLFIRINOX and GEM-alone groups, respectively, showing the superiority in the mFOLFIRINOX group (HR, 0.58; 95% CI, 0.46 to 0.73; p<0.0001). The mFOLFIRINOX group also showed a significantly prolonged OS (54.4 months vs 35.0 months: HR, 0.64; 95% CI, 0.48 to 0.86; p=0.003). Grade 3/4 adverse events occurred in 75.9% and 52.9% of the mFOLFIRINOX and GEM-alone groups, respectively, and the treatment completion rates were 66.4% and 79.0% for mFOLFIRINOX and GEM alone, respectively (p=0.002). Based on the study results, postoperative mFOLFIRINOX therapy has become one of the standard treatments for resected PDAC. Because of its high toxicity, postoperative mFOLFIRINOX therapy is recommended for patients with good performance status (PS).

GEM plus erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor (CONKO-005 trial, RTOG-0848 trial),^21,22 and GEM+nab-paclitaxel (GnP), one of the standard treatments for UR-PDAC (APACT trial),¹⁵ were also compared with adjuvant GEM in the global phase III trial. However, none of these therapies were recommended as the standard treatment for PDAC due to a lack of statistically significant efficacy by comparing with adjuvant GEM.

3. Different trends in Japan: postoperative S-1 therapy

The Japan Adjuvant Study Group of Pancreatic Cancer (JASPAC) conducted a phase III comparative study (JASPAC 01)¹² to examine the non-inferiority of S-1 to GEM in adjuvant chemotherapy after the PDAC resection. The study enrolled 385 patients and showed not only non-inferiority of the S-1 group to the GEM group in the primary endpoint of OS, but also demonstrated superiority (median OS S-1 vs GEM, 46.5 months vs 25.5 months: HR, 0.57; 95% CI, 0.44 to 0.72; p<0.0001). The pre-completion discontinuation rate of the adjuvant treatment was 42% and 28% in the GEM and S-1 groups (p=0.0050), respectively, mainly due to adverse events (25% and 21%, respectively) and recurrence (13% and 5%, respectively). The study results clearly changed the standard postoperative adjuvant therapy in Japan from GEM therapy to S-1 therapy due to its high safety and convenience.

However, S-1 is not widely used for treatment of the pancreatic cancer including adjuvant therapy in Europe and the United States. The major reason is that the maximum tolerated dose of S-1 for Caucasians is lower than that for Mongolians due to gastrointestinal toxicity,²³ mainly diarrhea, making it difficult to reproduce in the West the favorable antitumor effects of chemotherapy with S-1 reported in Asian clinical trials. The conversion efficiency of tegafur to 5-FU is higher in Caucasians due to polymorphisms in CYP2A6, resulting in higher gastrointestinal toxicity, especially diarrhea than that in Mongolians.^24,25 In Europe, S-1 is approved for the treatment of advanced gastric cancer in combination with cisplatin,²⁶ but the dose of S-1 was approved at about 60% of the dose under the original Japanese regimen. Additionally, S-1 is not approved for pancreatic cancer in Europe and United States. Due to the corporate strategy, development to expand the indication of S-1 for pancreatic cancer is not currently underway in the United States or Europe. Thus, S-1 has not become the standard of care for R-PDAC in Western countries.

Later, ESPAC-4 and PRODIGE24/ACCORD24 considered GEM+Cape and mFOLFIRINOX as the standard of care for R-PDAC in Western countries. In Japan, neither GEM+Cape nor mFOLFIRINOX became the standard of care mainly because the HR of the S-1 to GEM in the JASPAC-01 study (HR=0.57) was better than that of GEM+Cape to GEM in ESPAC-4 (HR=0.82) or that of mFOLFIRINOX to GEM in the PRODIGE24/ACCORD24 trial (HR=0.64). Then, adjuvant S-1 has been the standard postoperative adjuvant therapy to date.

4. Adjuvant chemoradiotherapy

A large number of case-control studies have suggested that adjuvant chemoradiotherapy (CRT) may prolong the prognosis;^27-35 postoperative CRT analyses with novel anticancer agents including GEM and erlotinib are still insufficient;^36-40 and meta-analyses have reported the benefits for patients with R1 resection compared to R0 (p=0.04).⁴¹ Postoperative adjuvant CRT has been one of the promising treatment modalities in the perioperative treatment of pancreatic cancer and remains a topic for further investigation.

The 2019 Clinical Practice Guidelines for Pancreatic Cancer committee⁴² conducted a meta-analysis of six RCTs comparing fluorouracil-based or GEM-based chemoradiation to surgery alone^8,36,43-46 to evaluate the efficacy of adjuvant CRT. Therefore, the risk ratio of adjuvant CRT compared to surgery alone was 1.01 (95% CI, 0.93 to 1.10). The benefit of adjuvant CRT on the prognosis is unclear, and then adjuvant CRT is not recommended based on the Japanese guidelines at present.

NEOADJUVANT THERAPY

1. Neoadjuvant therapy for R-PDAC

Although the aforementioned adjuvant chemotherapies are the current standard of care for patients with R-PDAC, 30% to 50% of patients who undergo laparotomy are unable to receive adjuvant therapy due to intraoperatively detected metastases, early postoperative recurrence, surgical complications, or poor PS. Conversely, neoadjuvant treatment has several theoretical advantages over adjuvant treatment, such as early treatment for micrometastasis under better physical condition, determination of tumor response for the treatment, and selection of patients with poor prognosis.⁴⁷ Then, several clinical trials have been conducted to develop preoperative treatments not only for BR-PDAC but also for R-PDAC (Table 3).^48-56

Table 3.

Prospective Study on Neoadjuvant Chemotherapy for Pancreatic Cancer before Radical Resection

Author/trial	Year	Resectability	Treatment	No. of patients	Primary outcome	Median	HR (95% CI)	p-value
Jang et al.48	2018	BR	CRT (54 Gy, GEM) → surgery → GEM	27	2-yr survival	40.7%	0.51 (0.27–0.93)	0.028
			Surgery → GEM	23		26.1%
Unno et al. Prep-02/JSAP0549-51	2019	R/BR-PV	GEM + S-1 → surgery → S-1	182	OS	36.7 mo	0.72 (0.55–0.94)	0.02
			Surgery → S-1	180		26.6 mo
Versteijne et al. PREOPANC-152,53	2020	R/BR	CRT (36 Gy, GEM) → surgery → GEM	119	OS	15.7 mo	0.73 (0.56–0.96)	0.025
			Surgery → GEM	127		14.3 mo
Takahashi et al. JASPAC0554	2020	R/BR	CRT (54 Gy, S-1) → surgery	52	R0 (OS)	52% (30.8 mo)	-	-
Yamaguchi et al. NUPAT-0155	2022	BR	mFOLFIRINOX → surgery	26	R0	73.1%	-	0.202
			GEM + nab-PTX → surgery	25		56.0%
Katz et al. A02150156	2022	BR	mFOLFIRINOX → surgery → FOLFOX6	65	18-mo survival	66.7%	-	-
			mFOLFIRINOX → SBRT (33-40 Gy) or HIGRT (25 Gy) → surgery → FOLFOX6	55		47.3%

HR, hazard ratio; CI, confidence interval; BR, Borderline Resectable; CRT, chemoradiotherapy; GEM, gemcitabine; R, resectable; PV, portal vein; OS, overall survival; mFOLFIRINOX, modified FOLFIRINOX; nab-PTX, nab-paclitaxel; SBRT, stereotactic body radiation therapy; HIGRT, hypofractionated image-guided radiation therapy.

In the 2010s, several clinical studies of preoperative treatment for R-PDAC were initiated in Europe. In 2015, randomized phase II trials of GEM+cisplatin+radiotherapy⁵⁷ and GEM+radiotherapy⁵⁸ were conducted; however, those trials could not be fully evaluated due to poor patient accrual. Evidence of preoperative treatment in R-PDAC is still lacking;^59-62 however, important results were recently reported in two phase III trials comparing preoperative treatment for upfront resection in patients with R-PDAC or BR-PDAC.

A randomized multicenter phase III study (PREOPANC-1) was conducted in the Netherlands to examine the significance of neoadjuvant chemoradiation therapy (NACRT) for R-PDAC and BR-PDAC. The NACRT group (36 Gy/15 F + GEM 3 cycles → surgery → postoperative GEM for 4 cycles) showed a better tendency in the OS than the surgery first group. Although the difference was not significant in the initial report (modified OS 16.0 months vs 14.3 months: HR, 0.78; 95% CI, 0.58 to 1.05; p=0.096),⁵² long-term follow-up analysis showed significantly better OS in the NACRT group (modified OS 15.7 months vs 14.3 months: HR, 0.73; 95% CI, 0.56 to 0.96; p=0.025).⁵³

A randomized phase III trial (Prep-02/JSAP05 trial)⁵⁰ was performed in Japan to investigate the clinical significance of neoadjuvant chemotherapy (NAC) with GEM+S-1 (GS) for T1-T3 PDAC without invading the peripancreatic major arteries (hepatic artery, celiac artery, and superior mesenteric artery). This trial confirmed that NAC-GS safely and effectively improved the prognosis compared with upfront surgery (modified OS 36.7 months vs 26.6 months: HR, 0.72; 95% CI, 0.55 to 0.94; p=0.015). Furthermore, subsequent resection could be safely performed without significant differences in the operative time, intraoperative blood loss, and postoperative complication rates.^49,51 Due to the following several limitations, (1) inclusion of 20% of BR-PDAC, (2) only tumors that could be biopsied and pathologically confirmed, and (3) age limit of 20 to 79 years, the study results just fell short by making neoadjuvant GS as the standard of care for R-PDAC. However, subgroup analysis in R-PDAC consisted of 80% of the enrolled patients revealed similar efficacy of the neoadjuvant GS. Then, using the results of the Prep-02/JSAP05 trial, the Japanese Clinical Practice Guidelines for Pancreatic Cancer were revised, and neoadjuvant GS therapy was recommended for R-PDAC.

The current most effective regimens, mFOLFIRINOX and GnP, have also being tried as preoperative treatments for R-PDAC. The randomized phase II SWOG S1505 compared perioperative mFOLFIRINOX and perioperative GnP in patients with R-PDAC.^63,64 The primary outcome was 2-year survival. Investigators planned to compare the two arms to determine the better treatment if the 2-year survival reached 58% or more. However, the 2-year OSs of 41.6% with mFOLFIRINOX and 48.8% with GnP missed the target rate of 58% at 2 years. Furthermore, neither regimen showed a statistical improvement in 2-year survival over historical control, and the results were negative. However, these regimens remain the most promising at present, and the results of the ongoing phase III trial of perioperative mFOLFIRINOX therapy are awaited.

2. Neoadjuvant therapy for BR-PDAC

Compared to R-PDAC, BR-PDAC is more locally progressing and is at a higher tumor stage, with a higher risk of positive microscopic margins and early recurrence. Therefore, the significance of preoperative treatment in BR-PDAC is clearly greater than that in R-PDAC.

In BR-PDAC, several retrospective studies^65-72 comparing neoadjuvant therapy with upfront surgery reported that neoadjuvant therapy improved the R0 resection rate and survival. Afterward, the efficacy of neoadjuvant therapy for BR-PDAC was evidently demonstrated in the phase II/III study reported from South Korea in 2018.⁴⁸ A total of 58 patients were randomized to neoadjuvant chemoradiation (54 Gy) with GEM or upfront resection. The intention-to-treat analysis demonstrated that the primary endpoint of the 2-year survival was significantly better in the NACRT group (40.7%) than that in the upfront surgery group (26.1%) (HR, 1.97; 95% CI, 1.07 to 3.62; p=0.028).

Although the efficacy of neoadjuvant treatment was verified, the standard treatment has not yet been established in BR-PDAC. Several promising clinical trials of the neoadjuvant treatment are ongoing in this field (Table 4).^73-81

Table 4.

Prospective Ongoing Study on Neoadjuvant Chemotherapy for Pancreatic Cancer before Radical Resection

Author/trial	Phase	Start year	Resectability	Treatment	Scheduled number of patients	Primary outcome
Labori et al. NorPACT-173	II/III	2017	R	mFOLFIRINOX → surgery → GEM + capecitabine	140	OS
				Surgery → GEM + capecitabine
Schwarz et al. PANACHE01-PRODIGE4874	II	2017	R	mFOLFIRINOX → surgery → adjuvant therapy	160	OS
				FOLFOX → surgery → adjuvant therapy
				Surgery → adjuvant therapy
Ferrone Alliance A02180675	III	2020	R	mFOLFIRINOX → surgery →mFOLFIRINOX	352	OS
				Surgery →mFOLFIRINOX
Koerkamp PREOPANC-376	III	2021	R	mFOLFIRINOX → surgery →mFOLFIRINOX	378	OS
				Surgery → mFOLFIRINOX
Janssen et al. PREOPANC-277	III	2018	R/BR	mFOLFIRINOX → surgery	368	OS
				GEM → CRT (36 Gy, GEM) → GEM → surgery → GEM
Grose et al. PRIMUS-00278	II	2019	R/BR	FOLFOX + nab-PTX → CRT → surgery	278	PFS
				GEM + nab-PTX → CRT → surgery
Unno Prep-03/NS014-179	I/II	2014	BR	GEM + S-1 + concurrent RT (50 Gy) → surgery	12–24/40	R0
Okada et al. NAC-GA80	II	2017	BR	GEM + nab-PTX → surgery	60	OS
Takahashi GABARNANCE81	II/III	2017	BR	GEM + nab-PTX → surgery	110	R0/OS
				CRT (54 Gy, S-1) → surgery

R, resectable; mFOLFIRINOX, modified FOLFIRINOX; GEM, gemcitabine; OS, overall survival; BR, borderline resectable; CRT, chemoradiotherapy; nab-PTX, nab-paclitaxel; RT, radiotherapy; PFS, progression-free survival.

In clinical practice of the United States or Europe, mFOLFIRINOX alone or mFOLFIRINOX followed by CRT or radiation therapy are the most common preoperative treatment for BR-PDAC. The A021501 phase II randomized clinical trial,⁵⁶ which was conducted by the Alliance for Clinical Trials in Oncology, compared those promising treatments, namely, eight cycles of mFOLFIRINOX and seven cycles of mFOLFIRINOX followed by stereotactic body radiotherapy at 33 to 40 Gy in five fractions or hypofractionated image-guided radiotherapy at 25 Gy in five fractions as preoperative treatment for BR-PDAC. Each treatment arm’s 18-month OS rate was compared with a historical control rate of 50%. In the interim analysis, mFOLFIRINOX with hypofractionated radiotherapy arm was closed because R0 resection rate (33%) was proven to be under the threshold value (40%). The 18-month OS rate of chemotherapy arm was 66.7% and that of chemotherapy plus radiation arm was 47.3%. The results of the trial suggest that mFOLFIRINOX could be a reference neoadjuvant treatment regimen for BR-PDAC. However, the role of radiotherapy in the preoperative treatment for BR-PDAC remains undefined because hypofractionated radiotherapy instead of a more common conventional CRT was applied for chemotherapy plus radiation arm in the trial. Further studies are needed to clarify the significance of preoperative radiation therapy in BR-PDAC.

PRACTICE AND DEVELOPMENT OF PERIOPERATIVE TREATMENT FOR PDAC IN JAPAN

The perioperative treatment in Japan is unique due to the following two reasons. First, several perioperative treatments using S-1 have been developed in Japan and showed good results. Second, the toxic regimen tolerability, such as FOLFIRINOX in the Japanese population, might not be equivalent to that of the Western population.

As previously mentioned, adjuvant S-1 and neoadjuvant GS are recommended for R-PDAC in Japanese guidelines for the treatment of PDAC (Fig. 1A). S-1, oral fluorouracil, is a key medication for gastrointestinal malignancies (the stomach, colorectal, biliary tract, and PDAC)^24,82,83 and is approved in many Asian countries. In Europe, S-1 is also approved by the European Medicines Agency and has been used for the treatment of advanced gastric cancer combined with cisplatin.^26,84 However, European people tend to have more severe gastrointestinal side effects of S-1, such as diarrhea. S-1 is more toxic to the digestive tract in Caucasians than in Mongoloids due to metabolic and pharmacological differences. Genetic polymorphism differences, such as the higher activity of CYP2A6, the enzyme that converts tegafur in S-1 to 5-FU, in Caucasians, may be the cause of different toxicity profiles.^25,82,85,86 The aforementioned perioperative treatments using S-1 are not recommended as the standard of care in Europe and the United States.

Fig. 1.

The strategy of PDAC treatment in Japan. (A) Current treatment strategy for R-PDAC in Japan. Perioperative treatment for R-PDAC is two cycles of neoadjuvant chemotherapy-GS (GEM=1,000 mg/m², days 1 and 8; S-1=80 mg/m², days 1–14) based on the results of the Prep-02/JSAP05 study and postoperative S-1 (S-1=80 mg/m², days 1–28) in four cycles based on the results of the JASPAC-01 study. (B) Current treatment strategy for BR-PDAC in Japan. For preoperative treatment for BR-PDAC, GS (GEM=1,000 mg/m², days 1 and 8; S-1=80 mg/m², days 1–14) may be administered for two cycles based on the results of the Prep-02/JSAP05 study. However, several clinical trials have sought a stronger and more effective regimen, and no fixed strategy has been established yet. For postoperative treatment, S-1 (S-1=80 mg/m², days 1–28) is administered for four cycles based on the results of the JASPAC-01 study.

PDAC, pancreatic ductal adenocarcinoma; R-PDCA, resectable PDAC; GEM, gemcitabine; GS, GEM+S-1; BR-PDAC, borderline resectable PDAC; mFOLFIRINOX, modified FOLFIRINOX; nab-PTX, nab-paclitaxel; CRT, chemoradiotherapy.

Conversely, postoperative therapy with mFOLFIRINOX has become the standard of care for R-PDAC in Europe and the United States, and FOLFIRINOX as preoperative treatment is also being developed. The postoperative toxicity of FOLFIRINOX is severe, especially in elderly people and in patients with poor PS, which increases the question of tolerability. Because of the high proportion of elderly patients in Japan, toxicity profiles are particularly important. When considering the efficacy and toxicity, both postoperative therapy with S-1 and preoperative GS therapy with S-1 balance between toxicity and efficacy seems suitable for Japanese patients with R-PDAC. Also, in East Asia with its large Mongoloid population, S-1 might be a key drug for R-PDAC.

S-1 is currently approved for the treatment of pancreatic cancer with locally advanced or metastatic disease in East Asian countries such as South Korea, Singapore, Taiwan, Thailand, and Malaysia. Moreover, adjuvant S-1 is recommended for R-PDAC as one of the treatments of grade I recommendations according to the clinical guidelines for the diagnosis and treatment of pancreatic cancer by the Chinese Society of Clinical Oncology.⁸⁷ Several clinical trials using S-1 in the perioperative treatment of pancreatic cancer are currently being conducted or planned in China (NCT03278015, NCT03777462) and Taiwan (NCT04070313). However, at this time, it has not been verified whether perioperative chemotherapy with S-1 shows the same excellent efficacy and safety in East Asian countries other than China as observed in the Japanese clinical trial. Then, the results of the future clinical trials from East Asia other than Japan are expected to elucidate significance of perioperative treatment using S-1 for pancreatic cancer in East Asia.

Meanwhile, perioperative treatment with FOLFIRINOX, GnP, or chemoradiation is being developed in Japan for BR-PDAC, requiring more intensive therapy, and for younger patients who are more tolerable to toxicity (Table 4, Fig. 1B). The Prep-03/NS014-1 trial⁷⁹ is a phase I/II study evaluating the efficacy of a GS+concurrent radiotherapy (50 Gy) regimen as NACRT. The NAC-GA trial⁸⁰ is a phase II trial using GnP as NAC. Results of NUPAT-01 trial,⁵⁵ a phase II trial of mFOLFIRINOX and GnP as NAC for BR-PDAC with a primary endpoint of R0 resection rate, were reported, showing that both groups had good R0 resection rates (73.1% vs 56.0%, respectively, p=0.202) and good 3-year survival rates (55.3% and 54.4%, respectively, p=0.389), demonstrating the NAC feasibility and tolerability with FOLFIRINOX or GnP. Moreover, the GABARNANCE trial,⁸¹ comparing the GnP therapy with S-1-based CRT (54 Gy) with the R0 resection rate and OS as primary endpoints, is awaiting results.

FUTURE PROSPECTS

Currently, not a few clinical trials to evaluate two effective regimens, FOLFIRINOX⁸⁸ and GnP⁸⁹ which are standard therapies for UR-PDAC, as neoadjuvant therapy for R-/BR-PDAC are conducted and attracted attention (Table 4). The PREOPANC-1 and Prep-02/JSAP05 trials reported favorable outcomes for the preoperative treatment in R-PDAC; however, both of them were subgroup analyses and have not been established as evidence. Therefore, at present, neoadjuvant therapy is not yet recommended for R-PDAC in Western guidelines, except in high-risk patients.³ The major ongoing phase III trials for R-PDAC include Alliance A021806 in the United States⁷⁵ and PREOPANC-3 in the Netherlands.⁷⁶ These are trials to verify the significance of preoperative treatment, using mFOLFIRINOX for preoperative treatment and postoperative adjuvant therapy. The design of the two trials is quite similar: only resectable pancreatic cancer is included, eight courses of mFOLFIRINOX are performed preoperatively, followed by pancreatectomy and four courses of mFOLFIRINOX postoperatively, and the primary endpoint is OS. The results of the two large phase III trials examining the significance of preoperative treatment with mFOLFIRINOX, the most promising perioperative treatment regimen, will provide important insights into the efficacy of preoperative treatment.

The necessity for radiation therapy in the preoperative treatment of R- or BR-PDAC is an important issue. At present, preoperative chemoradiation remains controversial because pancreatic cancer has the aspect of systemic disease with a high incidence of recurrence in distant organs, whereas local control is necessary preoperatively because negative microscopic margins are important for prolonged survival. Several clinical trials are ongoing to investigate the significance of adding CRT to preoperative systemic chemotherapy. As previously mentioned, no clear benefit was found from adding hypofractionated radiotherapy to mFOLFIRINOX therapy as preoperative treatment for BR-PDAC in A021501.⁵⁶ On the other hand, significance of adding conventional CRT to preoperative mFOLFIRINOX is presently examined in PANDAS-PRODIGE 44 phase II randomized clinical trial (NCT02676349). The results of the trial will provide important insights into preoperative radiation therapy for BR-PDAC.

Pancreatic cancer is conventionally known as a cold tumor as a target for immunotherapy.⁹⁰ Then, immune activation at multiple levels of the cancer immune cycle may be required in tumors with low immunogenicity such as pancreatic cancer.⁹¹ It has recently been suggested that preoperative radiotherapy may enhance antitumor immunity via immunogenic cell death and may be useful in controlling subclinical PDAC micro-metastases. When tumor cells succumb to radiation therapy, they also emit a specific combination of signals that elicits tumor-specific cytotoxic T lymphocyte responses. Not a few clinical trials are investigating the combination of radiotherapy with immunotherapy for pancreas cancer, including perioperative therapy for R-PDAC or BR-PDAC (NCT02305186, NCT03161379, NCT01959672, and NCT02648282).

When considering the merits to patients and health economics, the appropriate target should be selected and appropriate treatment provided. Patients with R-PDAC include a certain number of patients with a low risk of recurrence who does not necessarily require multimodality treatment with preoperative therapy, and thus, it may be possible to omit preoperative therapy for such patients. Several biomarkers such as carbohydrate antigen 19-9 value^92-94 and circulating tumor DNA^95-97 are being investigated to determine whether they can select patients at high or low risk of recurrence.

BR-PDAC can be classified into BR-PV with the portal vein invasion only and BR-A with arterial invasion. Although some reports suggest that the BR-A PDAC prognosis is equivalent to that of BR-PV,^67,98 BR-A PDAC is considered to have a significantly poorer prognosis than BR-PV PDAC.^5,65,99 The median survival of patients with resected BR-A PDAC has been reported to be approximately 10.0 to 18.1 months,^{5,65,67,98,100} whereas the median survival for nonoperative treatment of UR-PDAC was 8.5 to 18.6 months.^{72,88,89,98,100} Thus, the BR-PV and BR-A prognoses are very different, and then, it may be necessary to determine and distinguish the treatment strategy (optimal regimen and number of courses) for each population. More intensive and prolonged treatment may be necessary for BR-A than BR-PV. A multicenter single-arm phase II trial¹⁰¹ was performed to evaluate the NAC-GAS clinical efficacy and safety (including GEM, nab-paclitaxel, and S-1) in 47 eligible patients with BR-A in 2021. The grade III/IV toxicity rates occurred in 30% of patients during the GAS regimen, whereas R0 resection was 86%, and primary endpoints of the 2-year OS rate and median OS duration were 70.1% and 41.0 months, respectively, indicating good efficacy.

While clinical trials for preoperative treatment of pancreatic cancer require large patient enrollment, the study results should be rapidly published. In addition, as represented by S-1, drugs with different efficacy and toxicity among different ethnic groups will be developed in the future, and thereby, a cooperative framework should be constructed in East Asia, where people have the similar genetic background to quickly and accurately evaluate the efficacy of preoperative treatment.