Review ArticleReview
Open Access

Adjuvant Treatment for Resectable Pancreatic Cancer

TORU AOYAMA, KENTARO HARA, AYA SAITO and HARUHIKO CHO
Anticancer Research April 2025, 45 (4) 1329-1341; DOI: https://doi.org/10.21873/anticanres.17519

Abstract

Pancreatic cancer is the seventh leading cause of cancer-related death worldwide. Surgical resection, such as pancreatoduodenectomy or distal pancreatectomy, is the standard curative treatment for resectable pancreatic cancer. So far, several studies suggested that management of micro metastasis is one of the approaches to improve pancreatic cancer patients. The use of chemotherapy or chemo radiation therapy during perioperative periods is most promising adjuvant treatment. To introduce the adjuvant treatment during perioperative periods for pancreatic cancer, it is necessary to establish the optimal methods, regimen, and timing of adjuvant treatment. To date, many randomized trials have been conducted to examine the efficacy of adjuvant therapies. Since 2000, different evidence has emerged for postoperative adjuvant chemoradiation, postoperative adjuvant chemotherapy, and perioperative adjuvant chemotherapy for resectable pancreatic cancer. This review summarizes the background, current status, and future perspectives of adjuvant therapy for resectable pancreatic cancer.

Keywords:

Introduction

Pancreatic cancer is the seventh leading cause of cancer-related death worldwide (1, 2). Surgical resection, such as pancreatoduodenectomy or distal pancreatectomy, is the standard curative treatment for resectable pancreatic cancer (3, 4). The survival of patients with pancreatic cancer is gradually improving due to the introduction of multidisciplinary treatment, such as minimally invasive surgery, enhanced recovery after surgery, and perioperative nutritional treatment (5, 6). However, more than 50% of patients with pancreatic cancer experience recurrence, even when they receive curative resection. After the development of recurrent disease, the prognosis is limited (7, 8). The most common reason for recurrence is metastasis of tumor cells. Surgical resection can remove the visible tumor that exists in the surgical field but cannot remove or identify micro-metastatic tumor cells outside of the surgical field. Invisible tumor cells gradually grow and cancer recurs. Therefore, to improve patient survival, it is necessary to eradicate micrometastatic tumor cells before and/or after surgery. To date, many randomized trials have been conducted to examine the efficacy of adjuvant therapy; however, most trials conducted before 2000 have failed to show any survival benefit. Since 2000, different lines of evidence have emerged for postoperative adjuvant chemoradiation, postoperative adjuvant chemotherapy, and perioperative adjuvant chemotherapy for resectable pancreatic cancer. This review summarizes the background, current status, and future perspectives of adjuvant therapy for resectable pancreatic cancers.

Adjuvant Chemoradiation Strategies

There are seven pivotal trials on adjuvant chemoradiation therapy for resectable pancreatic cancer (Table I). Kalser et al. conducted a randomized trial to evaluate the efficacy of combined radiation therapy and fluorouracil (FU) as adjuvant therapy in comparison to surgery alone (9). The trial was conducted between 1974 and 1982. A total of 49 patients were enrolled, with 21 patients registered in the chemoradiation therapy arm and 22 patients registered in the surgery alone arm. Patients in the chemoradiation therapy arm received radiation therapy at a total dose of 4,000 rad. FU (500 mg/m2) was administered beginning with each course of radiation therapy and continued on a weekly basis for 2 years or until the development of recurrent disease. The median overall survival (OS) was 20 months in the chemoradiation therapy arm and 11 months in the surgery-alone arm. The estimated 1- and 2- year OS rates were 63% and 42%, respectively, in the chemoradiation therapy arm and 49% and 15% in the surgery alone arm. They concluded that adjuvant chemoradiation therapy following curative surgery for pancreatic cancer might prolong survival. Second, Klinkenbijl et al. conducted a phase III trial to evaluate the efficacy of adjuvant radiotherapy and 5-FU in comparison to surgery alone (10). The trial included 29 European institutions between 1987 and 1995. A total of 218 patients were enrolled, with 110 patients registered in the chemoradiation therapy arm and 108 patients registered in the surgery alone arm. Patients in the chemoradiation therapy arm received radiation therapy (40 Gy) and 5-FU (25 mg/kg, for a maximum daily dose of 1,500 mg). The primary endpoint was OS. The median OS was 24.5 months in the chemoradiation therapy arm and 19.0 months in the surgery-alone arm. The estimated 2- and 5- year OS rates were 51% and 28%, respectively, in the chemoradiation therapy arm and 41% and 22% in the surgery-alone arm. The median progression-free survival (PFS) was 17.4 months in the chemoradiation therapy arm and 16.0 months in the surgery alone arm. There were no differences in OS or PFS. They concluded that adjuvant chemoradiation therapy did not contribute to prolonged OS after the resection of pancreatic cancer. Third, Neoptolemos et al. conducted a randomized trial to evaluate the efficacy of adjuvant treatment in comparison to surgery alone [European Study Group for Pancreatic Cancer (ESPAC)-1] (11). This trial had a two-by-two factorial design for patients after curative resection for pancreatic cancer, and the patients were randomly assigned to receive chemoradiotherapy or chemotherapy, neither treatment, or both treatments. The primary endpoint was 2-year OS. The secondary endpoints were toxicity, recurrence, and quality of life. This trial was conducted at 53 institutions in 11 European countries between 1994 and 2000. A total of 289 patients were enrolled, with 145 patients registered in the chemoradiation therapy arm and 144 patients registered in the no-chemoradiation therapy arm. Chemoradiation therapy consisted of a 20-Gy dose to the tumor given in 10 daily and 5-FU (500 mg/m2 each of the first 3 days of radiotherapy and again after a planned break of 2 weeks). The median OS was 15.9 months in the chemoradiation therapy arm and 17.9 months in the no-chemoradiation therapy arm. The 2- and 5- year OS rates were 29% and 10%, respectively, in the chemoradiation therapy arm and 41% and 20% in the no-chemoradiation therapy arm. There were no significant differences in OS. They concluded that adjuvant chemoradiotherapy not only fails to provide a benefit but also reduces survival when administered before chemotherapy. Fourth, Morak et al. conducted a phase III trial to evaluate the efficacy of adjuvant radiotherapy and celiac axis infusion chemotherapy (RT/CAI) in comparison to surgery alone (12). The trial was conducted in the Netherlands between 2000 and 2007. A total of 120 patients were enrolled, with 59 patients registered in the RT/CAI alarm and 61 patients registered in the surgery-alone arm. Patients in the RT/CAI arm received radiation therapy (30×1.8 Gy), mitoxantrone (10 mg/m2, day 1), folinic acid (170 mg/m2, day 2-4), 5-FU (600 mg/m2, day 2-4), leucovorin, and cisplatin (60 mg/m2, day 5). The primary endpoint was OS. The secondary endpoints were treatment toxicity, disease-free survival (DFS), and recurrence rates. The median OS was 19 months in the RT/CAI arm and 18 months in the surgery-alone arm. There were no differences in OS. In contrast, the median time until progression was 12 months in the RT/CAI arm and seven months in the surgery-alone arm. There was a significant difference in the time to progression. They concluded that adjuvant chemoradiation therapy contributed to a prolonged time to progression after resection for pancreatic cancer. Fifth, Regine et al. conducted a phase III trial to determine whether the addition of GEM to adjuvant FU chemoradiation (chemotherapy plus radiation) improved survival in patients with resected pancreatic adenocarcinoma (13). This trial involved 164 institutions in Canada and the US between 1998 and 2002. A total of 451 patients were enrolled, with 221 patients registered in the GEM/CRT arm and 230 patients registered in the FU/CRT arm. Chemotherapy with either FU (250 mg/m2/per day) or GEM (1,000 mg/m2 once per week) was administered for three weeks prior to CRT and 12 weeks after CRT with continuous infusion of FU (250 mg/m2 per day) and radiation therapy (50.4 Gy). The primary endpoint was the OS of all patients and patients with pancreatic head tumors. The secondary endpoints were toxicity and DFS. The median OS for pancreatic head tumors was 20.5 months in the GEM/CRT arm and 16.9 months in the FU/CRT arm. The 3-year OS rates were 31% and 22% for the GEM/CRT and FU/CRT arms, respectively. There were no significant differences in OS. They concluded that GEM/CRT treatment was associated with a survival benefit in patients with resected pancreatic cancer, although this improvement was not statistically significant. Sixth, Laethem et al. conducted a phase II trial to evaluate the feasibility and tolerability of GEM and chemoradiation therapy (GEM/CRT) in comparison to GEM adjuvant treatment for resected pancreatic cancer (14). The trial included 29 institutions between 2004 and 2007. A total of 90 patients were enrolled, with 45 patients registered in the GEM/CRT arm and 45 patients registered in the GEM arm. Patients in the GEM/CRT arm received GEM treatment (1,000 mg/m2) on days 1, 8, and 15, every four weeks, for four cycles and radiation therapy (50.4 Gy). Patients in the GEM arm received GEM treatment (1,000 mg/m2) on days 1, 8, and 15, every four weeks, for four cycles. The primary endpoints of this trial were feasibility and tolerability. The secondary endpoints were DFS and OS. The median OS was 24.3 months in the GEM/CRT arm and 24.4 months in the GEM arm. The 2-year OS rates in the GEM/CRT and GEM arms were 50.6% and 50.2%, respectively. There were no significant differences in the OS between the GEM/CRT and GEM arms. In addition, median DFS was 11.8 months in GEM/CRT arm and 10.9 months in GEM arm. Seventh, Schmidt et al. conducted a phase III trial to evaluate the efficacy of FU+cisplatin (CDDP)+interferon alfa-2b (IFNα-2b) and chemoradiation therapy (FU+CDDP+ IFNα-2b/CRT) in comparison to FU+folinic acid (FA) therapy (FU+FA) for resected pancreatic cancer (15). The trial was conducted between 2004 and 2007. A total of 132 patients were enrolled, and 64 patients were registered in the FU+CDDP+ IFNα-2b/CRT arm and 68 patients in the FU+FA/CRT arm. Patients in the 5-FU+CDDP+ IFNα-2b/CRT arm received FU (200 mg/m2 per day, continuous infusion), cisplatin (30 mg/m2 per week), and 3 million units of IFNα-2b (three times a week) for 5.5 weeks combined with radiation (50.4 Gy), followed by two cycles of continuous FU. The patients in the FU+FA arm received bolus injections of FA (20 mg/m2) and FU (425 mg/m2) administered on five consecutive days every 28 days for six cycles. The primary endpoint was OS, and the secondary endpoint was DFS. Median OS was 26.5 months in the FU+CDDP+ IFNα-2b/CRT arm and 28.5 months in FU+FA arm, respectively. The median DFS was 15.2 months in the FU+CDDP+ IFNα-2b/CRT arm and 11.5 months in FU+FA arm. There were no significant differences in OS and DFS between the 5-FU+CDDP+ IFNα-2b/CRT and FU+FA arms. They concluded that FU+CDDP+ IFNα-2b/CRT treatment was not associated with a survival benefit in patients with resected pancreatic cancer.

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Table I.

Postoperative adjuvant chemo radiation therapy trials for resectable pancreatic cancer.

Adjuvant Chemotherapy Strategies

There are ten pivotal trials on postoperative adjuvant chemotherapy for resectable pancreatic cancer (Table II). First, Takada et al. conducted a randomized trial to evaluate the efficacy of adjuvant treatment in comparison to surgery alone (16). This study included 31 institutions in Japan between 1986 and 1992. A total of 508 patients were enrolled in this trial (173 with pancreatic cancer, 139 with bile duct carcinoma, 140 with gallbladder carcinoma, and 56 with ampulla of Vater cancer). Among the 173 patients with pancreatic cancer, 89 were registered in the mitomycin C (MMC) and 5-FU (MF) arm and 84 patients were registered in the surgery alone arm. Patients in the MF arm received MMC (6 mg/m2) and 5-FU (310 mg/m2) in two courses of treatment for five consecutive days (each during postoperative weeks 1 and 3), followed by daily oral 5-FU (100 mg/m2) from postoperative week 5 until disease recurrence. The primary endpoint was overall survival (OS). The secondary endpoint was DFS. The 5-year OS rate was 11.5% in the MF group and 18.0% in the surgery-alone arm. In addition, the 5-year DFS rate was 8.6% in the MF group and 7.8% in the surgery-alone arm. There were no significant differences in OS or DFS between the two groups. Second, Neoptolemos et al. conducted a randomized trial to evaluate the efficacy of adjuvant treatment compared to surgery alone (ESPAC-1) (11). This trial had a two-by-two factorial design for patients after curative resection for pancreatic cancer (PC), and the patients were randomly assigned to receive chemoradiotherapy or chemotherapy, treatment, or both treatments. The primary endpoint was the 2-year OS. A total of 289 patients were enrolled, with 147 patients registered in the chemotherapy arm; 142 patients did not receive chemotherapy. Chemotherapy consisted of leucovorin (20 mg/m2, day 1) and 5-FU (425 mg/m2, day 1-5) every 28 days for six cycles. Combination therapy consisted of chemoradiotherapy, followed by chemotherapy. After a median follow-up period of 47 months, there were significant differences in OS. The median OS was 20.1 months in the chemotherapy arm and 15.5 months in the no-chemotherapy arm. The two- and five- year OS rates were 40% and 21%, respectively, in the chemotherapy arm and 30% and 8% in the no-chemotherapy arm. They concluded that adjuvant chemotherapy was the standard treatment for patients with resectable pancreatic cancer. Third, Oettle et al. conducted a phase III trial to evaluate the efficacy of adjuvant chemotherapy with GEM in comparison to surgery alone (CONKO-001) (17, 18). This trial involved 88 institutions in Germany and Austria, between 1998 and 2004. A total of 368 patients were enrolled, with 186 patients registered in the GEM arm and 182 patients registered in the surgery alone arm. The patients in the GEM arm received GEM treatment (1,000 mg/m2) on days 1, 8, and 15, every four weeks, for six cycles. The primary endpoint was DFS. Secondary endpoints were toxicity, quality of life (QOL), and OS. After a median of 53 months of follow-up, there was a significant difference in DFS. The median DFS was 13.4 months in GEM arm and 6.9 months in the surgery alone arm. The estimated 3- and 5- year DFS rates were 23.5% and 16.5%, respectively, in the GEM arm and 7.5% and 5.5% in the surgery-alone arm. However, there were no differences in OS. The median OS was 22.1 months in the GEM arm and 20.2 months in surgery alone arm. The estimated 3- and 5-year OS rates were 34% and 22.5%, respectively, in the GEM arm and 20.5% and 11.5% in the surgery-alone arm. They also reported a follow-up study of CONKO-001. With a median follow-up period of 136 months, the 5- and 10-year OS rates were 20.7% and 12.2%, respectively, in the GEM arm and 10.1% and 7.7%, respectively, in the surgery alone arm. OS was significantly longer in the GEM arm than in the surgery-alone arm. Based on the results of the two studies, the authors concluded that adjuvant GEM treatment was effective for R0 or R1 resection of pancreatic cancer. Fourth, Ueno et al. conducted a phase III trial to evaluate the efficacy of adjuvant chemotherapy with GEM in comparison to surgery alone (JSAP-02) (19). This trial involved ten institutions in Japan between 2002 and 2005. A total of 119 patients were enrolled, with 58 patients registered in the GEM arm and 60 patients registered in the surgery alone arm. Patients in the GEM arm received three cycles of GEM treatment (1,000 mg/m2) on days 1, 8, and 15, every four weeks. The primary endpoint was OS, and the secondary endpoints were toxicity and DFS. There were significant differences in DFS. The median DFS was 11.4 months in the GEM arm and 5.0 months in surgery alone arm. The estimated 6-, 12-, and 24- month DFS rates were 70.7%, 49.0%, and 27.2%, respectively, in the GEM arm, and 43.3%, 26.7%, and 16.7% in the surgery alone arm. However, there were no differences in OS. The median OS was 22.3 months in the GEM arm and 18.4 months in surgery alone arm. The estimated 6-, 12-, 18-, 24-, and 60-month OS rates were 94.8%, 77.6%, 58.6%, 48.3%, and 23.9%, respectively, in the GEM arm, and 85.0%, 75.0%, 53.3%, 40.0%, and 10.6% in the surgery alone arm. They concluded that adjuvant GEM treatment contributed to prolonged DFS after the resection of pancreatic cancer. Fifth, Neoptolemos et al. conducted a phase III trial to determine whether fluorouracil plus folinic acid (5-FU/folinic acid) or GEM was superior, in terms OS, as an adjuvant treatment after the resection of pancreatic cancer (ESPAC-3) (20). The trial included 159 institutions in 17 countries between 2007 and 2009. A total of 1088 patients were enrolled, with 537 patients registered in the GEM arm and 551 patients registered in the FU/folinic acid (FU/FA) arm. Patients in the GEM arm received 6 cycles GEM treatment (1,000 mg/m2) on days 1, 8, and 15, every four weeks. Patients in the FU/FA arm received folinic acid (20 mg/m2, day 1) and fluorouracil (425 mg/m2, day 1-5) every 28 days, for six cycles. The primary endpoint was OS and the secondary endpoints were toxicity, QOL, and PFS. The median OS was 23.6 months in the GEM arm and 23.0 months in FU/FA arm. The estimated 12- and 24-month OS rates were 80.1% and 49.1%, respectively, in the GEM arm and 78.5% and 48.1%, respectively, in the FU/FA arm. There were no significant differences in OS between the FU/FA and GEM groups. They concluded that adjuvant GEM is the standard of care based on similar survival and lower toxicity than adjuvant FU/FA in patients with resected pancreatic cancer. Sixth, Uesaka et al. conducted a phase III trial to investigate the non-inferiority of S-1 to GEM as adjuvant treatment following resection of pancreatic cancer (JASPAC01) (21). This study included 33 institutions in Japan between 2007 and 2010. A total of 385 patients were enrolled, with 193 patients registered in the GEM arm and 192 patients registered in the S-1 arm. Patients in the GEM arm received GEM treatment for 6 cycles (1,000 mg/m2) on days 1, 8, and 15, every four weeks. Patients in the S-1 arm received an oral dose of S-1 (40–60 mg) for 28 consecutive days, followed by a 1-day rest (one cycle), for four cycles. The primary endpoint was OS, and secondary endpoints were toxicity, QOL, and relapse-free survival (RFS). The median OS was 25.5 months in the GEM arm and 46.5 months in S-1 arm. The estimated 3- and 5- year OS rates were 38.8% and 24.4%, respectively, in the GEM arm, and 59.7% and 44.1% in the S-1 arm. The median RFS was 11.3 months in the GEM arm and 22.9 months in S-1 arm. The estimated 3- and 5- year RFS rates were 22.6% and 16.8%, respectively, in the GEM arm, and 39.2% and 33.3% in the S-1 arm. There were significant differences in both OS and RFS between the GEM and S-1 arms. They concluded that S-1 adjuvant chemotherapy is the new standard adjuvant treatment for resected pancreatic cancer in Japan. Seventh, Neoptolemos et al. conducted a phase III trial to determine the efficacy and safety of GEM and capecitabine (GEM/CAP) relative to GEM monotherapy for resected pancreatic cancer (ESPAC-4) (22). This trial involved 92 institutions in European countries, between 2008 and 2014. A total of 732 patients were enrolled, with 367 patients registered in the GEM arm and 365 patients registered in the GEM/CAP arm. Patients in the GEM arm received six cycles of GEM treatment (1,000 mg/m2) on days 1, 8, and 15, every four weeks. Patients in the GEM/CAP arm received 6 cycles of GEM treatment (1,000 mg/m2) on days 1, 8, and 15, every four weeks, and capecitabine was administered orally for 21 days followed by seven days of rest (one cycle), for six cycles, at a daily dose of 1,660 mg/m2. The primary endpoint was OS and the secondary endpoints were toxicity, QOL, and RFS. The median OS was 25.5 months in the GEM arm and 28.0 months in the GEM/CAP arm. The estimated 12- and 24-month OS rates were 80.5% and 52.1%, respectively, in the GEM arm, and 84.1% and 53.8% in the GEM/CAP arm. There were significant differences in OS between the GEM/CAP and GEM arms. The authors concluded that the adjuvant combination of GEM/CAP should be the new standard of care following resection for pancreatic cancer. Eighth, Sinn et al. conducted a phase III trial to evaluate the efficacy of adjuvant chemotherapy with GEM and erlotinib in comparison to GEM alone (CONKO-005) (23). This trial included 57 German institutions between 2008 and 2013. A total of 436 patients were enrolled, with 219 patients registered in the gemcitabine and erlotinib (GEMErlo) arm and 217 patients registered in the GEM arm. Patients in the GEMErlo arm received GEM (1,000 mg/m2) on days 1, 8, and 15, every four weeks in combination with erlotinib 100 mg, orally once per day) on days 1 to 28, every four weeks. Patients in the GEM arm received GEM (1,000 mg/m2) on days 1, 8, and 15, every four weeks. The primary endpoint was DFS. The secondary endpoint was OS. The median DFS was 11.4 months in the GEMErlo arm and 11.4 months in the GEM arm. The estimated 1-, 2- and 5- year DFS rates were 47%, 25%, and 13%, respectively, in the GEMErlo arm and 48%, 25%, and 11%, respectively, in the GEM arm. There were no significant differences between the two groups. Moreover, the median OS was 24.5 months in the GEMErlo arm and 26.5 months in the GEM arm. The estimated 1-, 2-, and 5- year OS rates were 78%, 53%, and 23%, respectively, in the GEMErlo arm and 79%, 54%, and 20% in the GEM arm. There was no significant difference in OS between the two groups. GEM and erlotinib treatment did not improve DFS or OS over Gem treatment in patients with resectable pancreatic cancer. Ninth, Conroy et al. conducted a phase III trial to compare the efficacy and safety of modified fluorouracil, leucovorin, irinotecan, and oxaliplatin (mFOLFIRINOX) with GEM for resected pancreatic cancer (PRODIGE) (24). This trial included 77 institutions in France and Canada, between 2012 and 2016. A total of 493 patients were enrolled, with 246 patients registered in the GEM arm and 247 patients registered in the mFOLFIRINOX arm. Patients in the GEM arm received six cycles of GEM (1,000 mg/m2) on days 1, 8, and 15, every four weeks. Patients in the mFOLFIRINOX arm received oxaliplatin (85 mg/m2), irinotecan (150 mg/m2), leucovorin (400 mg/m2), and fluorouracil (2,400 mg/m2), every two weeks, for 12 cycles. The primary endpoint was DFS and the secondary endpoints were OS, cancer specific survival, metastasis-free survival, and safety. With a median follow-up period of 33.6 months, the median DFS was 12.8 months in the GEM arm and 21.6 months in the mFOLFIRINOX arm. The 1-, 2- 3-year DFS rates were 53.7%, 30.7%, and 21.4%, respectively, in the GEM arm, and 69.0%, 47.0%, and 39.7% in the mFOLFIRINOX arm. There were significant differences in DFS between the mFOLFIRINOX and GEM groups. In addition, the median OS was 35.0 months in the GEM arm and 54.4 months in the mFOLFIRINOX arm. The 3-year OS rate was 63.4% in the GEM arm and 48.6% in the mFOLFIRINOX arm. They concluded that adjuvant therapy with mFOLFIRINOX led to significantly longer survival in comparison to GEM in patients with pancreatic cancer after surgery. Tenth, Abrams et al. conducted a phase III trial to evaluate the efficacy of adjuvant chemotherapy with GEM and erlotinib in comparison to GEM alone (RTOG0848) (25). The trial was conducted between 2009 and 2014. A total of 322 patients were enrolled, with 159 patients registered in the GEMErlo arm and 169 patients registered in the GEM arm. Patients in the GEMErlo arm received gemcitabine (1,000 mg/m2) weekly, for 3 out of 4 weeks, for five cycles in combination with erlotinib (100 mg, daily) for five cycles. Patients in the GEM arm received gemcitabine (1,000 mg/m2, weekly), for 3 out of 4 weeks, for five cycles. The primary endpoint was OS. The median OS was 28.1 months in the GEMErlo arm and 29.9 months in the GEM arm. The estimated 3- year OS rates in the GEMErlo and GEM arms were 38.7% and 37.5%, respectively. There were no significant differences between the two groups. The estimated 3- year DFS rate was 20.2% in the GEMErlo arm and 22.7% in the GEM arm. There was no significant difference between the two groups. GEM and erlotinib treatment did not improve DFS or OS in resectable pancreatic cancer.

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Table II.

Postoperative adjuvant chemotherapy trials for resectable pancreatic cancer.

Perioperative Adjuvant Chemotherapy Strategies

There have been six trials on perioperative adjuvant treatment for resectable pancreatic cancer (Table III). Casadei et al. conducted a phase II trial to investigate the usefulness of neoadjuvant chemoradiation therapy in comparison to surgery alone for patients with resectable pancreatic cancer (26). This trial was conducted at a single institution in Italy, between 2007 and 2014. A total of 38 patients were enrolled, with 18 patients registered in the neoadjuvant chemoradiation therapy arm and 20 patients registered in the surgery alone arm. Patients in the neoadjuvant chemoradiation therapy arm received chemotherapy with GEM alone (1,000 mg/m2 on days 1 and 8, every 21 days, for two cycles, followed by combined chemoradiotherapy (conventional radiotherapy with 45 Gy and a boost of 9 Gy on the pancreatic lesion; chemotherapy with gemcitabine 50 mg/m2 twice weekly), for a total of six weeks. The primary endpoint was the R0 resection rate, and the secondary endpoints were toxicity, DFS, and OS. The R0 resection rate was 38.9% in the neoadjuvant chemoradiation therapy arm and 25.0% in the surgery alone arm, with no significant differences between the two groups. The median OS was 19.5 months in the surgery-alone arm and 22.4 months in the neoadjuvant chemoradiation therapy arm. No significant differences were observed between the groups. Second, Golcher et al. conducted a phase II trial to investigate the efficacy and safety of neoadjuvant chemoradiation therapy in comparison to surgery alone for resectable pancreatic cancer (27). This trial was conducted in Germany and Switzerland between 2003 and 2009. A total of 66 patients were enrolled, with 33 patients registered in the neoadjuvant chemoradiation therapy arm and 33 patients registered in the surgery alone arm. Patients in the neoadjuvant chemoradiation therapy arm received GEM (300 mg/m2) and CDDP (30 mg/m2) on days 1, 8, 22, and 29 of radiotherapy. Radiotherapy dose was 55.8 Gy or 50.4Gy. The primary endpoint was OS. The median OS was 18.9 months in the surgery-alone arm and 25.0 months in the neoadjuvant chemoradiation therapy arm. No significant differences were observed between the groups. In addition, the time to progression was 8.7 months in the surgery-alone arm and 8.4 months in the neoadjuvant chemoradiation therapy arm. There were no significant differences between the groups. Third, Reni et al. conducted a phase II/III trial to investigate the efficacy and safety of neoadjuvant preoperative or postoperative chemotherapy for patients with resectable pancreatic cancer (PACT-15 trial) (28). This trial was conducted at 10 institutions in Italy between 2010 and 2015. In the phase II trial, a total of 88 patients were enrolled, with 26 patients registered in the surgery and postoperative GEM adjuvant chemotherapy arm (arm A), 30 patients registered in the surgery and postoperative cisplatin+epirubicin+GEM+capecitabine (PEXG) adjuvant chemotherapy arm (arm B), and 32 patients registered in the surgery and perioperative PEXG adjuvant chemotherapy arm (arm C). Patients in arm A received GEM (1,000 mg/m2) on days 1, 8, and 15, every four weeks, for 6 months. Patients in arm B received adjuvant PEXG [cisplatin (30 mg/m2), epirubicin (30 mg/m2), gemcitabine (800 mg/m2), on days 1 and 15, every four weeks, and oral capecitabine (1,250 mg/m2) on days 1–28] for six months. The patients in arm C received PEXG treatment (same as arm B) for three months, both perioperatively and postoperatively. The primary endpoint was the event-free survival rate at one year. The event-free survival rate at one year was 23% in arm A, 50% in arm B, and 66% in arm C. The median OS was 20.4 months in arm A, 26.4 months in arm B, and 38.2 months in arm C. Five-year OS was 13% in arm A, 24% in arm B, and 49% in arm C. They concluded that a combination of treatments was effective and safe for patients with resectable pancreatic cancer. In addition, the neoadjuvant administration of an effective combination regimen appeared to provide an additional therapeutic benefit over that gained with adjuvant-only administration. Fourth, Versteijne et al. conducted a phase III trial to investigate the usefulness of perioperative chemoradiation therapy for postoperative adjuvant chemotherapy in resectable or borderline resectable pancreatic cancer (29). This trial was conducted at 16 institutions in the Netherlands between 2013 and 2017. A total of 246 patients were enrolled, with 119 patients registered in the perioperative chemoradiation therapy arm and 127 patients registered in the postoperative adjuvant chemotherapy arm. Patients in the perioperative chemoradiation therapy arm received 3 cycles of GEM [gemcitabine (1,000 mg/m2) on days 1, 8, and 15 of a 28-day cycle] and radiation therapy (36 Gy) before surgery and four cycles of GEM after surgery. Patients in the postoperative chemotherapy arm received six cycles of GEM (1,000 mg/m2 on days 1, 8, and 15 of a 28-day cycle) after surgery. The primary endpoint was OS, and the secondary endpoint was DFS. The median OS was 16.0 months in the perioperative chemotherapy arm and 14.3 months in the postoperative adjuvant chemotherapy arm. No significant differences were observed between the groups. In contrast, the median DFS was 8.1 months in the perioperative chemotherapy arm and 7.7 months in the postoperative adjuvant chemotherapy arm. They concluded that perioperative chemoradiotherapy for resectable or borderline resectable pancreatic cancer did not show a significant overall survival benefit. Fifth, Seufferlein et al. conducted a phase II trial to compare neoadjuvant chemotherapy with adjuvant chemotherapy with GEM and nab-paclitaxel for patients with resectable pancreatic cancer (30). This trial was conducted in 22 institutions in Germany between 2015 and 2019. A total of 127 patients were enrolled, with 59 patients registered in the perioperative chemotherapy arm and 59 patients registered in the postoperative adjuvant chemotherapy arm. The patients in the perioperative chemotherapy arm received 2 cycles of nab-paclitaxel plus gemcitabine [nab-paclitaxel (125 mg/m2) and gemcitabine (1,000 mg/m2) on days 1, 8, and 15 of a 28-day cycle] before surgery and four cycles of nab-paclitaxel plus gemcitabine after surgery. The patients in the postoperative chemotherapy arm received six cycles of nab-paclitaxel plus gemcitabine [nab-paclitaxel (125 mg/m2) and gemcitabine (1,000 mg/m2) on days 1, 8, and 15 of a 28-day cycle] after surgery. The primary endpoint was DFS at 18 months. The predefined DFS rate of 55% at 18 months was not achieved in either arm. In contrast, the median DFS was 11.5 months in the perioperative chemotherapy arm and 5.9 months in the postoperative adjuvant chemotherapy arm. The median OS was 25.5 months in the perioperative chemotherapy arm and 16.7 months in the postoperative adjuvant chemotherapy arm. Sixth, Sugiura et al. conducted a phase II trial to compare neoadjuvant chemoradiotherapy (NAC-RT) with S-1 and combination neoadjuvant chemotherapy with GEM and S-1 (NAC-GS) for patients with resectable pancreatic cancer (31). The trial was conducted in Japan between 2014 and 2017. A total of 103 patients were enrolled, with 51 registered in the NAC-RT arm and 51 patients registered in the NAC-GS arm. In the NAC-RT with S-1 group, patients received a total radiation dose of 50.4 Gy in 28 fractions with oral S-1. In the NAC-GS group, the patients received intravenous gemcitabine (1,000 mg/m2) with oral S-1, for two cycles. The primary endpoint was PFS. The 2-year PFS rates in the NAC-RT and NAC-GS arms were 45.0% and 54.9%, respectively. In addition, the 2-year OS rate was 66.7% in the NAC-RT arm and 72.4% in the NAC-GS arm. They concluded that NAC-RT with S-1 and NAC-GS are promising treatments for resectable pancreatic cancer.

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Table III.

Preoperative adjuvant chemotherapy trials for resectable pancreatic cancer.

Ongoing Studies and Future Prospects

Recently, immune checkpoint inhibitors (ICIs) have shown clinical benefits in various malignancies, including gastrointestinal cancers (32-34). In addition, ICIs have been introduced and used as adjuvant treatments. In esophageal cancer, ICIs were used as adjuvant treatment for one year after curative esophagectomy for esophageal cancer (35). Therefore, ICIs may have clinical benefits in pancreatic cancer. In the adjuvant setting for pancreatic cancer, there are two ongoing trials to evaluate the efficacy of ICIs as adjuvant treatment for pancreatic cancer. One of these is the “Randomized Phase II Study of Pembrolizumab With or Without Defactinib, a Focal Adhesion Kinase Inhibitor Following Chemotherapy as a Neoadjuvant and Adjuvant Treatment for Resectable Pancreatic Ductal Adenocarcinoma (PDAC)”. This trial (NCT03727880) evaluates the effectiveness, safety, and ability to increase the efficacy of the body’s immune system to fight pancreatic cancer by combining standard chemotherapy before and after surgery, with the pembrolizumab (PD-1 antibody) with and without the study drug defactinib in patients with “high risk” resectable pancreatic cancer. The other study is the “Phase I/II Trial of Combination Immunotherapy With Nivolumab and a CCR2/CCR5 Dual Antagonist (BMS-813160) With or Without GVAX Following Chemotherapy and Radiotherapy for Locally Advanced Pancreatic Ductal Adenocarcinomas” (NCT03767582). This study also evaluates the efficacy of ICIs for resectable pancreatic cancer in an adjuvant setting. These trials might show the clinical benefits of ICIs as an adjuvant treatment for pancreatic cancer.

Conclusion

There are clinical benefits of each treatment strategy for the adjuvant treatment of resectable pancreatic cancer. To optimize adjuvant treatment for resectable pancreatic cancer, it is necessary to understand the characteristics of each approach before adjuvant treatment.

Footnotes

  • Authors’ Contributions

    TA and KH contributed substantially to the concept and study design. TA, KH, and HC made substantial contributions to the data acquisition, analysis, and interpretation. TA, AS and HC were involved in drafting and critically revising the manuscript for important intellectual content. TA and HC approved the final version of the manuscript.

  • Conflicts of Interest

    The Authors declare no conflicts of interest in association with the present study.

  • Received February 28, 2025.
  • Revision received March 17, 2025.
  • Accepted March 18, 2025.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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