Pancreatic cancer is the seventh leading cause of cancer mortality in the world with an estimated 432,000 deaths per year. Its incidence is increasing worldwide, which may reflect rapid population growth and aging.[2–5] Although pancreatic cancer remains one of the most lethal malignancies, there is a continued gradual improvement in survival over the past 2 decades with the 5-year survival rate increased from 4% to 9%.[2,6] Progress in chemotherapy has clearly contributed to this survival improvement in patients with any stage of disease. In terms of resectable pancreatic cancer, the role of adjuvant therapy has been established and a treatment strategy of neoadjuvant therapy is emerging. In this review, we summarize the current understanding of adjuvant and neoadjuvant therapy with a focus mainly on randomized controlled trials.
Surgical resection offers the only chance of cure for patients with pancreatic cancer; however, surgery alone is not enough. Nearly 90% of patients experience recurrence after curative resection.[7,8] Most patients with localized tumor appear to have undetected micrometastasis at diagnosis, therefore, clinical trials of adjuvant therapy have been conducted since the 1970s to improve the outcomes (Table 1).
The first trial was reported in 1985. The Gastrointestinal Tumor Study Group (GITSG) randomly assigned patients with an R0 resection to surgery alone (n = 22) or adjuvant chemoradiotherapy with fluorouracil and follow-on chemotherapy (n = 21). This trial was prematurely closed because of a low rate of accrual and because the interim analysis showed a significant difference in overall survival between the 2 groups in favor of adjuvant therapy. Median overall survival in the adjuvant group was significantly longer than that in the observation group (20 vs 11 months, P = .035).
The European Organisation for Research and Treatment of Cancer (EORTC) trial randomized patients with pancreatic head and periampullary cancers to surgery alone or to receive chemoradiotherapy with concurrent fluorouracil.[10,11] There was no advantage of adjuvant therapy in survival in the total group of eligible patients. In the subset analysis of pancreatic cancer patients, the treatment group (n = 60) also failed to show improved overall survival compared with the observation group (n = 54) (17.1 vs 12.6 months, P = .099). Long-term results of this trial were reported in 2007, and the difference in survival remained insignificant (15.6 vs 12.0 months, P = .165). In the GITSG trial, patients in the treatment group received follow-on chemotherapy for 2 years or until disease recurrence, whereas in the EORTC trial, fluorouracil was given during the course of radiotherapy but not thereafter. A comparison of the 2 trials implies the importance of chemotherapy for a certain period of time.
The current standard of care for resected pancreatic cancer patients is adjuvant chemotherapy. The European Study Group for Pancreatic Cancer 1 (ESPAC-1) trial randomly assigned 289 patients into a two-by-two factorial design of chemotherapy vs no chemotherapy and chemoradiotherapy vs no chemoradiotherapy. ESPAC-1 demonstrated a significant survival benefit of adjuvant chemotherapy using fluorouracil compared with no chemotherapy (overall survival, 20.1 vs 15.5 months, P = .009), and also suggested that the addition of radiation therapy was of no benefit and possibly even deleterious (overall survival, 15.9 vs 17.9 months, P = .05).
The development of gemcitabine is a great landmark in the treatment of pancreatic cancer. In 1997, Burris et al demonstrated the significant improvements in survival and quality of life with gemcitabine compared with fluorouracil for advanced pancreatic cancer. The Charité Onkologie 001 trial was conducted to evaluate the efficacy of gemcitabine in the adjuvant setting. Patients with a postoperative carbohydrate antigen (CA) 19-9 level greater than 2.5 times the upper limit of normal were excluded. Patients undergoing curative resection (R0/R1) were randomly assigned to surgery alone (n = 175) and to receive adjuvant chemotherapy with 6 cycles of gemcitabine 1000 mg/m2 on days 1, 8, and 15 every 4 weeks (n = 179). The median disease-free survival, the primary end point of the trial, was significantly longer in the gemcitabine group compared to the observation group (13.4 vs 6.9 months, P < .001). Overall survival was not different between the 2 groups when first reported in 2007 (22.1 vs 20.2 months, P = .06), but long-term follow-up reported in 2013 revealed that adjuvant gemcitabine was significantly associated with prolonged overall survival (22.8 vs 20.2 months, P = .01).
Direct comparisons of adjuvant gemcitabine to fluorouracil were demonstrated in 2 randomized trials by the Radiation Therapy Oncology Group (RTOG) and the ESPAC.[15–17] Results of the 2 trials were similar, showing no significant differences between gemcitabine and fluorouracil in the adjuvant setting. RTOG 9704 trial randomized patients to receive either gemcitabine (n = 221, 1000 mg/m2 once weekly) or fluorouracil (n = 230, 250 mg/m2 per day) for 3 weeks before and 12 weeks after chemoradiation with fluorouracil. Gemcitabine failed to demonstrate clear advantages over fluorouracil in both all eligible patients (overall survival, P = .51) and pancreatic head cancer patients (overall survival, 20.5 vs 17.1 months, P = .12).[15,16] Given the identical chemoradiation regimen between the 2 arms, the benefit of chemoradiotherapy cannot be assessed in the trial, but the concept that there are no statistically significant differences between adjuvant gemcitabine and fluorouracil is consistent with that of ESPAC-3.
In the ESPAC-3, the largest randomized trial, patients were assigned to receive adjuvant gemcitabine (n = 537, 1000 mg/m2 once a week for 3 of every 4 weeks) or fluorouracil (n = 551, 425 mg/m2 given 1–5 days every 28 days). After a follow-up of 34.2 months, the median overall survival observed in the gemcitabine group was 23.6 months compared with 23.0 months in the fluorouracil group (P = .39). However, toxicity profiles of these 2 regimens differed in favor of gemcitabine. Treatment-related serious adverse events were reported more frequently in the fluorouracil group compare with the gemcitabine group (14% vs 7.5%, P < .001). Therefore, gemcitabine became the preferred choice for resected pancreatic cancer patients.
EORTC 40013 is a randomized phase II study to compare 4 cycles of gemcitabine chemotherapy (n = 45) vs 2 cycles of gemcitabine chemotherapy followed by 50.4 Gy radiation with gemcitabine (n = 45) in patients with an R0 resection. Although this trial was designed to evaluate feasibility and tolerability of adjuvant gemcitabine-based chemoradiotherapy and the primary end points included neither disease-free nor overall survival, the addition of radiation did not show a survival benefit (overall survival, 24.4 months in the chemotherapy group vs 24.3 months in the chemoradiotherapy group, not significant).
As gemcitabine monotherapy had been the standard of care for advanced pancreatic cancer for a long time until 2011,[13,19] gemcitabine had also been the standard of care after curative resection until recently. The Japan Adjuvant Study Group of Pancreatic Cancer 01 trial randomly assigned patients to receive gemcitabine (n = 193, 1000 mg/m2 once a week for 3 of every 4 weeks) or S-1 (n = 192, 40–60 mg according to body surface area, orally twice a day for 28 days of a 42-day cycle). S-1 is a combination drug of tegafur (a prodrug of fluorouracil), gimeracil, and oteracil potassium. The median overall survival in the S-1 group was significantly longer than the gemcitabine group (46.5 vs 25.5 months) with a hazard ratio (HR) of 0.57 [95% confidence interval (CI): 0.44–0.72, P < .0001]. S-1 was well tolerated and discontinuation of treatment before completion was less frequently observed in the S-1 group (28% vs 42%, P = .005). Based on these findings, adjuvant S-1 chemotherapy is currently recommended in Japan. This study was conducted only with a Japanese population. Additional trials in non-Asian populations are warranted because the pharmacokinetics and maximum tolerated dose of S-1 differ between Asian and Caucasian populations.
In the ESPAC-4 trial, patients were randomized to receive 1000 mg/m2 gemcitabine monotherapy once a week for 3 of every 4 weeks (n = 366) or gemcitabine plus 1660 mg/m2 capecitabine for 21 days of a 28-day cycle (n = 364). The median overall survival in the gemcitabine plus capecitabine group was 28.0 months compared with 25.5 in the gemcitabine monotherapy group. The HR was 0.82 (95% CI: 0.68–0.98, P = .032). Treatment completion rate (6 cycles) was 65% in the gemcitabine group and 54% in the gemcitabine plus capecitabine group.
Combination chemotherapy with fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) significantly improved survival than gemcitabine in patients with metastatic pancreatic cancer and good performance status. In 2018, results from the Partenariat de Recherche en Oncologie Digestive 24 and Canadian Cancer Trials Group Pancreatic Adenocarcinoma 6 (PROGIDE 24/CCTG PA.6) trial was reported, comparing modified FOLFIRINOX (mFOLFIRINOX, n = 247, 2400 mg/m2 fluorouracil, 400 mg/m2 leucovorin, 150 mg/m2 irinotecan, and 85 mg/m2 oxaliplatin every 2 weeks) to gemcitabine monotherapy (n = 246, 1000 mg/m2 once a week for 3 of every 4 weeks) as adjuvant therapy. Patients with a postoperative CA 19-9 level higher than 180 U/mL were excluded. The median disease-free survival, the primary end point, was 21.6 months in the mFOLFIRINOX group and 12.8 months in the gemcitabine group (HR: 0.58, 95% CI: 0.46–0.79, P < .001). The median overall survival was 54.4 months in the mFOLFIRINOX group and 35.0 months in the gemcitabine group (HR: 0.64, 95% CI: 0.48–0.86, P = .003). Treatment completion rate was 66.4% in the mFOLFIRINOX group and 79.0% in the gemcitabine group (P = .002). Adverse events of grade 3 or 4 occurred more frequently in the mFOLFIRINOX group (75.9% vs 52.9%), with 1 death due to treatment-related toxic effects in the gemcitabine group.
Given the evidence available to date, current preferred regimens as adjuvant therapy are gemcitabine plus capecitabine and mFOLFIRINOX according to the National Comprehensive Cancer Network (NCCN) guidelines. Other recommended regimens include gemcitabine, fluorouracil, and induction chemotherapy followed by chemoradiotherapy (±followed by subsequent chemotherapy). In the guidelines of the European Society for Medical Oncology (ESMO), mFOLFIRINOX is considered the first adjuvant therapeutic option in fit patients. Gemcitabine plus capecitabine is an option for more frail patients. Gemcitabine monotherapy has a place only in frail patients. Regarding chemoradiotherapy, the ESMO guidelines state that no adjuvant chemoradiation should be given to patients except clinical trials. In Japanese guidelines, S-1 monotherapy is recommended as adjuvant therapy. For patients with low tolerability for S-1, gemcitabine monotherapy would be used. The Japanese guidelines also recommend no adjuvant chemoradiation for resected pancreatic cancer patients.
In patients with metastatic pancreatic cancer, gemcitabine plus nab-paclitaxel demonstrated a significant survival benefit over gemcitabine monotherapy (overall survival, 8.5 vs 6.7 months, HR: 0.72, 95% CI: 0.62–0.83, P < .001). This combination regimen was being studied in the adjuvant setting in phase III Adjuvant Pancreatic Adenocarcinoma Clinical Trial (ClinicalTrials.gov NCT01964430), which was reported at the 2019 Annual Meeting of the American Society of Clinical Oncology (ASCO). Gemcitabine plus nab-paclitaxel did not meet the primary end point of improving disease-free survival compared with gemcitabine alone (19.4 vs 18.8 months, P = .1824), but did improve overall survival (40.5 vs 36.2 months, P = .045), which was a secondary end point. Detailed data will be presented in the near future. The RTOG 0848 trial (ClinicalTrials.gov NCT01013649) is ongoing to demonstrate the additional benefit of chemoradiotherapy with concurrent capecitabine or fluorouracil in patients with resected pancreatic head cancer who remain disease free after 5 cycles of gemcitabine-based adjuvant chemotherapy. Recently, a significant progression-free survival benefit of olaparib, a poly(adenosine diphosphate–ribose) polymerase inhibitor, as maintenance therapy in patients with a germline BRCA mutation and metastatic disease was reported. Although only a small proportion of pancreatic cancers have germline BRCA mutations, its use in the perioperative setting may be expected in the future.
Neoadjuvant therapy for resectable or borderline resectable pancreatic cancer offers theoretical advantages over the strategy of upfront surgery followed by adjuvant therapy, including early treatment of potential micrometastasis, increased likelihood of margin-negative resection, the guaranteed delivery of systemic therapy which could be hampered by postoperative complications, and better patient selection for surgery by excluding highly aggressive tumors. Meanwhile, the potential criticism is that delaying surgery may be at risk of losing the opportunity for resection due to disease progression during the course of neoadjuvant treatment.
When we confirm the superiority of neoadjuvant therapy to an upfront surgery approach, especially in terms of survival, comparisons in intention-to-treat analysis or otherwise propensity score matched analysis are important to eliminate patient selection bias and to make it clear whether it is just a selection of biologically favorable tumors or whether neoadjuvant treatment actually increases the probability of longer survival. Until recently, data from high-quality trials on neoadjuvant therapy were lacking. In the past year, however, reports of randomized trials have begun to increase (Table 2). In the latter half of this review on neoadjuvant therapy, we include randomized controlled trials as well as results from intention-to-treat or propensity score matched analyses.
Versteijne et al and Unno et al conducted meta-analyses of studies by intention-to-treat comparing neoadjuvant therapy vs upfront surgery in patients with resectable or borderline resectable pancreatic cancer. Based on the meta-analysis by Unno et al, the HR for death with neoadjuvant therapy was significant (HR: 0.66, 95% CI: 0.50–0.87, P = .003). Versteijne et al reported that the median overall survival by intention-to-treat was 18.8 months for neoadjuvant treatment compared with 14.8 months for upfront surgery. The overall resection rate was lower in patients receiving neoadjuvant treatment than that in patients undergoing upfront surgery (66.0% vs 81.3%, P < .001); however, the R0 resection rate among patients who underwent resection was higher in the neoadjuvant group (86.8% vs 66.9%, P < .001). Shubert et al investigated outcomes of neoadjuvant therapy vs upfront surgery in patients with stage III pancreatic cancer using an intention-to-treat analysis of the National Cancer Database. The median overall survival by intention-to-treat was 20.7 months for neoadjuvant therapy patients (n = 377) compared to 13.7 months for upfront surgery patients (n = 216, P < .001). Receipt of neoadjuvant therapy was independently associated with longer overall survival (HR: 0.68, 95% CI: 0.53–0.86, P = .001). In the analysis of a total of 884 patients with borderline resectable pancreatic cancer reported by Nagakawa et al, outcomes between neoadjuvant therapy and upfront surgery were compared using propensity score matching. Of 530 enrolled patients in the neoadjuvant group, 211 (40%) patients received neoadjuvant chemotherapy and 319 (60%) received neoadjuvant chemoradiotherapy. The overall resection rate was significantly lower in the neoadjuvant group compared with that in the upfront surgery group (75.1% vs 93.3%, P < .001), while the R0 rate among patients undergoing resection was significantly higher in the neoadjuvant group (85.7% vs 70.4%, P < .001). The median overall survival by intention-to-treat was 25.7 months in the neoadjuvant group compared with 19.0 months in the upfront surgery group (P = .015).
Two randomized trials conducted in the 2000s terminated early due to slow accrual without showing a survival benefit of neoadjuvant treatment.[34,35] Golcher et al randomized patients to undergo upfront surgery or to receive neoadjuvant chemoradiation concurrent with gemcitabine plus cisplatin. In both arms, adjuvant chemotherapy was recommended. Patients were considered eligible if tumor abutment with peripancreatic vessels was no more than 180 degrees. Seventy-three patients were enrolled, with 66 patients eligible for analysis. There was no significant difference in median overall survival by intention-to-treat between the neoadjuvant group and the upfront surgery group (17.4 vs 14.4 months, P = .96). Casadei et al randomized patients with resectable tumor to undergo upfront surgery (n = 20) or to receive neoadjuvant gemcitabine followed by chemoradiation (n = 18). Adjuvant gemcitabine was used in both arms. Tumors were considered resectable if venous involvement was less than 180 degrees. The R0 rate, the primary endpoint, was higher in the neoadjuvant group, but no significant difference was found (38.9% vs 25.0%, P = .489). Overall survival was not different between the 2 groups (median, 22.4 vs 19.5 months, P = .973).
Jang et al conducted a randomized trial comparing the outcomes of neoadjuvant chemoradiotherapy followed by surgery vs upfront surgery followed by adjuvant chemoradiotherapy in patients with borderline resectable pancreatic cancer. Chemoradiotherapy consisted of 54 Gy radiation with 400 mg/m2 gemcitabine once a week for 6 weeks. Adjuvant chemotherapy with 1000 mg/m2 gemcitabine once a week for 3 of every 4 weeks for 4 cycles was given after completion of chemoradiotherapy and surgery in both arms. Resectability status was defined according to the 2012 NCCN guidelines, which is different from the current NCCN guidelines. Tumor abutment with the superior mesenteric vein (SMV) or portal vein (PV) was considered borderline resectable in the 2012 NCCN guidelines, whereas abutment with the SMV/PV of ≤180 degrees without contour irregularity was regarded as resectable in the current NCCN guidelines.[37–39] This trial was terminated early because an interim analysis at the time of 50% case enrollment demonstrated the superiority of neoadjuvant treatment over upfront surgery in terms of survival. The median overall survival was significantly better in the neoadjuvant group (n = 27) compare to that in the upfront surgery group (n = 23) (21 vs 12 months, HR: 1.97, 95% CI: 1.07–3.62, P = .028). The overall R0 resection rate was also significantly higher in the neoadjuvant group (51.8% vs 26.1%, P = .004).
At the 2018 ASCO Annual Meeting, preliminary data of the PREOPANC-1 trial was presented by Tienhoven et al. The PREOPANC-1 randomly assigned patients with resectable or borderline resectable disease to the upfront surgery group (n = 127) or the neoadjuvant chemoradiation group (n = 119). Neoadjuvant chemoradiation consisted of 36 Gy radiation with 1000 mg/m2 gemcitabine on days 1, 8, and 15, preceded and followed by a modified course of gemcitabine. Adjuvant chemotherapy with gemcitabine was administered for 6 cycles in the upfront surgery group and for 4 cycles in the neoadjuvant group. Resectability status was based on the Dutch Pancreatic Cancer Group definitions, where tumor contact with the SMV/PV of ≤90 degrees was regarded as resectable, and tumor contact with any major artery of ≤90 degrees or the SMV/PV of 90 to 270 degrees was deemed borderline resectable. Accrual was completed in 2017, and 149 of 176 needed events were observed at the time of presentation. The neoadjuvant group tended to have better overall survival than the upfront surgery group (17.1 vs 13.7 months, P = .074), and there was a significant difference in disease-free survival (9.9 vs 7.9 months, P = .023). The overall resection rate was equivalent between the 2 groups (62% vs 72%, P = .15), while the R0 resection rate was significantly higher in the neoadjuvant group (P < .001). These findings show that chemoradiotherapy before surgery may be beneficial for patients with pancreatic cancer. Results of final data analysis will be reported soon.
At the 2019 ASCO Gastrointestinal Cancers Symposium, Unno et al reported the results of the Prep-02/JSAP05 trial which compared neoadjuvant chemotherapy (n = 182) vs upfront surgery (n = 180). Prep-02/JSAP05 is the first trial which completed the planned accrual and demonstrated a significant survival benefit of neoadjuvant therapy. Patients were eligible if they had resectable or borderline resectable pancreatic cancer without arterial abutment. Neoadjuvant chemotherapy regimen consisted of 1000 mg/m2 gemcitabine on days 1 and 8 plus S-1 at a dose according to body surface area daily for 14 days of a 21-day cycle for 2 cycles. Adjuvant chemotherapy with S-1 was administered for 6 months in both arms. The overall resection rate (86.3% vs 87.2%) and the R0 resection rate were equivalent between the 2 groups. The median overall survival by intention-to-treat was 36.7 months in the neoadjuvant group vs 26.6 months in the upfront surgery group (HR: 0.72, 95% CI: 0.55–0.94, P = .015).
Several randomized trials are currently ongoing to address the benefit of neoadjuvant treatment over upfront surgery for resectable and borderline resectable pancreatic cancer, including the use of gemcitabine, FOLFIRINOX, and gemcitabine plus nab-paclitaxel.[44–48] These trials are certainly of interest and will better define the role of neoadjuvant therapy.
The additional benefit from neoadjuvant radiation has also been investigated as in the adjuvant setting. Franko et al, using the National Cancer Database, compared the outcomes of neoadjuvant chemotherapy vs chemoradiotherapy vs chemotherapy followed by radiation. The median overall survival for chemotherapy-only, chemoradiotherapy-only, and chemotherapy followed by radiation were 25.6, 22.9, and 26.9 months, respectively. Significant difference of chemoradiotherapy-only was seen against chemotherapy-only (P = .017) and chemotherapy followed by radiation (P = .021). Multivariate Cox analysis showed that chemoradiation-only was associated with poor survival compared with chemotherapy-only, suggesting the importance of full dose systemic chemotherapy. Lutfi et al also used the National Cancer Database to compare patients receiving neoadjuvant chemotherapy with radiation vs those without radiation in a propensity score matching analysis. Patients receiving radiation had a decreased likelihood of nodal involvement, but showed a trend towards shorter overall survival (P = .0502). Other propensity score matched analyses in patients with resectable disease by Cloyd et al and in patients with borderline resectable disease by Nagakawa et al, respectively, did not show the survival benefit of neoadjuvant chemoradiotherapy over neoadjuvant chemotherapy. A randomized controlled trial, the ALLIANCE A021501, is ongoing, which randomizes patients with borderline resectable pancreatic cancer to neoadjuvant FOLFIRINOX or to FOLFIRINOX followed by stereotactic body radiotherapy. This may contribute new evidence to clarify the impact of neoadjuvant radiation.
We reviewed the currently available evidence for adjuvant and neoadjuvant therapy in patients with pancreatic cancer. From gemcitabine to mFOLFIRINOX, there are several options for patients who have recovered from surgery. Recent studies including randomized controlled trials increasingly support the use of neoadjuvant therapy for patients who are considered surgical candidates at diagnosis. However, taking into account a variety of neoadjuvant regimens and different definitions of resectability status, data from each study should be interpreted with caution. Our knowledge is still limited about the preferred regimen, treatment duration, and patient selection. Furthermore, as described in the NCCN guidelines, data showing the role of adjuvant therapy after surgery for patients who received neoadjuvant therapy are lacking, which will vary based on the response to neoadjuvant therapy and should be answered in the future studies.
Conflicts of interest
The authors declare no conflicts of interest.
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