Article ID: 25-00013
Purpose:Neoadjuvant pancreatic ductal adenocarcinoma (PDAC) treatment is evolving, and chemoradiotherapy (CRT) is emerging as a promising strategy for neoadjuvant therapy. Given the variability in radiotherapy protocols, this study aimed to evaluate the feasibility and safety of gemcitabine-based neoadjuvant chemoradiotherapy.
Methods:In this single-arm, phase 1 clinical trial, 31 patients with PDAC were enrolled between April 2016 and August 2019. All patients received preoperative gemcitabine-based chemoradiotherapy with adverse events as the primary endpoint. Multichannel radiation was administered at a total dose of 54 Gy in daily fractions of 1.8 Gy (five fractions per week), which represents a novel aspect of this study.
Results:Neoadjuvant therapy was completed in 24 patients, while seven were discontinued due to disease progression. The common adverse events included leukopenia (48.3%), thrombocytopenia (12.9%), and anemia (3.2%). Among the patients who underwent pancreatectomy, the R0 resection rate was 95.8%. Intention-to-treat analysis indicated a 2-year overall survival rate of 49.8% and a 2-year recurrence-free survival rate of 42.4%. High pretreatment CA19-9 levels were identified as predictive factors for overall survival (HR = 28.7, 95% CI:5.00-164.3).
Conclusions:Gemcitabine-based neoadjuvant chemoradiotherapy is a feasible and effective approach for achieving high R0 resection rates in resectable and borderline PDAC.
Despite aggressive treatments, pancreatic cancer exhibits a poor prognosis. It is the fourth leading cause of cancer-related death worldwide1). In recent years, several clinical trials have evaluated the efficacy of neoadjuvant therapy (NAT) for pancreatic ductal adenocarcinoma (PDAC)2-8) and have demonstrated improved outcomes in tumor response, R0 resection rates (complete removal of the tumor), and overall survival compared to those of patients who undergo upfront surgery3,9). This is an evolving field, and research attempts to identify an optimal approach are ongoing. NAT for PDAC involves the administration of chemotherapy and/or radiation therapy before surgical removal of the tumor.
The addition of radiotherapy to NAT, which remains controversial, has been demonstrated to control local tumors. This could shrink the tumor, increase the likelihood of complete surgical resection, and potentially improve the overall patient outcomes. In 2016, we introduced gemcitabine-based chemoradiotherapy (CRT) as a preoperative treatment for pancreatic cancer. Radiotherapy protocols can vary between institutions in terms of dose and, in particular, the target radiation field. In our protocol, the target radiation field covered the primary tumor along with the regional lymph nodes around the celiac and superior mesenteric arteries and the retroperitoneal soft tissue. Therefore, this prospective phase 1 clinical trial was conducted to evaluate the safety of neoadjuvant CRT at our hospital.
We conducted a prospective phase 1 clinical trial to investigate the safety of preoperative gemcitabine-based chemoradiation therapy and subsequent surgery for resectable (R-) and borderline resectable (BR-) PDAC at Fukushima Medical University. This study was prospectively registered in UMIN-CTR (University hospital Medical Information Network - Clinical Trials Registry, protocol number:UMIN000020977) on April 1, 2016. The study protocol was approved by our institutional ethics committee, which is guided by local policy, national law, and the World Medical Association Declaration of Helsinki (approval number: 2669). Informed consent was obtained from all patients and documented in writing.
The patients included in this study underwent radiographic evaluation for tumor staging using multidetector-row computed tomography (MDCT), magnetic resonance imaging with a contrast medium of gadolinium-ethoxybenzyl diethylenetriaminepentaacetic acid (EOB-MRI), and positron emission tomography with 2-deoxy-2-[18F] fluoro-D-glucose (FDG-PET). The extent of tumor involvement in the artery or portal vein was assessed using MDCT with a multiphase contrast-enhanced technique. The resectability of pancreatic tumors was classified based on the anatomical resectability criteria established in a previous study10).
Eligibility criteria for neoadjuvant gemcitabine-based CRTAll patients enrolled in this study met the following eligibility criteria:1) definitive radiographic evidence of a pancreatic tumor that was evaluated as R- or BR- PDAC;2) histopathologically diagnosed PDAC using endoscopic ultrasonographic fine needle aspiration;3) no evidence of distant metastasis;4) no evidence of para-aortic lymph node metastasis;5) no double cancer. In the current study, pre-treatment laparoscopic laparotomy with intra-abdominal cytology was not performed to examine peritoneal dissemination. The exclusion criteria were as follows:1) performance status of grade ≥2, according to the Eastern Cooperative Oncology Group criteria;2) age <18 years;3) inadequate bone marrow reserves as measured by a total white blood cell count of ≤3,500 cells/mm3, hemoglobin level of ≤9.0 g/dL, and a platelet count of ≤100,000 cells/mm3;4) laboratory tests with abnormal data, including aspartate aminotransferase level of >150 U/L (normal<33 U/L), alanine aminotransferase level of >150 U/L (normal <42 U/L), serum total bilirubin level of >2.0 mg/dL (normal <1.2 mg/dL) (after biliary drainage in cases of obstructive jaundice), or a serum creatinine level of >1.2 mg/dL (normal <1.2 mg/dL);5) a significant medical comorbidity due to which neoadjuvant treatment is not considered, such as interstitial lung disease or fibroid lung, active viral infection excluding viral hepatitis, and others;6) severe psychological disorder;7) severe allergy to any drug. In the initial study plan, the number of patients to be enrolled was set at 10;however, this was changed to 31.
Protocol neoadjuvant gemcitabine-based CRT and subsequent surgeryBased on a previous study of gemcitabine at a dose of 1,000 mg/m2 combined with 50 Gy radiation15), the NACRT protocol in this study was modified (details of the NACRT protocol are presented in Figure 1, A and B). Briefly, multichannel radiation was administered at a total radiation dose of 54 Gy, with a daily fraction of 1.8 Gy (5 fractions per week). The target radiation field covered the primary tumor, along with the regional lymph nodes around the celiac and superior mesenteric arteries and the retroperitoneal soft tissue. Patients were administered gemcitabine at a dose of 1,000 mg/m2 on days 1, 8, and 15 of the month;this procedure was repeated for three cycles. When adverse events such as grade 4 or higher neutropenia, thrombocytopenia, or cholangitis occurred, the planned gemcitabine treatment was skipped. After the completion of NACRT, restaging evaluations, including the aforementioned radiological examinations, were performed to evaluate the therapeutic effect of NACRT and determine the indication for surgery. Patients deemed eligible for surgery based on the final evaluation underwent surgery following a 4-week interval after their last chemotherapy treatment. After surgery, an oral anticancer agent combining tegafur (a prodrug of 5-FU), gimeracil, and oteracil (S-1) at a dose of 80 mg/m2/day was administered on days 1-28 of a 42-day cycle for 6 months as adjuvant chemotherapy.
Definition of OutcomesThe primary endpoint was the occurrence of adverse events associated with NACRT. Secondary outcomes were R0 resection rate, postoperative major complication occurrence rate, disease-free survival, and overall survival.
Statistical AnalysisDescriptive statistics were calculated for demographic, clinical, and laboratory characteristics. Continuous variables are reported as the median ± IQR, and the values for different subgroups were compared by using the Mann-Whitney U test or Wilcoxon signed-rank test as appropriate. Categorical variables were expressed as prevalence, and differences in the proportions of different patient groups were compared using Fisher’s exact test. Univariate and multivariate analyses of survival rates were performed using Cox proportional hazards regression analysis with stepwise selection to identify prognostic variables. A variable with P <0.2 on univariable analysis was set for multivariate analysis. P values <0.05 were considered as statistically significant. Stata version 18 (STATA Corp., College Station, TX, USA) was used for all statistical analyses.
Protocol for neoadjuvant gemcitabine-based chemoradiotherapy and subsequent surgery. A) Intravenous administration of gemcitabine (1,000 mg/m2) was initiated on days 1, 8, and 15 during each 4-week cycle. This procedure was repeated for 3 cycles. B) Three-dimensional radiation was administrated at a total radiation dose of 54 Gy with a daily fraction of 1.8Gy, 5 times per week, targeted to the following fields: the primary tumor, the celiac and superior mesenteric artery, and the retroperitoneal soft tissue.
The study enrolled 31 patients between April 2016 and September 2019. The patient characteristics are presented in Table 1. The median age of the entire population was 69 years (interquartile range, 65-76 years), and the proportion of males was 48.4%. Regarding the location of the pancreatic tumor, 24 patients (77.4%) possessed a pancreatic head tumor, and seven patients (22.6%) had a pancreatic body or tail tumor. There were 21 (67.7 %) and 10 (32.3 %) patients with R-PDAC and BR-PDAC), respectively.
Treatment, safety, and clinical outcome of NACRTAll the 31 enrolled patients underwent NACRT. Toxicity was evaluated based on the Common Terminology Criteria for Adverse Events 6.0. The overall toxicities associated with NACRT are summarized in Table 2. Grade 3/4 hematological toxicity was observed in 15 patients (18 episodes). Grade 3 pulsatile thrombocytopenia was observed in 11 patients (41%) and was mildly relieved by the temporary withdrawal of gemcitabine. Two of the 11 patients experienced grade 4 leukopenia, with no lethal infectious complications. During the three months of NACRT, two patients (6.5%) with pancreatic head tumors experienced biliary tract infections due to obstruction of the biliary stent. Although prophylactic proton pump inhibitors were prescribed to all patients to prevent radiation-induced gastric mucosal damage, two patients (6.5%) were diagnosed with gastric ulcers of the gastric antecubital region by evaluating the resected specimen. Twenty patients (64.5%) skipped at least one dose of gemcitabine owing to adverse events during the NACRT treatment period, whereas all other patients completed radiotherapy at a total radiation dose of 54 Gy. Figure 2 presents the clinical outcomes of the 31 patients. A total of 24 patients (77.4%) completed NACRT, whereas seven patients (22.6%) failed NACRT due to liver metastasis (n=6) or peritoneal dissemination (n=1). Tumor resection was performed in 24 patients who underwent NACRT.
Surgical outcomes and pathological findings of the resected specimen to evaluate the effect of NACRT on pancreatic tumorPancreaticoduodenectomy was performed in 17 patients (70.8%), and distal pancreatectomy was performed in six patients (25%). Regarding postoperative outcomes, two cases with major complications (pancreatic fistula) were observed. There were no cases of mortality at 90 days postoperatively in the current study cohort (Table 3).
The histopathological findings of patients who underwent pancreatectomy after NACRT are summarized in Table 4. Of the 24 patients, two patients exhibited positive metastasis in the para-aortic lymph nodes, and one patient was diagnosed with peritoneal dissemination after tumor resection. Pathological examination of the resected specimens revealed that R0 resection was achieved in 23 patients (95.8%).
Prognostic outcomes:results of intention-to-treat analysisThe intention-to-treat analysis demonstrated that the median overall survival (OS) time in the entire cohort was 21.7 months, and the median disease-free survival (DFS) time in patients who underwent surgery was 19.5 months (Figure 3). Among the 24 patients who underwent pancreatectomy, recurrence was observed in 14. The patterns of cancer recurrence are summarized in Table 5. Liver metastasis was the most frequent type of recurrence, occurring in 6 of 14 patients (42.8%). Localized recurrence was observed in only three patients, including one with a residual pancreas and two with a periarterial plexus.
Univariate and multivariate Cox regression analyses using pretreatment variables to identify potential predictors of survival are presented in Table 6. Multivariate analysis indicated that a pretreatment CA19-9 level >1,500 U/L was (P < 0.001) was an independent predictor for cancer survival in the patients who underwent NACRT. Figure 4 presents the impact of CA19-9 pretreatment on prognostic outcomes. Patients with CA19-9 levels exceeding 1,500 U/L prior to NACRT either did not complete preoperative treatment because of disease progression (intraoperative peritoneal dissemination) or experienced early recurrence. Notably, the production of CA19-9 involves the Lewis antigen, and individuals lacking this antigen may exhibit false-negative results, even in the presence of cancer due to the absence of CA19-9 elevation. In such cases, DUPAN-2, another tumor marker for pancreatic cancer, may play a complementary role. As presented in Case 2 of Figure 4, a high DUPAN-2 level had a negative impact on the prognostic outcome.
Baseline characteristic of the study population
Continuous variables are reported as a median and IQR (interquartile range). Abbreviations:CEA, carcinoembryonic antigen;CA19-9, carbohydrate antigen 19-9;ASA, American Society of Anesthesiologists
Adverse events of the neoadjuvant chemoradiotherapy in this study (N=31)
Patient flowchart.
Surgical outcomes in the resected cases
Histopathological findings of resected PDAC
※1;Positive lymph nodes (n=2) and peritoneal dissemination (n=1)
※2;Histological response to the neoadjuvant therapy was graded using a grading system adopted in the 7th Edition of the General Rules for the Study of Pancreatic Cancer (2016, Japan Pancreas Society).
Survival curves for overall survival of the entire cohort and recurrence free survival of the resected cohort.
Recurrence patterns in patients who had pancreatectomy
Recurrence was observed in 14 patients. One patient had synchronous metastasis of liver and dissemination.
Results of univariable and multivariable analysis to identify the predictors for overall survival in the patients with NACRT
Abbreviations:CI, confidence interval;HR, hazard ratio;PT, Prothrombin time;BR, borderline resectable;R, resectable;CA19-9, carbohydrate antigen 19-9;OR, odds ratio
In the multivariable Cox regression analysis, stepwise backward selection using p-value (a cut-off value of 0.2) was performed for variable selection.
Impact of pretreatment CA19-9 levels on oncological prognosis.
The current study investigating the feasibility of neoadjuvant gemcitabine-based CRT revealed that Grade 3 or higher hematological adverse events were observed in 11 patients (35.5%);however, all events resolved after the temporary discontinuation of gemcitabine treatment. The causes of NACRT failure were progression, such as liver metastasis or peritoneal dissemination. Among the 24 patients who completed NACRT, 23 (95.83%) underwent radical surgery. A meta-analysis of 24 studies on neoadjuvant chemoradiotherapy in patients with PDAC reported that the R0 resection rate in the neoadjuvant group ranged from 64% to 100%11).
In the 31 enrolled patients, no adverse events were observed during NACRT. Hematological toxicity was relatively frequent in these patients (Table 2). The adverse effects were ameliorated upon gemcitabine withdrawal, and this was comparable to the results of a previously reported study (the protocol was gemcitabine-based chemoradiation)12). There is concern that preoperative irradiation may cause inflammatory changes around the tumor, making surgery more difficult. Indeed, edematous connective tissue around the pancreas or pancreatic fibrosis (radiation field) was often observed in 17 patients who underwent surgery (70.8%), which was higher than that in patients who underwent upfront surgery (data not shown). However, no severe peripancreatic adhesions precluding continuation of surgery were observed (Table 3). Based on our experience, preoperative radiation therapy may not make surgery more difficult. Regarding short-term postoperative outcomes, postoperative pancreatic fistula grade B was observed in two patients (8.3%) with no mortality, and this was comparable to that of patients who underwent upfront surgery in our department (data not shown). A previous study reported no differences in short-term surgical outcomes between neoadjuvant treatment and upfront surgery13).
The goals of NAT for PDAC can be broadly divided into “local tumor control” and “systemic disease control.” Local tumor control by NAT results in downstaged tumors14), indicating that it reduces the size of the primary tumor and decreases the extent of local invasion. As the pancreas is located in the retroperitoneum and is in close contact with the arteries, portal veins, and/or nerve plexus, adequate surgical margins are difficult to achieve in some cases (potential risk of R1). Downstaging using NAT can increase the likelihood of achieving complete resection with clear surgical margins. In the current study, R0 resection was achieved in 95.83% of patients who underwent subsequent surgery, and this was a significant improvement compared to that of the upfront cohort in our hospital (R0 resection rate was approximately 80%). A meta-analysis demonstrated that neoadjuvant treatment was associated with a higher R0 resection rate than upfront surgery (estimated R0 resection rate:86.8% vs. 66.9%)11). In this study, we considered the therapeutic effects of NACRT on systemic disease control by evaluating the resection rate. Studies reported that the resection rate after NACRT ranged from 71% to 99%5,15). In the current study, seven of 31 patients (22.4%) failed NACRT due to disease progression (resection rate:77,6%), suggesting that the impact of NACRT on systemic disease control needs to be improved. Additionally, frequent recurrence patterns after surgery in our cohort were liver metastasis (40%) or peritoneal dissemination (33.3%), whereas localized recurrence around the pancreas was observed in 21.0% of the patients (Table 6). Together with these findings, the NACRT protocol effectively contributes to local tumor control rather than the early control of micrometastatic disease.
As presented in Figure 4, pretreatment CA19-9 levels exerted a significant impact on oncological prognosis. All patients with CA19-9 or DUPAN-2 levels >1,500 U/L experienced NACRT failure, peritoneal dissemination, or early recurrence within 6 months after surgery. These patients may develop micrometastases at the time of diagnosis. Multivariate Cox regression analysis for OS indicated that pretreatment with CA19-9 levels (>1,500 U/L) was an independent risk factor for OS (HR= 28.7, 95% confidential interval 5.00-164.3). Collectively, the therapeutic effect of NACRT and subsequent surgery in patients with high CA19-9 or DUPAN2 levels is limited. A new criterion for the resectability of pancreatic cancer was proposed, in which biological factors such as CA19-9 or 18-fluorodeoxyglucose positron emission tomography/computed tomography standardized uptake values of the primary tumor were potential surrogate markers for determining resectability and predicting prognosis16). Further studies are warranted to investigate the efficacy of NAT in patients with highly aggressive PDAC.
Implementation of NACRT for R-PDAC is a topic of ongoing research and debate17-19). A randomized controlled trial investigating the efficacy of gemcitabine-based CRT in patients with R- or BR- PDAC showed no significant improvement in OS in the NAT group compared with that in the upfront group (16.0 months vs 14.3 months)5). Considering the heterogeneity of pancreatic cancer, preoperative multidrug chemotherapy such as FOLFIRINOX or GnP therapy is considered promising20). Specific treatment protocols may vary based on individual patient characteristics, tumor stage, patient fitness, and institutional practices.
This study had some limitations, especially when considering the therapeutic effects of NACRT. The number of enrolled patients was small and heterogeneous (eligibility criteria:R- or BR-PDAC). Additionally, this study used a single-arm design, in which the treatment efficacy of NACRT was not fully evaluated. Finally, long-term follow-up data were not available, which limited the assessment of long-term outcomes in patients with pancreatic cancer. Further studies are warranted to evaluate the impact of NACRT, particularly on short-term surgical and prognostic outcomes.
The current study demonstrates the feasibility of using NACRT in our hospital. NAT exhibits a high rate of R0 resection. However, the value of the NACRT protocol is limited to patients with aggressive PDAC (patients with high levels of pretreatment CA19-9). A preoperative treatment regimen involving intensive chemotherapy should be considered to control distant metastases.
DFS, disease-free survival
EOB-MRI, magnetic resonance imaging with gadolinium-ethoxybenzyl diethylenetriamine pentaacetic acid contrast medium.
FDG-PET, positron emission tomography with 2-deoxy-2-[18F] fluoro-D-glucose
MDCT, multidetector-row computed tomography
NAT, neoadjuvant therapy
NACRT, neoadjuvant chemoratiotherapy
OS, overall survival
PDAC, pancreatic ductal adenocarcinoma
In regard to ethical approval and consent to participate, ethical approval and patient consent were obtained and documented in writing.
Availability of data and materials:The datasets used and/or analyzed in the current study are available from the corresponding author upon reasonable request.
Competing interests:The authors declare no conflicts of interest pertinent to this manuscript.
Funding:The authors received no sources of support for this study.
Author’s contributions:
NS, AK, and SM designed the study, its main conceptual ideas, and proof outline. NS, TI, YK, JH, MM, ST, HC, TA, AK, and TK collected data. NS, AK, and SM helped interpret the results and drafted the manuscript. SM supervised the project. NS and AK prepared the manuscript. All the authors have read and approved the final version of the manuscript.
Acknowledgements:Not applicable
