Introduction: Pancreatic cancer (PC) represents an unfavorable prognosis condition, even in patients with resectable disease. The aim of this series was to investigate the role of treatment intensification with adjuvant chemoradiation (CRT) in radically resected PC patients. Methods: Data from PC patients who underwent radical surgery, adjuvant chemotherapy (CT), and CRT throughout a 20-year period were retrospectively collected. Actuarial local control (LC) and the overall survival (OS) were the primary endpoints, with disease-free survival and metastasis-free survival (MFS) representing secondary endpoints. Results: The analysis included 108 PC patients treated with adjuvant CRT and CT from January 2000 to August 2019. Median age was 66 years (range: 40–83), and all patients underwent radical surgical resection with adjuvant CT (88, 81.5%) plus concomitant CRT (101, 93.5%) or radiotherapy alone (7, 6.5%). The median dose delivered to the tumor bed was 50.4 Gy (range: 45–50.6 Gy), while median dose to regional lymphatic drainage stations was 39.6 Gy (range 39.6–45 Gy). Concomitant CT was a gemcitabine-based regimen in the vast majority of patients (87, 80.6%). Median follow-up time was 21 months; the 2- and 5-year LC rates were 75.8% and 59.1%, respectively. Perineural invasion at pathological assessment was found significantly associated with LC (p = 0.028). Median OS was 40 months with 2- and 5-year OS rates of 73.9% and 41.6%, respectively. Conclusions: The outcomes of this series suggest to investigate the possible impact of adding adjuvant CRT to CT in PC patients. Timing and combination of modern CRT with new systemic therapies need to be further investigated to personalize therapy and optimize clinical advantages.

Pancreatic cancer (PC) with 132,600 estimated new diagnoses and 128,000 deaths per year is projecting to become the second leading cause of cancer-related deaths for both genders in 2030 [1, 2]. Radical surgery represents the only potentially curative approach, but only the 20% of patients have resectable disease at diagnosis [3‒5].

Important prognostic information could be assessed on the basis of pathological examination. The definition of margin status, tumor grade, and size; lymphovascular space invasion (LVSI); perineural invasion (PNI); and lymph node involvement have been demonstrated to impact PC resected patients’ prognosis [6‒8].

Even in patients with resectable disease, PC prognosis remains unfavorable with high rates of local and distant recurrences [8, 9]. These disappointing outcomes underline the need of effective adjuvant treatments to improve survival outcomes in patients with resected pancreatic adenocarcinoma.

The role of adjuvant chemotherapy (CT) has been widely assessed in randomized trials, mainly with gemcitabine-based schedules as standard of care [10, 11]. CT treatment intensification trials with more aggressive regimens have also shown good results in terms of overall survival (OS) [12‒14]. The Japan Adjuvant Study Group of Pancreatic Cancer (JASPAC) 01 multicenter phase III trial randomly assigned patients to receive adjuvant CT gemcitabine or S-1. Median OS for S-1 schedule was 46.5 months (37·8–63.7) versus 25.5 months (22·5–29.6) with gemcitabine; also, median relapse-free survival was higher in the S-1 group (22.9 months [17·4–30.6]) than in the gemcitabine group (11.3 months [9·7–13.6]) [12].

The phase III multicenter ESPAC-4 randomized trial investigated the benefit of adding capecitabine to gemcitabine-based monotherapy schedule in radically resected PC. The combination regimen resulted in an increase of median OS with 28.0 (23·5–31.5) months compared to 25.5 (22·7–27.9) months in the monotherapy schedule.

A phase III trial of the Canadian Cancer Trials Group and the Unicancer-GI-PRODIGE Group recently showed the impact of the adjuvant FOLFIRINOX regimen on survival outcomes. The median OS in the FOLFIRINOX group was 54.4 months (41.8 to not reached) and 35.0 months (28.7–43.9) in the gemcitabine group even if with higher incidence (75.9%) of toxic effects [14].

The impact of treatment intensification with adjuvant chemoradiation (CRT) is still under debate with main focus on the combination timing with adjuvant CT. The Gastrointestinal Tumor Study Group (GITSG) randomized trial showed an improved OS in patients undergoing CRT plus adjuvant CT after definitive surgery [15, 16]. Furthermore, the European Organization for Research and Treatment of Cancer (EORTC) designed a randomized trial to confirm the impact of CRT on survival outcomes shown by GITSG trial [17]. Adjuvant radiotherapy in combination with 5-fluorouracil was shown to be safe and well tolerated, even if no significant improvement in median survival was shown. A late reanalysis of the EORTC trial addressed a significant impact of CRT in specific subgroups of patients [18].

The ESPAC-1 trial showed a detrimental effect on survival for patients undergoing CRT compared to CT or surgery alone [19‒21]. Following studies seemed to suggest that the slightly low prescription dose for CRT in the ESPAC-1 study (split course 40 Gy schedule) could affect LC and OS outcomes [22, 23].

In this pattern of uncertainty, also, meta-analysis [24, 25], pooled analysis [26, 27], and single-center analysis [28, 29] have been carried out in order to identify specific subsets of patients with poor prognostic factors in which CRT could have a relevant role. The aim of this analysis was to report our series of radically resected PC managed postoperatively with CRT and adjuvant CT, also to suggest a possible role of postoperative CRT in maximizing adjuvant treatment in poor prognostic factors subsets.

Eligibility Criteria

This is an observational monocentric study aimed to investigate the impact of adjuvant CRT in radically resected PC patients treated at Fondazione Policlinico Universitario A. Gemelli IRCCS. Clinicopathological and outcome data from PC patients, who had undergone primary radical surgery and adjuvant CT plus concomitant chemoradiotherapy from 2000 to 2019, were collected. Inclusion criteria were age ≥18 years, ECOG performance status ≤2, and complete macroscopic resection of histologically proven PC. Exclusion criteria were lack of pathological tumor (pT) and/or nodal stage assessment, neoadjuvant treatment, synchronous or metachronous cancer metastatic disease (M1). The variables collected for analysis were age, sex, tumor location (head, body, tail), tumor grade (1–3), microscopic residual disease (R0/R1), lymphovascular space invasion (LVSI), PNI, pT stage, and pathological nodal stage (pN0/pN+).

Treatment Protocol

Patients included in the analysis underwent radical surgery on primary disease. Adjuvant gemcitabine-, 5-fluorouracil-, or capecitabine-based CRT was delivered, with CT (gemcitabine alone or FOLFIRINOX schedule). The indications for adjuvant CRT were established following multidisciplinary tumor board considering risk factors at pathological examination: tumor stage, presence of positive resection margins (R+), positive lymph nodes (pN+) PNI and LVSI, and high-grade disease.

Clinical target volumes (CTVs) were defined according to pathological examination and clinical preoperative and postoperative contrasted enhanced CT scan. CTV1 included the tumor bed, while CTV2 covered regional lymphatic drainage stations according to national and European guidelines [30, 31].

Patients received 3D-conformal radiation therapy (3D-CRT) or intensity-modulated RT (IMRT) technique-based CRT. The total dose ranged between 45 and 50.6 Gy and was prescribed according to the guidelines of International Commission on Radiation Units Measurements (ICRU) report guidelines 62 and 83 for 3D-CRT and IMRT, respectively.

Endpoints and Analysis of Data

Primary study endpoints were the actuarial local control (LC) and the OS rates; secondary endpoints were the disease-free-survival (DFS) and metastasis-free-survival (MFS) rates. LC was defined as the time from the date of adjuvant CRT and the date of in-field radiotherapy relapse/progression of disease or the last follow-up visit. OS was calculated from the date of diagnosis to death or last follow-up visit. The time from the date of adjuvant CRT and the date of distant failure was considered for MFS, while DFS was considered as the time from the date of adjuvant CRT to LC failure or distant progression.

Actuarial outcomes results were analyzed through the Kaplan-Meier method; log-rank tests were used to evaluate subgroups differences. Prism version 8.31 for macOS software (1994–2019 GraphPad Software, La Jolla California USA, www.graphpad.com) was used to perform statistical analysis.

The analysis enrolled 108 patients with PC treated with adjuvant CRT from January 2000 to August 2019. Median age was 66 years (range: 40–83), and the male-female ratio was 62/46.

All patients underwent radical surgical resection, followed by adjuvant CT (88, 81.5%) plus concomitant CRT (101, 93.5%) or radiotherapy alone (7, 6.5%) on the basis of risk factors at pathological examination. Pathological examination revealed pancreatic ductal adenocarcinoma (PDAC) histology in 107 patients (99.1%) and colloid carcinoma histology in 1 patient (0.9%). Table 1 summarizes patient characteristics. pT stage, according to the 7th edition of the AJCC cancer staging manual [32], was pT3 in the large majority of patients (70, 65%); nodal involvement was found in 61 patients (56.5%), positive surgical margins were found in 31 patients (28.7%), while LVSI and PNI were found in 50 (46.3%) and 52 (48.1%) patients, respectively.

Table 1.

Patients’ characteristics

 Patients’ characteristics
 Patients’ characteristics

All patients completed adjuvant (C-)RT treatment; only 4 patients had major treatment interruption longer than 7 days. The RT technique was 3D-CRT and IMRT in 80 (74.1%) and 28 (25.9%) cases, respectively.

The median dose on CTV2 regional lymphatic drainage stations was 39.6 Gy (range 39.6–45 Gy), while the CTV1 tumor bed received median 50.4 Gy (range: 45–50.6 Gy). Concomitant CT was gemcitabine-based regimen (87, 80.6%), 5-fluorouracil-based (6, 5.6%), or capecitabine-based (5, 4.6%). Table 2 summarizes treatment protocol.

Table 2.

Treatment protocol

 Treatment protocol
 Treatment protocol

With a median follow-up time of 21 months from adjuvant (C-)RT (range; 1–200), the 2- and 5-year LC rates were 75.8% and 59.1%, respectively (Fig. 1). The presence of PNI at pathological examination was found significantly associated with LC (p = 0.028). No significant association of margin status (p = 0.073), nodal status (p = 0.511), or LVSI (p = 0.769) with local recurrence was found (Fig. 2).

Fig. 1.

Kaplan-Meier plot: local control (LC), overall survival (OS), disease-free survival (DFS), and metastasis-free survival (MFS) for the whole population.

Fig. 1.

Kaplan-Meier plot: local control (LC), overall survival (OS), disease-free survival (DFS), and metastasis-free survival (MFS) for the whole population.

Close modal
Fig. 2.

Kaplan-Meier plot: local control (LC) and overall survival (OS) for nodal status (N), margin status (R), lymphovascular space invasion status (LVSI), and perineural invasion status (PNI).

Fig. 2.

Kaplan-Meier plot: local control (LC) and overall survival (OS) for nodal status (N), margin status (R), lymphovascular space invasion status (LVSI), and perineural invasion status (PNI).

Close modal

Median OS was 40 months with 2- and 5-year OS rates of 73.9% and 41.6%, respectively; no significant association with clinicopathological assessment was found. As per secondary endpoints, median DFS was 29 months with 2- and 5-year rates of 54.4% and 35.3%, respectively. The 2- and 5-year rates of MFS were 62.1% and 46.8%, respectively, with a median value of 44 months. Table 3 shows 2- and 5-year LC and OS analysis.

Table 3.

Analysis of 2-year, 5-year, and median actuarial local control (LC) and overall survival (OS) time

 Analysis of 2-year, 5-year, and median actuarial local control (LC) and overall survival (OS) time
 Analysis of 2-year, 5-year, and median actuarial local control (LC) and overall survival (OS) time

Despite the impact of CT adjuvant therapeutic strategies in PC being widely assessed, the role of CRT is still controversial. This study was designed with the aim to report the outcomes of CRT adjuvant treatment intensification in radically resected PC.

The role of CRT in patients with resected PC was first investigated by the GITSG randomized trial [15]. This multicentric prospective trial showed an improvement in terms of OS (mOS: 20 vs. 11 months; p = 0.03) in patients with resected PC undergoing adjuvant CRT compared to surgery alone. Data of GITSG were further confirmed by a sequential enrollment of additional 30 patients treated with adjuvant CRT [16].

Furthermore, the EORTC designed a prospective randomized multicenter trial to evaluate the potential benefit of adjuvant CRT on survival outcomes, compared to observation [17]. Two hundred eighteen patients were randomly assigned to CRT (40 Gy split course with concurrent infusional 5-fluorouracil) plus sequential CT or to observation. No significant improvement in median survival (19 months for observation vs. 24.5 months for CRT) was demonstrated.

However, a late reanalysis of the EORTC trial addressed a significant impact of CRT on 2-year OS (37% CRT vs. 23% observation; p = 0.049) in the cluster of patients with negative-margin resected head PC [18]. The ESPAC-1 trial was also designed to address the choice of appropriate adjuvant therapy for resected PC patients. The trial was structured into four arms in which patients were randomized to CRT alone, CT alone, both CRT and CT, or observation.

The long-term results of the ESPAC-1 trial, with a 47-month median follow-up, showed a survival benefit for adjuvant CT (mOS 20 vs. 16 months; p = 0.011). On the other hand, CRT was found to be detrimental with a mOS of 14 months compared to no CRT mOS of 17 months [19‒21].

In the present analysis, survival and locoregional control following adjuvant CRT were found to be interesting; median OS was 40 months with 2- and 5-year OS rates of 73.9% and 41.6%, respectively. Also, LC rates were appealing with 2- and 5-year LC rates of 75.8% and 59.1%, respectively. Furthermore, mOS of the presented series seem to be comparable, and even slightly superior, to outcomes presented in series of patients treated with exclusive adjuvant CT, addressing a potential role of CRT in adjuvant setting [10, 12, 13].

As far as radiotherapy schedule is concerned, both GITSG EORTC and ESPAC-1 trials were designed to deliver a split course 40 Gy RT. Controversial results of the previous mentioned trials were address to the low-dose RT schedule delivered and received criticism from authors who further analyzed the impact of dose escalation on OS [22, 23].

Hall et al. [22] compared survival outcomes of PC cancer patients treated with different dose levels of adjuvant CRT. The dose level between 50 and 55 Gy was shown to have led to higher survival rates (mOS 23 months) as compared to dose levels of <40 Gy, 40–55 Gy, and >55 Gy (mOS 15, 20, 16 months, respectively) [22].

Morganti et al. [23] performed a multicentric pooled analysis of 1,248 resected PC patients treated with adjuvant CRT. A total of 514 patients were addressed for the analysis; four dose-level groups (group 1: <45 Gy, group 2: ≥45 and <50 Gy, group 3: ≥50 and <55 Gy, group 4: ≥55 Gy) were defined. A significant impact of higher dose was demonstrated as group 4 (≥55 Gy) showed a 28-month OS (p = 0.004) compared to the other groups [23].

The outcomes of the presented series seem to confirm good results related to higher CRT doses as the whole population analyzed received at least a 45 Gy maximum dose (with over 90% patient receiving >50.4 Gy maximum dose). Despite this evidence, the maximum dose level was not found to be significantly correlated to OS and LC.

The IMRT technique has been shown to be useful to lower the dose to OAR with good outcomes in terms of LC [33‒35]. In our series, the RT technique was not significantly correlated to LC and OS.

In the definition of best adjuvant treatment approach, the evaluation of clinicopathological risk factors is a challenging task. Several studies showed a significant impact of surgical margins on local recurrence and consequently on survival [7‒9]. Also, the relationship between survival outcomes and other prognostic factors have been analyzed such as pre- and postsurgical Ca 19.9 levels, tumor dimension, positive lymph node status, and LVSI and PNI evidence at pathological examination [7, 27, 36‒41].

In our series, positive surgical margins were found in 31 patients (28.7%), a slightly low incidence rate as compared to ESPAC-4 (60%) and PRODIGE (43%) trials, while being quite higher than JASPAC-01 (13%) and CONKO-001 (17%) trials. In the previously mentioned trials, a variation in the definition of R1 resection was also found. In the JASPAC-01 trial, the definition of R1 resection was based on the microscopic presence of tumor cells on the surface of the resection margin, while our experience as for ESPAC-04, PRODIGE, and CONKO-001 trials reported microscopic evidence of tumor within 1 mm of a resection margin classified as R1 [42, 43].

In our experience, no significant association of margin and nodal status with survival outcomes was found in log-rank test analysis. These results seem to be in contrast with evidence from phase III randomized trial of adjuvant CT [13, 14]. The lower rate of incidence could be addressed as a possible reason for the no significant correlation in our series.

The relationship of OS and LC such as for DFS and MFS with other prognostic risk factors was analyzed, assessing the significant association of LC with the presence of PNI at pathological examination (p = 0.028). As previously mentioned, PNI has been shown to be a relevant independent prognostic factor for both OS and LC; the results of our series seem to strengthen the impact of adjuvant CRT in the presence of high-risk factors [38‒41].

The authors are aware of limits regarding this analysis, such as the small sample size, the retrospective nature of the study, and the related lack of some relevant clinical data. Furthermore, the impact of the study could be strengthened with a more efficacious adjuvant CT schedule such as FOLFIRINOX [14, 44] combined with the modern RT approach [45‒47].

Current guidelines, based on previously reported data, suggested that specific subsets of patients (patients with R+ margins, positive lymph nodes, high postoperative CA 19-9 serum levels) may be more likely to benefit from adjuvant CRT [48, 49]. The opportunity to investigate the role of modern radiotherapy in adjuvant setting has been also underlined. In this pathway, the RTOG is conducting trial 0848 to establish the role of adding CRT to the gemcitabine-based CT schedule (ClinicalTrials.gov NCT01013649). Further studies are also investigating the possible impact of different RT treatment modalities, such as stereotactic body radiation therapy (ClinicalTrials.gov NCT02461836). However, the results of our series seem to suggest a favorable impact of treatment intensification with CRT in association to adjuvant CT, even if the previously mentioned randomized trial has not strongly supported this evidence.

The role of CRT in resectable PC patients following upfront radical surgery and adjuvant CT is still controversial. Our study showed encouraging rates of survival and LC. Median OS of 40 months and the 2- and 5-year survival rates of 73.9% and 41.6%, respectively, suggest that the impact of adding modern adjuvant CRT to CT regimens should be investigated also to identify specific patient subsets that could benefit from this combined modality. Furthermore, pursuing an integrated effective treatment strategy, new prospective studies should be designed to investigate the impact and the best combination of modern CRT with new systemic therapies.

The study was conducted according to the guidelines of the Declaration of Helsinki. Patients enrolled signed an informed consent for data collection and publication, according to the study design requirements and also to department regulation. This study design was approved by internal committee of Fondazione Policlinico Universitario A. Gemelli IRCCS on February 25, 2022.

The authors declare there are not competing interests.

All the authors received no specific funding for this work.

Conception and design: G.C. Mattiucci, L. Salvatore, A.G. Morganti, S. Alfieri, G. Tortora, and V. Valentini. Data collection: AD’Aviero, M. Bensi, F. Castronovo, P. De Franco, B. Di Stefano, and S. Reina. Analysis and interpretation of data: C. Bagalà, F. Cellini, G. Macchia, V. Masiello, R. Menghi, and G. Quero. Manuscript writing: G.C. Mattiucci, A.D’. Aviero, and L. Salvatore. The final manuscript approval: G.C. Mattiucci, L. Salvatore, A.D’. Aviero, C. Bagalà, M. Bensi, F. Castronovo, F. Cellini, G. Macchia, P. De Franco, B. Di Stefano, V. Masiello, R. Menghi, G. Quero, S. Reina, A.G. Morganti, S. Alfieri, G. Tortora, and V. Valentini.

Datasets used and analyzed for this study could be provided upon reasonable request from corresponding author.

Additional Information

Co-first authors: G.C. Mattiucci and L. Salvatore contributed equally to this work.

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