Adjuvant chemoradiation in pancreatic cancer: impact of radiotherapy dose on survival

Pancreatic carcinoma is projected to become the second leading cause of cancer mortality by 2030 with a 5-year overall survival (OS) rate around 7% [1]. At diagnosis, around 20% of pancreatic cancer patients present with a resectable tumor, 30% with a locally advanced tumor and 50% with metastatic disease [2]. Radical surgery with tumor-free margins is the only treatment with the potential to achieve long-term survival [3].

Nevertheless, both local or distant relapses commonly affect patients’ survival [4]. Therefore, local and systemic adjuvant treatments have been proposed to improve OS. Many clinical trials evaluated the efficacy of adjuvant chemo-radiotherapy (CRT) and chemotherapy (CT).

The efficacy of CT has been demonstrated [5‐7] but the potential impact of CRT in the adjuvant setting remains controversial. In fact, an improved OS after postoperative CRT was described in several reports including: randomized trials as the Gastrointestinal Tumor Study group (GITSG) [8, 9] and European Organization for Research and Treatment of Cancer (EORTC) [10, 11] trials, single center analyses [12‐14], meta-analyses [15] or pooled analyses [16, 17], and tumor registry studies [18‐22].

On the other hand, the European Study Group for Pancreatic Cancer-1 (ESPAC-1) trial reported negative results after adjuvant CRT [5, 23, 24]. Characteristic of this study was the prescription of a relatively low dose of radiotherapy (RT) (40 Gy with split course regimen) similar to the previous GITSG [8, 9] and EORTC [10, 11] trials. It could be hypothesized that this dose was ineffective in improving local control (LC) of the disease and ultimately OS as suggested by some studies [25]. In fact, in the GITSG study, the incidence of local recurrence was 33% in patients who underwent surgery alone and 49% in patients undergoing adjuvant CRT and CT [9]. However, only few studies evaluated the impact of postoperative CRT dose on clinical outcome [25, 26].

Our previous pooled analysis confirmed the positive impact of adjuvant CRT on OS [27]. Therefore, on the basis of the above considerations, a secondary analysis of that study was performed in order to assess the impact of CRT dose on clinical outcome in terms of OS. The purpose of this paper is to report the results of this secondary analysis.

Median follow-up time was 35 months (range: 3–120 months). The median age for the entire cohort of 514 patients was 63 years (range: 29–85 years). No differences between patients receiving different RT dose (< 45 Gy, ≥ 45 and < 50 Gy, ≥ 50 and < 55 Gy, ≥ 55 Gy) were observed in terms of median age, mean tumor diameter and tumor site while type of resection (p < 0.001), grading (p < 0.001), rate of R1 resection (p = 0.032), tumor stage (p = 0.006), incidence of lymph nodes involvement (p = 0.001), and adjuvant CT treatment (p < 0.001) were different between the groups. In particular, the cohort of patients who received a dose ≥ 55 Gy differed significantly from the other groups both for more unfavourable prognostic characteristics (higher percentage of patients with positive margins, with tumor diameter ≥ 30 mm, with pT4 and pN+ stage) and for an increased use of adjuvant CT (Table 1). Concurrent CT was based on 5-FU regimen in 71.6% of patients, while 28.4% of patients were treated with different regimens: gemcitabine (14.4%), capecitabine (9.5%), gemcitabine + 5-FU (3.1%) and tegafur (1.4%). All patients who underwent adjuvant CT were treated with gemcitabine.

The main result of our study is that increasing RT doses is significantly associated with an improved OS after resection for PDCA with radical intent. This finding has important clinical consequences as well our study clearly shows that postoperative RT dose higher than 45 Gy should be prescribed due to its association with significantly improved prognosis. In addition, our study raises doubts about the dose (50 Gy) recommended by international guidelines [28] especially for patients presenting negative prognostic factors at diagnosis (e.g., high Ca 19–9 level, R1 margin of resection, larger than 3 cm mass). In fact, our results suggest that higher doses (≥ 55 Gy) should be considered when feasible.

We should admit that the comparison in terms of survival, including only the two groups treated with the highest doses (50–55 Gy and > 55 Gy), showed a statistically significant improvement in the second group at univariate analysis but with only a trend at multivariate analysis. However, it should be noted that the possibility of detecting a statistically significant difference was limited by the presence in the first group of 79/336 (23.5%) patients receiving a dose of 54.0–55.0 Gy and in the second group of 6/80 patients (7.5%) receiving a dose < 56 Gy. In other words, more than 30% of the patients included in this sub-analysis received a dose between 54 and 56 Gy, practically equivalent from the clinical point of view.

CRT is a combined modality treatment option for PDAC in the adjuvant setting. The use of postoperative CRT in resected PDAC was initially founded on the results from the GITSG trial which demonstrated an improved survival in patients treated with adjuvant CRT and CT [8]. The results from this trial were confirmed by the non-random enlargement of the sample size with 30 patients in the postoperative CRT arm [9]. That study received some criticism mostly about its small sample size (n = 51) and low dose of RT delivered with the obsolete approach of a split-course regimen.

The use of a low dose was justified by the fact that in 1973 when the protocol was designed, the criteria for RT quality assurance were not developed and RT was delivered with supervoltage equipment and anterior-posterior/posterior-anterior fields. Unfortunately, although the technological improvement could have allowed the use of higher doses, in subsequent studies the same RT regimen was used [5, 10].

Few analyses were previously published on the impact of dose in the adjuvant CRT of PDAC. In an analysis of patients with PDAC receiving postoperative CRT with 2 different dose levels, Abrams and colleagues did not observe a significantly different survival between patients undergoing lower dose (50.4 Gy: median survival: 14.4 months) and patients receiving a higher dose (57.6 Gy: median survival: 16.9 months) [26]. However, it should be noted that in their analysis only 23 patients with resected PDAC were included.

More recently, Hall and coworkers analyzed 1385 patients with PDAC treated with postoperative RT +/− CT. Patients receiving a dose of 50–55 Gy showed a significantly higher survival compared to patients receiving doses < 40 Gy, 40 to < 50 Gy, and doses > 55 Gy. They concluded that, on the basis of these results, the optimal dose of adjuvant CRT should range between 50 Gy and 55 Gy [25].

The results of our study differ from those of the Hall’s analysis with regard to patients treated with doses > 55 Gy. In fact, the survival of these patients was significantly improved and worsened in our analysis and in that of Hall and colleagues, respectively. The authors of the cited study hypothesized that patients who underwent higher doses were at least in part those with greater suspicion (for example on CT-simulation) of residual macroscopic disease or that lower survival was due to more serious toxic effects after high-dose RT. The reasons for the opposite result we observed may be due to the following reasons: i) our study involved patients treated in a small number of centers (all academic and research centers with extensive experience in the treatment of PDAC) while the analysis of Hall et al. was performed on data from the National Cancer Data Base and only about one third of the patients had been treated in academic/research cancer programs facilities; ii) all patients included in the Hall’s study were treated from 1998 to 2002, while 72.2% of our patients were treated later when the experience in treating PDAC patients with conformal radiotherapy techniques was probably improved.

Moreover, a significant impact of CRT dose on OS was recorded and confirmed by multivariate analysis. From the analysis we excluded patients who had received a dose < 40 Gy. In fact, we hypothesized that the delivery of doses < 40 Gy was likely due to disease progression in the course of CRT.

This study has obvious limitations, in particular the retrospective nature and the lack of data regarding some parameters (Table 1). Moreover, even if the total number of analyzed patients is 514, only 26 patients received a dose < 45 Gy. This low number may explain the lack of difference in survival in some subgroups of patients (Table 3).

How the different disease (higher T and N stage, higher rate of R1 resection, larger tumors) and treatment (increased use of CT) characteristics in the group treated with > 55 Gy influenced the final result of the analysis is not easy to interpret. However, it should be emphasized that in the multivariate analysis, the lymph node involvement was statistically correlated to survival while the same did not happen for adjuvant CT. Therefore, as a whole, it is not possible to state that this subgroup of patients presented more favourable characteristics compared to others.

This result in some way allows us to better interpret the conflicting results of published studies. In fact, in studies showing an improved survival with the use of adjuvant CRT, doses of 50–50.4 Gy were used [13, 14]. In contrast, the randomized EORTC [10] and ESPAC-1 [5] trials showed lack or a negative impact of CRT with a dose of 40 Gy.

The results of this analysis confirm the ineffectiveness of low doses in improving the clinical outcome and justify the use of higher doses of RT in future studies on adjuvant CRT. The use of higher doses seems feasible as suggested by the acceptable toxicity reported in some studies using doses > 50 Gy [30, 31]. Furthermore, with the use of conformal techniques (3D-conformal or intensity modulated RT), it is possible to administer even higher doses or to intensify the treatment with accelerated regimens. For example, in a dose escalation study based on the 3D-conformal technique with a concomitant boost on the tumor bed, a dose of 55 Gy was reached with a slightly accelerated fractionation (2.2 Gy/fraction) and with concurrent capecitabine. Although this regimen is equivalent to a dose of 57.2 Gy in 2 Gy/fraction (α/β ratio: 3) and despite the administration of two cycles of gemcitabine before CRT, no patient showed grade > 2 toxicity [35]. In addition, it was observed that the use of intensity modulated RT allows a reduction of the radiation dose to healthy organs [36] without an increased incidence of local recurrence [37].

However, higher than standard doses should be prescribed with caution in patients previously treated with neoadjuvant or adjuvant multiple-drug CT, being the impact of intensified systemic treatments on tolerance to subsequent CRT not known.

Finally, based on the inefficiency of low CRT dose in the adjuvant setting, the results of randomized trials should not be further considered as those achievable with modern RT. On the contrary, even in the meta-analysis of Liao and colleagues, data from GITSG, EORTC and ESPAC-1 trials were included [38].

In a secondary analysis from a retrospective study of patients who underwent radical pancreatectomy, there was a significant relationship between RT dose and OS. This result should lead to reconsider the role and doses of postoperative CRT at least in some categories of patients with higher risk of local recurrence. In addition, based on the current availability of new and more effective systemic therapies, further studies seem justified in order to define the optimal integrated adjuvant therapies and in particular their best sequence.