Abstract
Aim: To determine the impact of postoperative chemoradiation (POCR) on overall survival (OS) after resection of pancreatic adenocarcinoma (PAC) in elderly (≥75 years) patients. Materials and Methods: A multi-center retrospective review of 1248 patients who underwent complete resection with macroscopically negative margins (R0-1) for invasive PAC was performed. Exclusion criteria included age <75 years, metastatic or unresectable disease at surgery, macroscopic residual disease (R2), treatment with intraoperative radiotherapy (IORT) and postoperative death. Results: A total of 98 patients were included in the analysis (males=39.8%, females=60.2%; R1 resections=33.7%; pN1=61.2%); 63 patients received POCR and 26 patients received adjuvant chemotherapy alone. The median follow-up was 25.6 months. The mean age for the entire cohort of patients was 78.1±2.9 (SD) years. No differences were observed between patients receiving or not receiving POCR in terms of age (p=0.081), tumor diameter (p=0.412), rate of R1 resection (p=0.331) and incidence of lymph node-positive disease (p=0.078). The only factor predicting an improved OS was POCR. The median OS was 69.0 months in patients treated by POCR and 23.0 months in patients treated without POCR (p=0.008). Even by Cox multivariate analysis, the only significant predictor of OS was POCR (hazard ratio=0.449; 95% confidence interval=0.212-0.950; p=0.036). Conclusion: The study represents the first comparative approach on POCR in elderly patients after resection of PAC. OS was higher in patients who received POCR. Further analyses are warranted to evaluate the toxicity rate/grade and the impact of POCR on patient quality of life.
Pancreatic adenocarcinoma represents the fourth cause of death from cancer in Western countries. Surgical resection remains the only chance of cure, but only a minority of tumors are potentially resectable at diagnosis. Furthermore, even in resectable patients, treatment outcomes remain relatively poor despite complete resection. The cure rates have been modestly improved by the use of adjuvant therapies.
The majority of patients with pancreatic cancer are over the age of 65 years. But this age group is under-represented within clinical trials, and it is unknown whether older patients achieve results similar to younger ones in terms of survival and treatment tolerance. In addition, there exist no clinical trials dedicated to the elderly (1).
In particular, limited data are available on the safety and efficacy of radical pancreatectomy (RP) in elderly patients. It has been observed that there is increased incidence of postoperative mortality and pneumonia after RP among all elderly patients 75 years of age or more, as well as an increased incidence of postoperative complications among patients aged 80 years or more (2). More specifically, these patients have an increased risk of postoperative pancreatic fistula (3). However, it has even been observed that most elderly adults with pancreatic cancer survive longer than one year after RP and more than one third survive longer than two years (4). Hence, even if the rate of complications is increased, it is considered acceptable and it is therefore justified to offer RP to elderly patients who do not have significant comorbidities.
With regard to adjuvant chemotherapy, there are few data on the elderly population. Elderly patients are under-represented in phase III clinical trials, and as a consequence, the efficacy of adjuvant chemotherapy in older patients with pancreatic cancer is not clear (5). Maréchal and colleagues (1) observed that we can only reasonably argue that selected elderly patients with PAC can benefit from curative surgery and postoperative chemotherapy.
Postoperative chemoradiation (POCR), usually associated with adjuvant chemotherapy, is another option for therapy after RP. Although this treatment's role is still debated, several studies have documented its efficacy in improving the prognosis of resected patients. The major randomized trials on POCR did exclude elderly patients. However, the population of older patients seems to be under-represented. In the Gastrointestinal Tumor Study Group GITSG study the median age of patients undergoing POCR was 64 years, with 41% of patients enrolled in the study less than 60 years of age (6, 7). In the European Organization for Research and Treatment of Cancer study the median age in patients undergoing POCR was 59 years (8, 9). Finally, in the European Study Group for Pancreatic Cancer study, the median age was 61 years, with an interquartile range of 54-67 years (10, 11).
Furthermore, only a few retrospective single-institution studies have been published on the results of POCR in elderly patients (12, 13). Accordingly, the purpose of this analysis was to evaluate the impact of POCR on the survival of a population of elderly patients from several Institutions previously treated with RP.
Materials and Methods
Study design and participants. Clinical data (N=1248) from nine different Institutions (Baltimore, Rochester, Montpellier, Madrid, Salzburg, Verona, Campobasso, Milan, and Rome) were pooled for this analysis on an individual patient basis (14). Patients were treated between 1995 and 2008. The following variables were analyzed: age, gender, tumor location (head, body, tail), tumor grade (1-4), microscopically involved surgical margins (no/yes), pathological tumor stage, pathological nodal stage, adjuvant chemotherapy and POCR. Overall survival was the primary objective of the analysis and was calculated from the date of diagnosis. The following exclusion criteria were used: death within 60 days of surgery, neoadjuvant treatment, metastatic disease (M1), different diagnoses other than ductal adenocarcinomas (i.e. ampullary and periampullary tumors, cholangio-carcinoma, duodenal cancer, islet cell tumor and mucinous cystoadenocarcinoma), patients treated with intraoperative radiation therapy (IORT) or experimental pancreatic cancer vaccine therapy, missing data on pathological tumor stage or nodal status. By excluding ineligible patients and patients with missing survival data, 955 patients remained as the reference database. Of the remaining patients, 98 aged 75 years or more were selected for this analysis (Figure 1).
Adjuvant chemoradiation. The details of POCR have been described in detail elsewhere (15-19). In brief, adjuvant external-beam RT was delivered with linear accelerators using multiple-field techniques, with a median RT dose of 50.4 Gy and daily fraction of 1.8 Gy. All patients received a continuous course of radiation therapy without a planned break. Concurrent chemotherapy was based on 5-fluorouracil or capecitabine in most centers; gemcitabine was used in two centers and tegafur in one. Adjuvant chemotherapy was gemcitabine-based in most centers.
Statistical analysis. Statistical analysis was performed with SYSTAT, version 11.0 (SPSS, Chicago, IL, USA). Comparison of means was performed using a t-test for two independent samples. Actuarial survival was calculated using the Kaplan–Meier method (20) and comparisons between survival curves were performed using the log-rank test (21). Multivariate analyses were performed including factors with p<0.1 on univariate (log-rank) analysis, using Cox proportional hazard modeling (22).
Results
Patients' characteristics. The median follow-up time for patients overall was 25.6 months. Demographic data for patients are shown in Table I. The median age for the entire cohort of patients was 78.1±2.9 (SD) years. No differences between patients receiving or not adjuvant chemoradiation were observed in terms of age (78.4±2.9 years versus 77.4±2.8 years; p=0.081), tumor diameter (2.3±0.6 cm versus 2.7±1.2 cm; p=0.412), rate of R1 resection (37.3% versus 31.4%; p=0.331) and incidence of lymph node-positive disease (74.3% versus 54.9%; p= 0.078).
Flow-chart of patient selection.
Overall survival of 98 patients with R0-1 resection who received (median survival=69.0 months) or did not receive (median survival=24.0 months; p=0.008) adjuvant chemoradiation.
Overall survival. Table II shows the results of the univariate analysis. The only factor predicting for better overall survival was POCR. The median OS was 69.0 months in patients treated by POCR and 23.0 months in patients treated without POCR (p=0.008) (Figure 2). Table III shows the results of the multivariate Cox analysis. Even by Cox analysis, the only significant predictor of better overall survival was POCR [hazard ratio (HR)=0.449; 95% confidence interval (CI)=0.212-0.950; p=0.036].
Characteristics of the patient cohort.
Discussion
Pancreatic ductal adenocarcinoma is a tumor with poor prognosis that frequently affects elderly patients. However, there exists only limited evidence in the literature on the effect of the treatments currently available for this sub-group of patients. In particular, only few studies analyzed the results of RP in elderly patients, showing an increased but acceptable rate of complications (2, 4) and a median survival similar to that of younger patients (3).
Univariate analysis including five year overall survival (OS), median survival time and log-rank p-value.
The evidence for adjuvant chemotherapy is even more limited than that on RP. Maréchal and colleagues noted that retrospective studies performed in the non-resectable setting provide some understanding on outcomes in older patients with pancreatic adenocarcinoma. They concluded that selected elderly patients with pancreatic adenocarcinoma can benefit from curative surgery and postoperative chemotherapy as do their younger counterparts, without a significant increase in morbidity and mortality (1).
Nagrial and colleagues assessed a community cohort of 439 patients with a diagnosis of pancreatic ductal adenocarcinoma who underwent operative resection. Overall only 47% of patients received adjuvant therapy. Older patients (aged >70 years) were less likely to receive adjuvant chemotherapy (51.5% vs. 29.8%; p<0.0001) and had a particularly poor outcome when adjuvant chemotherapy was not delivered (median survival=13.1 months; HR=1.89, 95% CI=1.27-2.78, p=0.002). They concluded that increased use of adjuvant therapy in older individuals should be encouraged as they constitute a large proportion of patients with pancreatic cancer (5).
Multivariate Cox analysis. Variables are ranked according to their p-value in the Cox analysis. Hazard ratios (HR) with their confidence interval (CI) are reported.
With regard to POCR, the impact on survival outcome in the elderly population was assessed in only a few retrospective single-Institution studies in the literature (12, 13). Therefore, we analyzed our multi-institutional database to evaluate the role of POCR in elderly patients. This multicenter retrospective study showed a significant improvement of overall survival on treatment with POCR as compared to adjuvant chemotherapy alone (p=0.008), which was confirmed by multivariate analysis.
This analysis presents obvious limitations. First of all, this is a retrospective analysis. In particular, there exists no information on patient selection criteria for adjuvant therapy and we lack data on performance status. Therefore, it is possible that patients receiving POCR presented more favorable prognostic factors or were more healthy. In general, the outcomes observed in patients undergoing POCR seem particularly favorable compared to those reported in the POCR arms of randomized trials. Therefore, although the benefit in terms of survival has been confirmed in the multivariate analysis, it is not possible to determine whether patients who received POCR had more favorable characteristics in terms of prognostic factors not considered in the current analysis (such as Eastern Cooperative Oncology Group Performance Status, comorbidity, and baseline CA19-9 values). Furthermore, the analysis only reported overall survival, since data on disease-specific survival were missing. For this specific age group, the results in terms of cause-specific survival may be different from those of overall survival (23). Another limitation of the analysis is the lack of data on toxicity and patterns of failure. Therefore, it is not possible to assess the effect of POCR on local control and disease-free survival. Similarly, it is not possible to weigh the observed survival advantage taking into account toxicity and impact on quality of life of the recorded advantage in terms of survival. Nevertheless, the results seem to justify further studies on adjuvant treatment in elderly patients with PAC. Such studies should strive to report their results in terms of toxicity and quality of life.
To date, the majority of published studies of adjuvant therapies for patients with pancreatic adenocarcinoma (chemotherapy alone and concurrent radiochemotherapy alone or combined in different times with chemotherapy) have aimed to identify the most effective therapy in the overall population of resected patients. Conversely, future studies on adjuvant therapies should attempt to elucidate methods for individualizing treatment based upon patient characteristics (e.g. age and comorbidities); tumor-related variables, such as residual disease, lymph node status and CA19-9 level before and after surgery, as well as biological markers (e.g. Small Mother Against Decapentaplegic, and Secreted Protein Acidic and Rich in Cysteine). A potentially useful method for drawing such conclusions is the development of predictive methods based upon large patient datasets derived from multiple centers (24).
In conclusion, the results of the present analysis showed a positive effect of POCR on overall survival of elderly patients with PAC. Therefore, this treatment should be considered in selected elderly patients, especially those with high risk of local recurrence.
Footnotes
↵* Both Authors share senior authorship.
↵‡ Current affiliation: Department of Surgery, Università Politecnica delle Marche Polytechnic University, Ancona, Italy;
↵§ Current affiliation: Radiation Oncology Unit, Department of Experimental, Diagnostic and Specialty Medicine-DIMES, University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy.
Conflicts of Interest
No actual or potential conflicts of interest exist regarding this article.
- Received February 28, 2015.
- Revision received March 18, 2015.
- Accepted March 20, 2015.
- Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
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