Using a population-based dataset, we observed a modest improvement in overall survival with adjuvant therapy for surgically-resected pancreatic cancer that persisted after controlling for other factors influencing outcomes. While the current status of adjuvant therapy following resection of pancreatic cancer lacks a consensus, the five previous studies have demonstrated a consistent, modest survival benefit.3
A 7 month prolongation of median survival was observed in the GITSG trial of 5-FU-based chemoradiation17
; while a more modest 2 month prolongation was observed in the CONKO trial of adjuvant gemcitabine.21
Despite over twenty years of clinical trials in the adjuvant therapy of pancreatic adenocarcinoma, only 1256 patients have been enrolled in these randomized trials which has been insufficient to allow the identification of patients subgroups who are more or less likely to benefit from adjuvant treatment strategies.18, 21-24
It is interesting to note that despite these trial data, up to one-half of patients in the latter time period did not receive therapy; whether this is due to referral patterns, changing reimbursement, or emerging pessimism of the disease is unclear.
Unlike the majority of adjuvant trials in other common malignancies (i.e. lung, colon and breast), the clinical trials of adjuvant therapy in pancreatic cancer have grouped together patients with Stage I-III disease with variable stratification of factors known to affect prognosis (e.g. lymph node status and histologic grade). Picozzi et al. have reported careful analysis of the reported trials of adjuvant therapy and noted variations among the trials that have confounded the interpretation of data.3
The GITSG trial had no stratification criteria, and did not report node positivity or tumor grade in the patient demographics.18
More recent trials such as the CONKO trial included some stratification variables (resection margin, T-stage and N-stage), though histologic grade has not been a stratification criteria in any of the recent major trials despite the impact on outcome that we and others have reported.11,13
The effect of tumor grade is more powerful on survival that tumor size, and may be more significant than lymph node status; we observed that patients with a well-differentiated tumor had a mean survival of 32 months while those with poorly differentiated tumors had a mean survival of just 7 months (). In the EORTC study, there was a 9% difference in the incidence of poorly differentiated tumors between the treatment arms21
while the ESPAC-1 study had an 8% difference in the incidence of poorly differentiated tumors among the treatment arms.23
Therefore, differences in established prognostic variables among treatment arms may have confounded the outcomes of past trials. Our data suggests that tumor grade has a greater impact in accounting for the differences in outcome from adjuvant therapy than tumor size or lymph node status, and should be considered as a stratification variable in future clinical trials of adjuvant therapy.
Some of the improvements in survival in the adjuvant therapy group may be accounted for by selection bias. Those patients who received adjuvant therapy were slightly younger and thus may have had fewer comorbidities as well as recovered from the procedure with a greater functional reserve allowing them to undergo adjuvant therapy. Similarly, patients receiving adjuvant therapy generally had more advanced/aggressive disease manifest by larger tumors, higher rate of node-positivity, and lower proportion of well-differentiated tumors. Our data does not allow us to investigate specific chemotherapy regimens, although there is an improvement in survival by diagnosis year, which may suggest that newer chemotherapeutic agents (e.g., gemcitabine) may have had a positive impact on disease control and survival. We do not believe that this improvement in survival over time is a consequence of stage migration, as there was no change in the survival over time in patients who received surgery alone.
Additional variables we examined that may impact outcome from surgical treatment as well as adjuvant therapy included age, sex, and ethnicity. Although younger patients who received adjuvant therapy appeared to do poorly, this likely represents a selection bias; a more aggressive approach is generally taken with younger patients as demonstrated by a higher proportion of younger patients receiving adjuvant therapy. Age was therefore not included in our multivariate analysis as opposite effects of adjuvant therapy were seen in older and younger patients and proportional hazards assumptions were not met. Women initially did not appear to have longer survival compared to men on univariate analysis (); however, on multivariate analysis, after accounting for other prognostic features, women overall did slightly better than men (). This may suggest an impact of hormonal factors or other clinicopathologic differences between men and women in this disease.
We did not include race or socioeconomic status in our multivariate analysis as we have previously noted that these are not predictors of survival in our cohort; rather, that they predict stage of disease at diagnosis and receipt of treatment, which are better predictors of survival.11, 25
Furthermore, there was no difference in receipt of adjuvant therapy by socioeconomic groups (). We did note that non-Hispanic white patients under 60 years had markedly worse survival with receipt of adjuvant therapy. Previous studies have suggested that non-Hispanic white patients are more likely to present with earlier stage disease, and more likely to receive treatment (surgical and non-surgical) than African-American or Asian patients11, 25-28
, and our analysis did show that a higher proportion of non-Hispanic white patients under 60 years did receive adjuvant therapy. Whether the decrement in survival seen in the adjuvant treatment group is a product of a selection bias due to earlier presentation of disease in non-Hispanic white patients, increased referrals for surgery, or related to morbidities of the adjuvant therapy itself is unclear. Additionally, there is the possibility of different biologic characteristics of tumors in different racial/ethnic groups which may affect both natural history of disease, and responsiveness to chemotherapeutics.28
In summary, our analysis of a large population-based database demonstrates that adjuvant therapy after curative resection for pancreas cancer benefits specific subgroups of patients - specifically, patients with positive lymph nodes or poorly differentiated tumors. The lack of benefit in “favorable” subgroups (i.e. well differentiated tumors and node-negative disease) is more likely a consequence of the relative lack of efficacy of current treatment regimens. Therefore, future trials of adjuvant treatment regimens should either stratify patients for entry based on known prognostic variables (e.g. tumor grade or lymph node status) or focus on patients with poor prognostic features to allow the identification of therapeutic regimens with activity.