A total of 243417 patients with pancreatic malignancy were identified from the SEER-Medicare data for the years of 1975–2016. Of these, 7864 patients did not have survival data, and 43722 patients whose survival time was 0 month, thus excluded from our analysis. A total of 115371 patients did not undergo surgery, and in 46211 patients, surgical data were not available, thus these were also eliminated. Lastly, 30249 patients met the inclusion criteria and were included in our study. The selection of patients was shown in Figure s1.
3.1 Baseline characteristics of patients.
Of the 30249 patients included in this study, 21295 were in the surgery group (S group), and 8954 were in the combined surgery and radiotherapy group (S + R group). The demographics of the two groups were shown in Table S1.
Patients in the S group were significantly older and more likely to be female than the S + R group. There were more tumors located at pancreatic body and tail in the S group whereas a higher number of pancreatic head tumors were found in the S + R group. Most histological types of adenocarcinoma, carcinoma, and infiltrating duct carcinoma were identified in the S + R group, while there were more neuroendocrine neoplasms recorded in the S group. Patients with local-stage (AJCC 7th stage I, T0-2, N0, M0) disease underwent local excision (including lymph node biopsy) in the S group and patients in the S + R group were mostly with regional-stage (AJCC 7th stage II, T 3–4, N1) and received regional surgery as well as chemotherapy. There were no significant differences in follow time and histologic grade between the 2 groups. More patients were still alive in the S group at the last follow-up.
3.2 Analysis of survival and risk factor
The overall median survival of all patients was 23 months, with the 1, 3, 5-year survival rate of 49%, 32%, and 25% respectively. The median survivals in the S and S + R group were 24 and 21 months respectively, as demonstrated in Fig. 1a. The 1, 2, 3, and 5-year overall survival (OS) rates in the S group were 68%, 49%, 40%, and 31% respectively, while the 1, 2, 3, 5-year survival rates in the S + R group were 75%, 45%, 30%, and 20% respectively, for which the differences in the two groups were statistically significance (p < 0.001), given that the 1-year OS appeared superior in the R + S group whereas the 2,3,5-year OSs were better in the S group, as demonstrated in Fig. 1b.
The univariate and multivariate analysis of the entire cohort showed that factors including age, gender, diagnosis year, primary site, ICD-0-3 classification, summary stage, AJCC 7th stage, T, N, M, surgery primary tumor site (surgery T), surgery regional lymph node (surgery N), additional radiotherapy and chemotherapy were related to OS, as shown in TableS2. Factors such as patients in the R + S group (HR 0.89, 95%CI: 0.86–0.92), additional chemotherapy (HR 0.75, 95%CI: 0.72–0.77), diagnosis year between 1999–2006 (HR 0.88, 95%CI: 0.80–0.98) and 2007–2016 (HR 0.80, 95%CI: 0.72–0.89), pancreatic duct tumor (HR 0.82, 95%CI: 0.73–0.92), neuroendocrine neoplasms (HR 0.16, 95%CI: 0.15–0.18), mesenchymal tumor (HR 0.42, 95%CI: 0.32–0.55), mucinous adenocarcinoma (HR 0.63, 95%CI: 0.59–0.68), carcinoma (HR 0.49, 95%CI: 0.43–0.55), and other histologic type (HR 0.60, 95%CI: 0.56–0.64), and number of dissected lymph node with 1–3 (HR 0.89, 95%CI: 0.83–0.97), and more than 4 (HR 0.78, 95%CI: 0.73–0.83) were associated with lower risk of mortality. On the other hand, factors as independent predictors of higher mortality were age at 20–44 (HR 5.46, 95%CI: 2.82–10.56), 45–64 (HR 7.46, 95%CI: 3.86–14.39), 65–84 (HR 9.28, 95%CI: 4.81–17.9), ≥ 85 (HR 11.86, 95%CI: 6.11–23.03), tumor overlapping lesion of pancreas (HR 1.1,95%CI: 1.02–1.18), adenosquamous carcinoma and squamous (HR 1.12, 95%CI: 0.99–1.27), regional invasion (HR 2.15, 95%CI: 2.03–2.27), distant involvement (HR 3.66, 95%CI: 3.42–3.91), T2 (HR 1.51, 95%CI: 1.33–1.73), T3 (HR 1.69, 95%CI: 1.47–1.96), T4 (HR 1.60, 95%CI: 1.23–2.09), N1 (HR 1.49, 95%CI: 1.41–1.57) and total pancreatectomy (HR 1.14, 95%CI: 1.08–1.21).
3.3 Stratification analysis by subgroup population
Our analysis showed that the median survival and OS of patients in the S group were better than the S + R group (p < 0.001), and additional radiotherapy was a reverse risk factor for prognosis. To investigate the specific patient population that benefited from the radiotherapy, stratified analyses of prognosis in different subgroups were performed. The median survival and OS between the two groups were significantly different in the subcategories, as shown in Table S3. First, the median survivals based on histologic types classified by adenocarcinoma/carcinoma, infiltrating duct carcinoma, adenosquamous carcinoma, and squamous in the S group and S + R group were 15 (95%CI: 15–16) vs 21 (95%CI: 20–21) months (p < 0.0001), 17 (95% CI: 16–18) vs 21 (95%CI: 21–22) months (p < 0.0001), 10 (95% CI: 9–13) VS 18 (95%CI: 14–26) months (p < 0.0001), respectively, as demonstrated in Fig. 2a-2c. Second, patients with the pancreatic head (21 months, 95%CI 21–22) and duct tumor (28 months, 95%CI 25–40) had better survival prognosis in the S + R group, compared with 19 (95%CI 18–19) months (p = 0.0003) and 18 (95%CI: 15–24) months (p < 0.0001) in the S group, respectively, as shown in Fig. 2d,TableS3.However, patients with pancreatic body/tail tumor (56 months,95%CI 51–61) were not survival benefit from adjuvant radiotherapy (22 months, 95% CI 21–24) (p < 0.0001), as seen in Fig. 2e.Last, specific tumor stages demonstrated variable benefits to radiotherapy. Patients with regional invasion were the main beneficiaries, as shown in Fig. 2c. Also, patients staged by AJCC 7th II and III had median survivals of 26 (95%CI: 24–27) and 21 (95%CI: 19–25) months in the S + R group respectively, which were significantly better when compared with 22 (95%CI: 21–22) (p < 0.0001) and (95%CI: 13–16) 14 months (p < 0.0001) in the S group (Fig. 2g,2h). The median survival of T3, T4, N1 in the S + R and S group were 25 (95%CI: 24–26) vs 20 (95%CI: 19–21) months (p < 0.0001), 21 (95%CI: 19–24) vs 13 (95%CI: 12–16) months (p < 0.0001), and 24 (95%CI: 22–25) vs 18 (95%CI: 18–19) months (p < 0.0001), respectively, as shown in Fig. 2i, 2j, and 2 k. Furthermore, the modality of resection as well as chemotherapy had induced variability in patients benefited from radiotherapy. In this instance, patients who underwent a total pancreatectomy and received radiotherapy had a better survival (20 months, 95%CI: 19–21) than those without (19 months, 95%CI: 18–21) (p = 0.016), as shown in Fig. 2f, while the addition of chemotherapy conferred to significantly improved survival at 22 (95%CI: 21–23) vs 21 (95%CI: 20–22) months (p = 0.002), as demonstrated in Fig. 2l. On the other hand, there was no difference in the survival in the subset analyses of factors including the number of removed lymph nodes, histologic grade, age, and race, as shown in Table S3.
3.4 Interaction analyses for Subgroups and sub-stratification
The stratified analysis showed that patients with the pancreatic body and tail tumors did not benefit from additional radiotherapy, but the subpopulations with specific histologic behavior, stage, and surgical approaches benefited from additional radiotherapy. Therefore, we next investigated whether the additional radiotherapy to survival benefits in the S + R group would be observed at different primary site combined with other features, as shown in TableS4, In this instance, patients with pancreatic head cancer, regional pancreatectomy (22 months, 95%CI: 21–22 vs 19 months, 95%CI: 18–20, p < 0.0001), and the number of lymph node excision of more than 4 (23 months, 95%CI: 22–24 vs 20 months, 95%CI: 19–21, p < 0.0001) derived survival benefits to additional radiotherapy, as shown in Fig. 3a and 3b. On the other hand, patients with pancreatic body/tail histologic classified by adenocarcinoma/carcinoma (21 months, 95%CI: 19–23 vs 15 months, 95%CI: 14–17, P < 0.0001) and infiltrating duct carcinoma (22 months, 95%CI: 20–26 vs 17 months, 95%CI: 16 − 10, P < 0.0001), T4 stage (24 months, 95%CI: 17–34 vs 12 months, 95% CI: 9–13, P = 0.027), III stage (24 months, 95%CI: 18–34 vs 12 months, 95% CI: 9–18, P = 0.018) were identified as highly selection groups that benefited from additional radiotherapy, as shown in Fig. 3c-3 f. Unexpectedly, patients with staged N1 disease (pancreatic body/tail) had no survival benefit from additional radiotherapy. Moreover, more patients with pancreatic head cancer appeared to have a significantly better survival outcome.
3.5 Interaction analyses of the primary site combined histologic subgroup
To further investigate for factors in patients with pancreatic body and tail malignancies that benefited from additional radiotherapy, the three-factor combination among histologic type, primary site, and other clinicopathologic features were additionally refined. In this sub-stratified evaluation, other tumor sites and histologic behavior were excluded due to small sample size, as well as definitive survival benefits from surgery alone and reverse risk for survival, as shown in TableS2 and TableS4. Except for patients with stage T1 disease and infiltrating duct carcinomas, almost all patients with pancreatic head cancer had an improved survival following additional radiotherapy, as demonstrated in TableS5. Unexpectedly, patients with AJCC 7th stage I disease with adenocarcinoma/carcinoma and infiltrating duct carcinoma in both pancreatic heads (21 months, 95%CI: 20–22 vs 15 months, 95%CI: 15–16, p < 0.0001) and body/tail (21 months, 95%CI: 19–23 vs 15 months, 95%CI: 14–17, p < 0.0001) had improved survival prognosis with additional radiotherapy, as shown Fig. 4a-4d. Similar survival benefit from additional radiotherapy was also observed in patients with stage T2 adenocarcinoma of the pancreatic head (29 months, 95%CI: 22–38 vs 20 months, 95%CI: 17–25, p < 0.05), as shown in Fig. 4e. Almost all patients with pancreatic body/tail adenosquamous carcinoma/squamous had no survival benefit from additional radiotherapy, as shown in TableS5. However, a higher number of patients with pancreatic body/tail cancer of adenocarcinoma/carcinoma in staged T3, N1, additional chemotherapy, and any number of lymphadenectomies showed better survival when received additional radiotherapy, as seen in TableS5, Fig. 4f-4i. From here, a further sub-stratified analysis was not performed due to the small sample size.
3.6 The sequence of surgery and radiotherapy and survival, radio source
Following the identification of a specific patient population that benefited from the additional radiotherapy in addition to surgery, the next concern involving the sequence between surgery and radiotherapy was addressed, as demonstrated in TableS6. A total of 7664 and 1099 patients received adjuvant and neoadjuvant radiotherapy respectively. The median survival was 21 months (95%CI: 20–22) vs 25 months (95%CI: 23–27), while the 1, 3, and 5-year OSs were 74%, 29%, and 20% vs 81%, 35%, and 20% in the adjuvant and neoadjuvant populations respectively, for which the differences were statistically significant (p = 0.001), as shown in Fig. 5a. There were 76 patients that received radiotherapy both before and after surgery, with the median survival of 26 months (95%CI: 20–32) and the 1, 3, and 5-year OS of 85%, 32%, and 19% respectively, which were significantly better than those having either radiotherapy before or after surgery only (p = 0.002), as shown in Fig. 5b. Last, a small proportion of patients had intraoperative radiotherapy with or without further adjuvant radiotherapy, for which the survival difference between these two subgroups was not statistically significant (p = 0.588), as shown in Fig. 5c.