Stereotactic body radiotherapy for locally-advanced unresectable pancreatic cancer—patterns of care and overall survival

Introduction

A majority of non-metastatic pancreatic cancer patients present with unresectable disease, ultimately limiting their 5-year survival to approximately 7% (1). Treatment at this stage usually includes chemotherapy and/or radiation therapy. The role of conventionally fractionated radiotherapy (CFRT) is controversial, however, as several studies have published contradictory results regarding its efficacy when combined with chemotherapy compared to chemotherapy alone (2-4). While a more recent trial, LAP07, did not demonstrate a statistically significant difference in median survival between the two, it did demonstrate that a significant portion of individuals experienced locoregional progression. It also illustrated the potential improvements in quality of life afforded by the addition of radiotherapy through the delayed and/or decreased need for salvage therapies (4). These results not only encourage the need for improved systemic treatments but local therapies as well.

These local therapies, however, must have tolerable toxicity profiles. Many studies have commented on the relatively low potential benefit of CFRT in relation to the increased toxicity (2,5). Thus other modalities of radiation therapy, such as stereotactic body radiation therapy (SBRT), with potentially more favorable toxicity profiles warrant further investigation (6). SBRT allows for a higher biologically equivalent dose to be delivered both with more conformality and in a shorter period of time, potentially widening the therapeutic ratio, increasing patient convenience, and minimizing interruptions in systemic therapy.

Use of SBRT for the treatment of pancreatic cancer is not novel as reports establishing its feasibility were published in the early 2000’s (7-10). However, early adoption was limited by concerns of bowel toxicity due to a lack of awareness of the sensitivity of the adjacent duodenum to high dose per fraction (up to 25 Gy in 1 fraction) and larger margins used in initial experiences (8,10,11). With increased awareness of the importance of duodenal dose and incorporation of fractionation over 3–5 fractions, multiple single-institutional series and prospective phase 1–2 studies have more recently demonstrated favorable local control (LC) and toxicity profiles (6,9,12). Thus, we hypothesize that the utilization of SBRT may be increasing on a national level over more recent years, and therefore used a national database to investigate the patterns of care for the utilization of SBRT and CFRT for patients with locally-advanced unresectable pancreatic cancer, while also evaluating factors predictive of treatment decisions and observing survival outcomes.

Methods

Data source

De-identified data, exempt from IRB review, for patients with non-operative, non-metastatic, histologically confirmed pancreatic adenocarcinoma who either received CFRT (1.5–4.0 Gy per fraction to a dose of ≥45 Gy, n=11,879) or SBRT (6–15 Gy per fraction to a dose of ≥20 Gy, n=474) from 1998 to 2012 was taken from the National Cancer Database (NCDB). The NCDB, which includes greater than 1,500 Commission on Cancer accredited facilities and maintained by the American College of Surgeons and the American Cancer Society, is a national clinically oriented oncologic database encompassing more than 70% of newly diagnosed cancers in the United States (13).

Patient selection

Within the NCDB, 23,941 patients with unresectable, non-metastatic, histologically confirmed pancreatic adenocarcinoma treated with CFRT or SBRT were identified. While the NCDB does not define or describe particular factors leading to a patient’s inability to undergo resection, typical criteria include solid tumor contact with superior mesenteric artery (SMA) or celiac artery >180°, contact with first jejunal SMA branch, aortic involvement, unreconstructible superior mesenteric vein (SMV) due to tumor involvement or occlusion, or contact with the most proximal draining jejunal branch into the SMV (14).

Definition of variables

SBRT was defined as ≥20 Gy at 6–15 Gy/fraction. CFRT was defined as ≥45 Gy at 1.5–4 Gy/fraction. Patients receiving <45 Gy of external beam radiation therapy (EBRT) were excluded to avoid inclusion of patients treated with palliative intent. Metropolitan, urban, and rural areas were defined using the 2013 U.S. Department of Agriculture Rural-Urban Continuum. “Metropolitans” were counties in metropolitan areas, “urban” areas were counties with an urban population of ≥2,500 but not in a metropolitan region, and “rural” areas were counties with an urban population of <2,500. Distance from residence to facility was measured using the treating facilities address and the center of the patient’s zip code. Facility location was defined Northeast, South, Midwest, or West: Northeast: CT, MA, ME, NH, NJ, NY, PA, RI, VT; South: AL, AR, DC, DE, FL, GA, KY, LA, MD, MS, NC, OK, SC, TN, TX, VA, WV; Midwest: IA, IL, IN, KS, MI, MN, MO, ND, NE, OH, SD, WI; West: AZ, AK, CA, CO, ID, HI, MT, NM, NV, OR, UT, WA, WY.

Statistical analysis

Data was analyzed using IBM SPSS, version 24.0 (IBM, Armonk, NY, USA). Univariate analysis was performed on all available factors potentially predictive for receipt of each given treatment modality. Univariate analysis was performed to identify significant factors (P<0.05) to be utilized in multivariable models. Propensity scores indicative of the likelihood of treatment utilization were generated from the significant variables (P<0.05) identified by the multivariable models to account for indication bias (15). A 1:1 nearest neighbor propensity matched cohort was generated. Balance among propensity matched cohorts was confirmed based on year of diagnosis, age, Charlson/Deyo score, race, insurance, residential setting, median income, high school degree, distant from residence to facility, facility type, facility location, case volume, T stage, nodal stage, primary location, chemotherapy, radiotherapy, and radiotherapy dose (all P>0.10).

Parsimonious multivariable survival analysis was performed for both the entire cohort and the propensity-match subset. Cox-Proportional Hazards modelling was used to formulate the multivariate section of survival analysis while log-rank statistics were used for the univariate analysis.

Results

Baseline characteristics

Baseline patient demographics and characteristics are given in Table 1. The median age was 68 years old, with an interquartile range (IQR) of 59–75 years old. Most patients were white (80%), lived in a metropolitan area (78%), had government insurance (59%), and had stage T4 (47%) disease. In the study cohort, patients predominantly received CFRT (97%) and of the total population, 50% received EBRT ≥45 Gy at 1.5–4 Gy/fraction. Eighty-nine percent (89%) also received chemotherapy. Patients treated with SBRT received from 6–12 Gy per fraction over 3–5 fractions for a total dose ranging from 24–40 Gy. The most common dose (Gy) per fraction in patients receiving SBRT were 8 (25.7%), 10 (18.8%), or 12 (16.5%). A majority of patients receiving SBRT were administered a dose of 30 Gy (24.9%), 24 Gy (24.1%), or 36 Gy (14.6%). Three and five were the most common number of fractions that patients receiving SBRT received, 65.2% and 28.5% respectively.

Table 1 Baseline characteristics of all patients with non-metastatic, unresectable pancreatic cancer who received EBRT or SBRT (n=23,941)
Full table

Trends in SBRT utilization

Utilization of SBRT increased from 0.2% to 7.4% (P<0.01) from 1998 to 2012 (Figure 1) with chemotherapy use remaining relatively constant at 89–91%. Patients receiving SBRT were less likely to receive chemotherapy than patients treated with CFRT (70.8% vs. 93.5%, P<0.05). SBRT patients receiving chemotherapy were started on chemotherapy greater than 1 week before radiation therapy (73.2% vs. 28.9%) and were less likely to begin chemotherapy the same week (4.5% vs. 59.9%) compared to patients receiving CFRT and chemotherapy.

Figure 1 Utilization of SBRT and CFRT from 1998 to 2012 for individuals with locally-advanced pancreatic cancer. SBRT, stereotactic body radiotherapy; CFRT, conventionally fractionated radiotherapy.

Factors predictive of preferential SBRT utilization

Preferential use of SBRT over CFRT on multivariate analysis were later year of diagnosis, age ≥75 years, metropolitan residence, increased residential area income, increased distance from facility to residence, northeast facility location, increased facility volume, and no chemotherapy in the initial treatment plan (P<0.05). Exclusive to univariate analysis were lower T stage, smaller tumor size, and no nodal involvement for predicted utilization of SBRT (P<0.05). The factors most predictive of use were diagnosis >2010, facility volume >80 cases, and no prior chemo with 51, 7, and 6 odds ratios, respectively. These results are depicted in Table 2.

Table 2 Comparative utilization of conventionally fractionated EBRT ≥45 Gy vs. SBRT ≥20 Gy at 6–15 Gy/fraction
Full table

Survival outcomes

Median follow-up was 11.0 months (IQR: 7.2–17.0 months) and 18.4 months for survivors (IQR: 8.7–30.9 months). Unadjusted median overall survival (OS) for CFRT was 11.2 vs. 12.6 months for SBRT (P=0.002), depicted in Figure 2. Both the unadjusted multivariable model and the propensity-score matched multivariable model held this statistically significant OS advantage (HR =0.79, 95% CI: 0.70–0.91, P=0.001 and HR =0.79, 95% CI: 0.66–0.94, P=0.010, respectively). Multivariate analysis also showed factors that were associated with improved OS such as diagnosis after 2010, younger age, lower comorbidity score, white race, non-government insurance, higher residential area median income, facility location, facility volume, tumor size <3 cm, nodal stage zero, and receipt of chemotherapy (P<0.05). Results depicted in Table 3.

Figure 2 Unadjusted Kaplan-Meier survival analysis for treated with SBRT. SBRT, stereotactic body radiotherapy; CFRT, conventionally fractionated radiotherapy.

Table 3 Unadjusted multivariable Cox proportional hazard models for OS for patients who received conventionally fractionated EBRT ≥45 Gy or SBRT ≥20 Gy at 6–15 Gy/fraction
Full table

Discussion

In this analysis, we demonstrated an increased utilization of SBRT in patients with locally-advanced unresectable pancreatic cancer along with an associated small absolute OS benefit when compared with CFRT. Patients treated with SBRT saw an approximate OS benefit of 1.4 months compared to their CFRT treated counterparts, a finding consistent in the propensity matched model. Our analysis also exposed several positive prognostic factors for OS such as diagnosis after 2010, lower comorbidity score, younger age, tumor size <3 cm, nodal stage zero, and receipt of chemotherapy (P<0.05). Several of these factors have already been discussed in the literature (3,16-20).

Many groups have quantified OS in their studies evaluating SBRT, but we are unaware of any to date that have directly compared the survival outcomes of SBRT versus CFRT (6,9,12,21,22). The enhanced survival observed in our study might be explained by the high rates of LC (~72% at 1 year) afforded by dose escalation seen with SBRT (20,23,24). Improved LC is perhaps associated with better OS as LC addresses the modest portion of individuals who die specifically from local disease (25,26). It is important to highlight the improvement in OS favoring SBRT seen herein was observed despite a higher proportion of patients in the CFRT group receiving systemic therapy (70.8% vs. 93.5%).

To our knowledge, this report is also the first to utilize a national dataset to describe the increased utilizations of SBRT in treating patients with unresectable pancreatic cancer over the last decade. This trend is likely due to increased provider comfortability with the technique, the lack of clear benefit with CFRT, and the favorable toxicity profile. SBRT potentially offers other therapeutic benefits as well. For example, complications such as biliary or gastric obstruction, significant problems possibly experienced by patients, could be reduced with improved LC (27). Avoiding these complications would reasonably improve quality of life, and in fact, several studies have demonstrated a positive association between LC and quality of life in patients with locally-advanced pancreatic cancer (22,28). SBRT also offers a shorter treatment time which decreases stress on patients and families. Short treatment times also minimize interruptions in systemic therapy—important especially for a disease where the predominant pattern of failure is distant metastasis—and may even increase the ease of future integration of radiation with additional novel systemic therapies currently being explored such as CD40 agonists and immune checkpoint inhibitors (29,30).

We have also been the first to identify factors associated with preferential use of SBRT over CFRT: later year of diagnosis, age ≥75 years, metropolitan residence, increased residential area income, increased facility volume, no chemotherapy in the initial treatment plan, etc. The two strongest predictors in our analysis that pointed toward increased use of SBRT were diagnosis after 2010 and facility case volume. It is not surprising that use of SBRT steadily climbed from 1998 to 2012 as some of the first reports suggesting the benefit of SBRT were not published by the Stanford group until 2004. In fact, a 4.3-fold increase in the odds ratio illustrating increased utilization was seen from 1998–2001 to 2002–2005 alone. As more evidence was compiled depicting the rates of LC and OS, a further increase in the odds ratio was seen in 2006–2009 (27.1), ultimately culminating in a 51.3-fold increase in odds ratio in 2010–2012 compared to 1998–2001 (12,28,31). Increased pancreatic cancer volume at a given facility, specifically >80 cases, also served as a marker for increased preference for SBRT, although it was not as significant as year of diagnosis. Likely, institutions performing more cases, like academic institutions—another predictive factor for SBRT use—were more conformable with this new modality for treating non-operable pancreatic cancer.

Limitations of our study include those prevalent in many studies which extract data from large national databases: incomplete data, ascertainment bias, and coding error. Moreover, we were unable to collect toxicity data, LC, or disease free survival, as this information was not included in the NCDB. Many studies previously mentioned have commented on the toxicity profiles seen using SBRT. Most note mild but tolerable acute toxicities. However, in the past, there were concerns about significant rates of late bowel toxicity (≥ grade 2) as high as 47% seen in a study performed in 2008 (25 Gy/1 fx) where the importance of duodenal dose was not as well appreciated (11,12). More recent groups, though, have increased the fractionalization to as much as 5–6 fractions with close attention the duodenal dose constraints and have thus experienced much lower rates of late toxicity (<~10%) (6,22,28). Another limitation of this study is the unknown chemotherapy regimens received by the patients. The NCDB categorizes whether patients received chemotherapy but not which regimen they received, if they completed the course, etc. Thus we were unable to capture the potential impact for utilization of modern multi-agent chemotherapy regimens such as, FOLFIRINOX or Gemcitabine/Nab-Paclitaxel, which have dramatically improved OS relative to historical results for single agent chemotherapy such as was used in most trials comparing chemotherapy alone to chemotherapy plus radiation in locally-advanced pancreatic cancer (3,32,33). Of note, a number of ongoing studies are investigating the integration of SBRT and chemotherapy regimens such as FOLFIRINOX in locally-advanced (NCT01926197) and borderline resectable pancreatic cancer (ALLIANCE A021501). Lastly, our study does not address the cost effectiveness of SBRT versus CFRT. Studies have acknowledged that evaluating cost effectiveness is a difficult endeavor (34). However, at least one group was able to evaluate treatment cost effectiveness for locally advanced pancreatic cancer and found SBRT to be more cost effective that conventional radiotherapy and IMRT (35).

Conclusions

The use of SBRT has increased significantly from 1998 to 2012. Moreover, compared to CFRT, SBRT is associated with a small absolute improvement in OS. These findings, along with shorter treatment time, make SBRT an attractive option for patients with unresectable pancreatic cancer warranting further research.

Acknowledgements

None.

Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.

Ethical Statement: De-identified data, exempt from IRB review, for patients with non-operative, non-metastatic, histologically confirmed pancreatic adenocarcinoma who either received CFRT or SBRT from 1998 to 2012 was taken from the National Cancer Database (NCDB).

References

1. Bilimoria KY, Bentrem DJ, Ko CY, et al. Validation of the 6th edition AJCC Pancreatic Cancer Staging System: report from the National Cancer Database. Cancer 2007;110:738-44.
2. Chauffert B, Mornex F, Bonnetain F, et al. Phase III trial comparing intensive induction chemoradiotherapy (60 Gy, infusional 5-FU and intermittent cisplatin) followed by maintenance gemcitabine with gemcitabine alone for locally advanced unresectable pancreatic cancer. Definitive results of the 2000-01 FFCD/SFRO study. Ann Oncol 2008;19:1592-9. [Crossref] [PubMed]
3. Loehrer PJ Sr, Feng Y, Cardenes H, et al. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. J Clin Oncol 2011;29:4105-12. [Crossref] [PubMed]
4. Hammel P, Huguet F, van Laethem JL, et al. Effect of Chemoradiotherapy vs Chemotherapy on Survival in Patients With Locally Advanced Pancreatic Cancer Controlled After 4 Months of Gemcitabine With or Without Erlotinib: The LAP07 Randomized Clinical Trial. JAMA 2016;315:1844-53. [Crossref] [PubMed]
5. Klaassen DJ, MacIntyre JM, Catton GE, et al. Treatment of locally unresectable cancer of the stomach and pancreas: a randomized comparison of 5-fluorouracil alone with radiation plus concurrent and maintenance 5-fluorouracil--an Eastern Cooperative Oncology Group study. J Clin Oncol 1985;3:373-8. [Crossref] [PubMed]
6. Herman JM, Chang DT, Goodman KA, et al. Phase 2 multi-institutional trial evaluating gemcitabine and stereotactic body radiotherapy for patients with locally advanced unresectable pancreatic adenocarcinoma. Cancer 2015;121:1128-37. [Crossref] [PubMed]
7. Koong AC, Le QT, Ho A, et al. Phase I study of stereotactic radiosurgery in patients with locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys 2004;58:1017-21. [Crossref] [PubMed]
8. Koong AC, Christofferson E, Le QT, et al. Phase II study to assess the efficacy of conventionally fractionated radiotherapy followed by a stereotactic radiosurgery boost in patients with locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys 2005;63:320-3. [Crossref] [PubMed]
9. Schellenberg D, Kim J, Christman-Skieller C, et al. Single-fraction stereotactic body radiation therapy and sequential gemcitabine for the treatment of locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys 2011;81:181-8. [Crossref] [PubMed]
10. Hoyer M, Roed H, Sengelov L, et al. Phase-II study on stereotactic radiotherapy of locally advanced pancreatic carcinoma. Radiother Oncol 2005;76:48-53. [Crossref] [PubMed]
11. Murphy JD, Adusumilli S, Griffith KA, et al. Full-dose gemcitabine and concurrent radiotherapy for unresectable pancreatic cancer. Int J Radiat Oncol Biol Phys 2007;68:801-8. [Crossref] [PubMed]
12. Schellenberg D, Goodman KA, Lee F, et al. Gemcitabine chemotherapy and single-fraction stereotactic body radiotherapy for locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys 2008;72:678-86. [Crossref] [PubMed]
13. Bilimoria KY, Bentrem DJ, Stewart AK, et al. Comparison of commission on cancer-approved and -nonapproved hospitals in the United States: implications for studies that use the National Cancer Data Base. J Clin Oncol 2009;27:4177-81. [Crossref] [PubMed]
14. National Comprehensive Cancer Network. Pancreatic Adenocarcinoma, version 1, 2017. Available online: https://www.nccn.org/patients/guidelines/pancreatic/files/assets/common/downloads/files/pancreatic.pdf
15. Rosenbauum P, Armitage P, Colton T. Propensity score. In: Encyclopedia of Biostatistics. 2nd edition. Wiley, 2005:4267-72.
16. Crane CH, Varadhachary GR, Yordy JS, et al. Phase II trial of cetuximab, gemcitabine, and oxaliplatin followed by chemoradiation with cetuximab for locally advanced (T4) pancreatic adenocarcinoma: correlation of Smad4(Dpc4) immunostaining with pattern of disease progression. J Clin Oncol 2011;29:3037-43. [Crossref] [PubMed]
17. Small W Jr, Mulcahy MF, Rademaker A, et al. Phase II trial of full-dose gemcitabine and bevacizumab in combination with attenuated three-dimensional conformal radiotherapy in patients with localized pancreatic cancer. Int J Radiat Oncol Biol Phys 2011;80:476-82. [Crossref] [PubMed]
18. Elshaer M, Gravante G, Kosmin M, et al. A systematic review of the prognostic value of lymph node ratio, number of positive nodes and total nodes examined in pancreatic ductal adenocarcinoma. Ann R Coll Surg Engl 2017;99:101-6. [Crossref] [PubMed]
19. Lin JY, Zhang XM, Kou JT, et al. Analysis of prognostic factors for pancreatic head cancer according to para-aortic lymph node. Cancer Med 2016;5:2701-7. [Crossref] [PubMed]
20. Comito T, Cozzi L, Clerici E, et al. Can Stereotactic Body Radiation Therapy Be a Viable and Efficient Therapeutic Option for Unresectable Locally Advanced Pancreatic Adenocarcinoma? Results of a Phase 2 Study. Technol Cancer Res Treat 2017;16:295-301. [Crossref] [PubMed]
21. Schellenberg D, Quon A, Minn AY, et al. 18Fluorodeoxyglucose PET is prognostic of progression-free and overall survival in locally advanced pancreas cancer treated with stereotactic radiotherapy. Int J Radiat Oncol Biol Phys 2010;77:1420-5. [Crossref] [PubMed]
22. Chuong MD, Springett GM, Freilich JM, et al. Stereotactic body radiation therapy for locally advanced and borderline resectable pancreatic cancer is effective and well tolerated. Int J Radiat Oncol Biol Phys 2013;86:516-22. [Crossref] [PubMed]
23. Brunner TB, Nestle U, Grosu AL, et al. SBRT in pancreatic cancer: what is the therapeutic window? Radiother Oncol 2015;114:109-16. [Crossref] [PubMed]
24. Petrelli F, Comito T, Ghidini A, et al. Stereotactic Body Radiation Therapy for Locally Advanced Pancreatic Cancer: A Systematic Review and Pooled Analysis of 19 Trials. Int J Radiat Oncol Biol Phys 2017;97:313-22. [Crossref] [PubMed]
25. Kamisawa T, Isawa T, Koike M, et al. Hematogenous metastases of pancreatic ductal carcinoma. Pancreas 1995;11:345-9. [Crossref] [PubMed]
26. Iacobuzio-Donahue CA, Fu B, Yachida S, et al. DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer. J Clin Oncol 2009;27:1806-13. [Crossref] [PubMed]
27. Tozzi A, Comito T, Alongi F, et al. SBRT in unresectable advanced pancreatic cancer: preliminary results of a mono-institutional experience. Radiat Oncol 2013;8:148. [Crossref] [PubMed]
28. Rwigema JC, Parikh SD, Heron DE, et al. Stereotactic body radiotherapy in the treatment of advanced adenocarcinoma of the pancreas. Am J Clin Oncol 2011;34:63-9. [Crossref] [PubMed]
29. Beatty GL, Torigian DA, Chiorean EG, et al. A phase I study of an agonist CD40 monoclonal antibody (CP-870,893) in combination with gemcitabine in patients with advanced pancreatic ductal adenocarcinoma. Clin Cancer Res 2013;19:6286-95. [Crossref] [PubMed]
30. Johansson H, Andersson R, Bauden M, et al. Immune checkpoint therapy for pancreatic cancer. World J Gastroenterol 2016;22:9457-76. [Crossref] [PubMed]
31. Chang DT, Schellenberg D, Shen J, et al. Stereotactic radiotherapy for unresectable adenocarcinoma of the pancreas. Cancer 2009;115:665-72. [Crossref] [PubMed]
32. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011;364:1817-25. [Crossref] [PubMed]
33. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 2013;369:1691-703. [Crossref] [PubMed]
34. Rahman F, Seung SJ, Cheng SY, et al. Radiation costing methods: a systematic review. Curr Oncol 2016;23:e392-408. [Crossref] [PubMed]
35. Murphy JD, Chang DT, Abelson J, et al. Cost-effectiveness of modern radiotherapy techniques in locally advanced pancreatic cancer. Cancer 2012;118:1119-29. [Crossref] [PubMed]