The American College of Radiology Appropriateness Criteria® are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. The panel reviewed the pertinent literature and voted on five variants to establish appropriate recommended treatment of borderline and unresectable pancreatic cancer. The guidelines reviewed the use of radiation, chemotherapy, and surgery. Radiation technique, dose, and targets were evaluated, as was the recommended chemotherapy, administered either alone or concurrently with radiation. This report will aid clinicians in determining guidelines for the optimal treatment of borderline and unresectable pancreatic cancer.
Summary of Literature Review
Pancreatic cancer diagnosis and treatment remain among the most challenging areas of oncology. The American Cancer Society estimates that there will be approximately 49,000 cases of pancreatic cancer diagnosed in 2015, with an essentially equal distribution between men and women. This incidence will be associated with approximately 40,500 deaths, again about equal in men and women, and representing 3% of all cancers and 7% of cancer deaths. Even for cases of early-stage disease, the 5-year survival rate between 1999 and 2006 was only 23%. Once the disease involves lymph node metastases, the 5-year survival rate drops to 9%; the 5-year survival rate among patients with metastatic disease is approximately 2%. Given these results, and with no effective screening techniques yet identified, the challenge to develop effective therapy remains daunting.
Treatment recommendations are clearly defined for patients with resectable or distantly metastatic pancreatic cancer. Surgical resection of localized disease remains the only proven curative treatment, and even then, rates of 5-year survival are only 18% to 24%. Widely metastatic disease is treated with chemotherapy. Questions remain regarding the optimal treatment for locally advanced and borderline resectable disease, and the purpose of these appropriateness criteria is to assess the merits of these options for different patient groups (see Variants 1–5).
Diagnosis and Definition of Locally Advanced and Borderline Pancreas Cancer
The clinical evaluation of the patient suspected of having pancreas cancer begins with appropriate imaging studies, ideally through a multidisciplinary clinic or tumor board. Based on these results, surgery at a high-volume institution should be considered in patients with a high likelihood of resection based on current guidelines, with others being spared exploration as a means of defining the extent of their disease.
The most common choice of imaging for visualization of the pancreatic tumor is the multiphase or triphasic computed tomography (CT) scan. Triphasic CT imaging (rapid, small-increment arterial-phase, portal-venous–phase, and parenchymal contrast data sets) allows assessment of the pancreas and adjacent vasculature as compared to standard CT techniques. These images are best obtained prior to interventions such as biopsy or stent placement, as these can limit the accuracy of interpretation. Endoscopic ultrasound can provide information regarding the extent of disease and it can be used to obtain tissue for diagnosis with fine-needle aspiration. Magnetic resonance imaging and magnetic resonance cholangiopancreatography can also be used and may provide more refined assessment of point of pancreatic duct obstruction, peritoneal carcinomatosis, vascular involvement, and small liver lesions.[8,9]
With these tools, the resectability of pancreatic cancer can be determined preoperatively in the great majority of cases. Per the guidelines of the National Comprehensive Cancer Network (NCCN), resectable tumors are those with no arterial tumor contact (ie, no contact with the celiac axis [CA], superior mesenteric artery [SMA], or common hepatic artery [CHA]), no tumor contact with the superior mesenteric vein (SMV) or portal vein (PV), or ≤ 180° contact without vein contour irregularity.
NCCN defines unresectable disease, in lesions of the pancreatic head/uncinate process, as including solid tumor contact with the SMA > 180°, solid tumor contact with the CA > 180°, solid tumor contact with the first jejunal SMA branch, an unreconstructible SMV/PV due to tumor involvement or occlusion, or contact with the most proximal draining jejunal branch into the SMV. In the body and tail of the pancreas, this includes solid tumor contact of > 180° with the SMA or CA, solid tumor contact with the CA and aortic involvement, or unreconstructible SMV/PV due to tumor involvement or occlusion.
Borderline resectable tumors in the pancreatic head/uncinate process are classified as having solid tumor contact with the CHA without extension to the CA, hepatic artery bifurcation allowing for safe and complete resection and reconstruction, or solid tumor contact with the SMA of ≤ 180°. In the pancreatic body/tail, borderline resectable tumors include solid tumor contact with the CA of ≤ 180° and solid tumor contact with the CA of > 180° without involvement of the aorta and with an intact and uninvolved gastroduodenal artery. Borderline unresectable (venous) disease includes solid tumor contact with the SMV or PV of > 180°; contact of ≤ 180° with contour irregularity of the vein or thrombosis of the vein but with a suitable vessel proximal and distal to the site of involvement, allowing for safe and complete resection and vein reconstruction; or solid tumor contact with the inferior vena cava.
The ideal definition of borderline resectable tumor should be free of subjective terminology, can be applied using routine axial pancreatic-protocol CT images, and should be reproducible. According to Katz et al, borderline resectable pancreatic cancer is defined radiographically as localized tumors with 1 or more of the following: (1) interface between the primary tumor and SMV/PV measuring ≥ 180° of the circumference of the vein wall; (2) short-segment occlusion of the SMV/PV, with normal vein above and below the level of obstruction amenable to resection and venous reconstruction; (3) short-segment interface (of any degree) between tumor and hepatic artery, with normal artery proximal and distal to the interface that is amenable to resection and arterial reconstruction; and/or (4) an interface between the tumor and SMA or celiac trunk measuring < 180° of the circumference of the artery wall.
1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65:5-29.
2. Wolfgang CL, Herman JM, Laheru DA, et al. Recent progress in pancreatic cancer. CA Cancer J Clin. 2013;63:318-48.
3. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364:1817-25.
4. Pawlik TM, Laheru D, Hruban RH, et al. Evaluating the impact of a single-day multidisciplinary clinic on the management of pancreatic cancer. Ann Surg Oncol. 2008;15:2081-8.
5. Fong Y, Gonen M, Rubin D, et al. Long-term survival is superior after resection for cancer in high-volume centers. Ann Surg. 2005;242:540-4.
6. Katz MH, Marsh R, Herman JM, et al. Borderline resectable pancreatic cancer: need for standardization and methods for optimal clinical trial design. Ann Surg Oncol. 2013;20:2787-95.
7. Tummala P, Junaidi O, Agarwal B. Imaging of pancreatic cancer: an overview. J Gastrointest Oncol. 2011;2:168-74.
8. Schima W, Ba-Ssalamah A, Goetzinger P, et al. State-of-the-art magnetic resonance imaging of pancreatic cancer. Top Magn Reson Imaging. 2007;18:421-9.
9. Vachiranubhap B, Kim YH, Balci NC, Semelka RC. Magnetic resonance imaging of adenocarcinoma of the pancreas. Top Magn Reson Imaging. 2009;20:3-9.
10. NCCN Clinical Practice Guidelines in Oncology. Pancreatic adenocarcinoma. Version 2.2015. http://www.nccn.org/professionals/physician_gls/PDF/pancreatic.pdf. Accessed May 5, 2016.
11. 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.
12. Moertel CG, Frytak S, Hahn RG, et al. Therapy of locally unresectable pancreatic carcinoma: a randomized comparison of high dose (6000 rads) radiation alone, moderate dose radiation (4000 rads + 5-fluorouracil), and high dose radiation + 5-fluorouracil: The Gastrointestinal Tumor Study Group. Cancer. 1981;48:1705-10.
13. Cohen SJ, Dobelbower R Jr, Lipsitz S, et al. A randomized phase III study of radiotherapy alone or with 5-fluorouracil and mitomycin-C in patients with locally advanced adenocarcinoma of the pancreas: Eastern Cooperative Oncology Group study E8282. Int J Radiat Oncol Biol Phys. 2005;62:1345-50.
14. Moertel CG, Childs DS Jr, Reitemeier RJ, et al. Combined 5-fluorouracil and supervoltage radiation therapy of locally unresectable gastrointestinal cancer. Lancet. 1969;2:865-7.
15. Radiation therapy combined with Adriamycin or 5-fluorouracil for the treatment of locally unresectable pancreatic carcinoma. Gastrointestinal Tumor Study Group. Cancer. 1985;56:2563-8.
16. Treatment of locally unresectable carcinoma of the pancreas: comparison of combined-modality therapy (chemotherapy plus radiotherapy) to chemotherapy alone. Gastrointestinal Tumor Study Group. J Natl Cancer Inst. 1988;80:751-5.
17. 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.
18. Boz G, De Paoli A, Innocente R, et al. Radiotherapy and continuous infusion 5-fluorouracil in patients with nonresectable pancreatic carcinoma. Int J Radiat Oncol Biol Phys. 2001;51:736-40.
19. Whittington R, Neuberg D, Tester WJ, et al. Protracted intravenous fluorouracil infusion with radiation therapy in the management of localized pancreaticobiliary carcinoma: a phase I Eastern Cooperative Oncology Group Trial. J Clin Oncol. 1995;13:227-32.
20. 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.
21. 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.
22. Sultana A, Tudur Smith C, Cunningham D, et al. Systematic review, including meta-analyses, on the management of locally advanced pancreatic cancer using radiation/combined modality therapy. Br J Cancer. 2007;96:1183-90.
23. Hammel P, Huguet F, Van Laethem J-L, et al. Comparison of chemoradiotherapy (CRT) and chemotherapy (CT) in patients with a locally advanced pancreatic cancer (LAPC) controlled after 4 months of gemcitabine with or without erlotinib: final results of the international phase III LAP 07 study. J Clin Oncol. 2013;31(suppl):abstr LBA4003.
24. Huguet F, Hammel P, Vernerey D, et al. Impact of chemoradiotherapy (CRT) on local control and time without treatment in patients with locally advanced pancreatic cancer (LAPC) included in the international phase III LAP 07 study. J Clin Oncol. 2014;32(suppl):abstr 4001.
25. Mohiuddin M, Regine WF, Stevens J, et al. Combined intraoperative radiation and perioperative chemotherapy for unresectable cancers of the pancreas. J Clin Oncol. 1995;13:2764-8.
26. Willett CG, Del Castillo CF, Shih HA, et al. Long-term results of intraoperative electron beam irradiation (IOERT) for patients with unresectable pancreatic cancer. Ann Surg. 2005;241:295-9.
27. Kim EJ, Ben-Josef E, Herman JM, et al. A multi-institutional phase 2 study of neoadjuvant gemcitabine and oxaliplatin with radiation therapy in patients with pancreatic cancer. Cancer. 2013;119:2692-700.
28. Small W Jr, Berlin J, Freedman GM, et al. Full-dose gemcitabine with concurrent radiation therapy in patients with nonmetastatic pancreatic cancer: a multicenter phase II trial. J Clin Oncol. 2008;26:942-7.
29. 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.
30. Ben-Josef E, Schipper M, Francis IR, et al. A phase I/II trial of intensity modulated radiation (IMRT) dose escalation with concurrent fixed-dose rate gemcitabine (FDR-G) in patients with unresectable pancreatic cancer. Int J Radiat Oncol Biol Phys. 2012;84:
31. Hong TS, Ryan DP, Blaszkowsky LS, et al. Phase I/II study of proton-based short course chemoradiation and early surgery for adenocarcinoma of the pancreas. Int J Radiat Oncol Biol Phys. 2010;78:S99-S100.
32. Hong TS, Ryan DP, Borger DR, et al. A phase 1/2 and biomarker study of preoperative short course chemoradiation with proton beam therapy and capecitabine followed by early surgery for resectable pancreatic ductal adenocarcinoma. Int J Radiat Oncol Biol Phys. 2014;89:830-8.
33. Kozak KR, Kachnic LA, Adams J, 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. 2007;68:1557-66.
34. 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.
35. 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.
36. Mellon EA, Hoffe SE, Springett GM, et al. Long-term outcomes of induction chemotherapy and neoadjuvant stereotactic body radiotherapy for borderline resectable and locally advanced pancreatic adenocarcinoma. Acta Oncol. 2015;54:979-85.
37. Moningi S, Dholakia AS, Raman SP, et al. The role of stereotactic body radiation therapy for pancreatic cancer: a single-institution experience. Ann Surg Oncol. 2015; 22:2352-8.
38. Bilimoria KY, Bentrem DJ, Ko CY, et al. National failure to operate on early stage pancreatic cancer. Ann Surg. 2007;246:173-80.
39. Ishikawa O, Ohigashi H, Imaoka S, et al. Is the long-term survival rate improved by preoperative irradiation prior to Whipple’s procedure for adenocarcinoma of the pancreatic head? Arch Surg. 1994;129:1075-80.
40. Evans DB, Rich TA, Byrd DR, et al. Preoperative chemoradiation and pancreaticoduodenectomy for adenocarcinoma of the pancreas. Arch Surg. 1992;127:1335-9.
41. Evans DB, Varadhachary GR, Crane CH, et al. Preoperative gemcitabine-based chemoradiation for patients with resectable adenocarcinoma of the pancreatic head. J Clin Oncol. 2008;26:3496-502.
42. Pisters PW, Abbruzzese JL, Janjan NA, et al. Rapid-fractionation preoperative chemoradiation, pancreaticoduodenectomy, and intraoperative radiation therapy for resectable pancreatic adenocarcinoma. J Clin Oncol. 1998;16:3843-50.
43. Pisters PW, Wolff RA, Janjan NA, et al. Preoperative paclitaxel and concurrent rapid-fractionation radiation for resectable pancreatic adenocarcinoma: toxicities, histologic response rates, and event-free outcome. J Clin Oncol. 2002;20:2537-44.
44. Talamonti MS, Small W Jr, Mulcahy MF, et al. A multi-institutional phase II trial of preoperative full-dose gemcitabine and concurrent radiation for patients with potentially resectable pancreatic carcinoma. Ann Surg Oncol. 2006;13:150-8.
45. Varadhachary GR, Wolff RA, Crane CH, et al. Preoperative gemcitabine and cisplatin followed by gemcitabine-based chemoradiation for resectable adenocarcinoma of the pancreatic head. J Clin Oncol. 2008;26:3487-95.
46. White RR, Tyler DS. Neoadjuvant therapy for pancreatic cancer: the Duke experience. Surg Oncol Clin N Am. 2004;13:675-84, ix-x.
47. Gillen S, Schuster T, Meyer Zum Buschenfelde C, et al. Preoperative/neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis of response and resection percentages. PLoS Med. 2010;7:e1000267.
48. Hong TS, Ryan DP, Blaszkowsky LS, et al. Phase I study of preoperative short-course chemoradiation with proton beam therapy and capecitabine for resectable pancreatic ductal adenocarcinoma of the head. Int J Radiat Oncol Biol Phys. 2011;79:151-7.
49. Huguet F, Andre T, Hammel P, et al. Impact of chemoradiotherapy after disease control with chemotherapy in locally advanced pancreatic adenocarcinoma in GERCOR phase II and III studies. J Clin Oncol. 2007;25:326-31.
50. Krishnan S, Rana V, Janjan NA, et al. Induction chemotherapy selects patients with locally advanced, unresectable pancreatic cancer for optimal benefit from consolidative chemoradiation therapy. Cancer. 2007;110:47-55.
51. Louvet C, Labianca R, Hammel P, et al. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005;23:3509-16.
52. 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.
53. Ferrone CR, Marchegiani G, Hong TS, et al. Radiological and surgical implications of neoadjuvant treatment with FOLFIRINOX for locally advanced and borderline resectable pancreatic cancer. Ann Surg. 2015;261:12-7.