|Year : 2021 | Volume
| Issue : 2 | Page : 121-126
Emergence of SBRT in borderline resectable pancreatic cancer: Is it the way forward?
Kaustav Talapatra1, Shreyasee Karmakar2, Ajinkya Gupte2, Amrita Srivastava2
1 Department of Radiation Oncology, Nanavati-Max Superspeciality Hospital, Mumbai, Maharashtra, India
2 Department of Radiation Oncology, Kokilaben Dhirubhai Ambani Hospital, Mumbai, Maharashtra, India
|Date of Submission||06-Oct-2021|
|Date of Acceptance||10-Dec-2021|
|Date of Web Publication||23-Feb-2022|
Dr. Shreyasee Karmakar
Department of Radiation Oncology, Kokilaben Dhirubhai Ambani Hospital, Mumbai, Maharashtra
Source of Support: None, Conflict of Interest: None
Pancreatic cancers are aggressive cancers with poor survival outcomes and few effective treatment modalities. The previously used protracted chemo-radiotherapy (CTRT) regimens have not had encouraging results. Stereotactic body radiotherapy (SBRT) has shown encouraging results in the treatment paradigm of borderline resectable pancreatic cancers. Though body of level I evidence is weak currently, studies have shown better resectability with negative margins with neoadjuvant SBRT. Precise contouring, good image guidance, strict quality assurance, and multi-disciplinary spatial co-operation are crucial for its success. High biologically effective dose, smaller margins, short duration of treatment, and strategic sequencing are the key to better outcomes.
Keywords: Borderline resectable pancreatic cancer (BRPC), radiotherapy in pancreatic cancer, stereotactic body radiotherapy
|How to cite this article:|
Talapatra K, Karmakar S, Gupte A, Srivastava A. Emergence of SBRT in borderline resectable pancreatic cancer: Is it the way forward?. J Curr Oncol 2021;4:121-6
| Introduction|| |
Pancreatic cancers through the decades have been one of the most aggressive cancers with poor survival outcomes and few effective treatment modalities. At diagnosis, only 20% of patients present with resectable tumor. It is also a fact about pancreatic cancers that about 40% of all pancreatic cancers present at a locally advanced stage and around 60% have local progression. Various groups such as National Comprehensive Cancer Network (NCCN), Americas Hepato-Pancreato-Biliary Association/Society of Surgical Oncology/Society for Surgery of the Alimentary Tract (AHPBA/SSO/SSAT), and the University of Texas MD Anderson Cancer Center (MDACC) have defined pancreatic cancers into three groups: potentially resectable, borderline resectable pancreatic cancer (BRPC), and locally advanced pancreatic carcinoma (LAPC). These groups have been made with respect to superior mesenteric artery (SMA), superior mesenteric vein (SMV), common hepatic artery (CHA), portal vein (PV), and celiac axis (CA). As per NCCN guidelines, BRPC in the head of pancreas is the solid tumor contact with CHA without extension to CA or artery bifurcation and variant arterial anatomy, contact with SMA <180°, contact with SMV or PV <180° without venous contour irregularity or thrombosis which allows safe and complete arterial and venous resection and reconstruction. In the pancreatic body or tail, BRPC is the solid tumor contact with the CA of <180° or contact with CA>180° without involvement of the aorta and gastroduodenal artery in order to allow a modified Appleby surgery. The complications related to local progression are disastrous, and one-third of deaths is from issues such as biliary obstruction, PV occlusion, and gastric outlet obstruction.
The previously used protracted chemo-radiotherapy (CTRT) regimens have not had encouraging results. It is of utmost importance that achieving effective local control particularly in borderline resectable cancers/locally advanced disease may result in significant improvement in outcomes and survival. Enhancing resectability of the tumor can increase survival in such patients.
Stereotactic body radiation therapy (SBRT) is a modern technique of delivering high doses to the target over a short duration in about 1–5 fractions. As such, in the current times, it has garnered significant interest for borderline and locally advanced pancreatic cancer (LAPC) patients. Moreover, SBRT being an extremely focal form of radiotherapy, when delivered safely, is well tolerated and is associated with high rates of R0 resection and decreased post-operative complications. SBRT has also given a new paradigm in the treatment of BRPC.
| Therapeutic Principle|| |
Pancreatic tumors are known to be intrinsically radio-resistant and to achieve high local control, higher biologically effective dose (BED) of >100 Gy is required for ablation and effective outcomes. It is also true that surrounding radiosensitive organs at risk (OAR) like duodenum reduce the ability to deliver optimum dose. With SBRT and use of image guidance with appropriate motion management techniques, it is now feasible to precisely deliver high dose radiation to the tumor with better sparing of surrounding normal tissue.
| Evidence Related to Feasibility and Safety of SBRT in LAPC|| |
The mainstay of pancreatic cancer treatment traditionally was surgery; however, rates of positive resection margin were very high. Around 25% of patients with resectable pancreatic cancer have positive margin post-surgery, with the positivity rates being higher in patients with BRPC. The 5-year survival decreases from around 25% to 8–10% in patients with positive resection margins. Addition of neoadjuvant chemotherapy with or without radiotherapy decreases the margin positivity rates in BRPC. Chemotherapy with or without conventionally fractionated radiation therapy (CFRT) is considered in LAPC, and role of SBRT is emerging. Stanford Phase I study was one of the earliest dose escalation studies to evaluate the feasibility of delivering SBRT to patients with LAPC. It enrolled patients to receive 15, 20, and 25 Gy in one fraction and recommended a dose level of 25 Gy for adequate local control without causing significantly adverse gastrointestinal toxicity. Retrospective studies and phase 2 multi-institutional trial evaluating fractionated SBRT to a dose of 24–36 Gy delivered in 3–5 fractions in LAPC found median overall survival (OS) in a range of 10–14 months with minimal toxicity.,,,
The ongoing phase III Stanford study is looking into metastasis-free survival in patients of LAPC treated with or without SBRT, and the results are currently awaited.[Table 1] summarizes the evidence related to feasibility and safety of SBRT in LAPC.
| Evidence Related to Comparison of SBRT with Other Radiation Techniques in Treatment of LAPC|| |
[Table 2] enumerates the limited data comparing SBRT with other radiation techniques in LAPC treatment. de Geus et al. reviewed the role of SBRT for LAPC in 14,331 patients and found that SBRT is associated with a significantly better outcome than chemotherapy alone or in conjunction with IMRT (median OS—chemotherapy: 9.9 months, IMRT: 12 months, SBRT: 13.9 months).
|Table 2: Evidence related to comparison of SBRT with other radiation techniques in the treatment of LAPC|
Click here to view
The CrisP international systematic review and meta-analyses aimed to characterize the efficacy and safety profile of SBRT vs. conventionally fractionated EBRT with concurrent chemotherapy for definitive treatment of LAPC. They did not find significant difference in 1-year OS between SBRT and CFRT. However, there was significantly more acute grade 3/4 toxicity in the CFRT arm (5.6% for SBRT vs. 37.7% for CFRT).
| Evidence Related to Role and Benefit of SBRT in Treatment of BRPC|| |
There is paucity of data regarding role and benefit of SBRT in BRPC, and the evidence is still emerging [Table 3]. Chuong et al. had evaluated the role of induction chemotherapy followed by SBRT in 30 patients of BRPC. Patients received SBRT in five fractions to a dose of 30–40 Gy to the tumor–vessel interface (TVI) and up to 25–30 Gy to the remainder of the gross disease. R0 resection was possible in around 96% of the patients and was well tolerated with minimal toxicities. Following this, Chuong et al. in 2013 further evaluated the role of SBRT in 73 patients of BRPC and LAPC. Patients received median doses of 35 Gy to the region of vessel involvement and 25 Gy to the remainder of the tumor. Around 97% of the patients had R0 resection and BRPC patients who underwent R0 resection had statistically significant improvement in 1-year overall survival and disease-free survival when compared with non-surgical patients with acute or late grade 3 or more toxicity being <5%. In a study evaluating 110 BRPC patients who received neoadjuvant chemotherapy and SBRT to a dose of 30 Gy to tumor and 40 Gy to TVI in five daily fractions, resectability rate with negative margin was found to be 96% with a median OS of 19.2 months. However, grade 3 or more potentially radiation-related toxicity was around 7%. The recent phase III randomized ALLIANCE trial had compared patients receiving neoadjuvant-chemotherapy with or without SBRT, but did not find survival benefit with addition of SBRT.
|Table 3: Evidence related to role and benefit of SBRT in the treatment of BRPC|
Click here to view
In patients with BRPC and select LAPC appropriate for down-staging prior to surgery, ASTRO recommends neoadjuvant chemotherapy followed by multifraction SBRT. For patients with LAPC not appropriate for down-staging to eventual surgery, a definitive therapy regimen of systemic chemotherapy followed by multifraction SBRT is recommended. SBRT in post-operative patients should be considered only in clinical trials setting.
| Patient Selection Criteria|| |
Patients with histopathologically proven borderline resectable pancreatic cancer and those with good ECOG score are considered suitable for SBRT. Patients with active duodenal and gastric ulcers should be omitted; however, patients with resolving ulcers can be considered. Distance of tumor from surrounding structures such as stomach and bowel has to be taken into account, and patients with direct tumor invasion of bowel and stomach are not deemed suitable. Also, SBRT should not be considered if doses to OARs are unlikely to be achieved. Patients with bilirubin level of <2 mg/dL are considered for SBRT.
| Key Features in Contouring, Planning, and Treatment|| |
Apart from identifying the gross tumor and surrounding critical structures such as duodenum, it is also important to identify the TVI which is the area where gross tumor volume (GTV) is involving or within 5 mm of major vessels in the upper abdomen. This region merits a higher differential dose as this will ensure a better resectability rate and thus better outcome. Therefore, one must keep in mind components such as contouring, planning, and treatment delivery in carcinoma pancreas. [Figure 1](A) shows contour of TVI (pink) along with 3 mm margin (orange). This in turn corresponds to the high dose PTV (red) which has been generated by giving 0 mm margin to the contour TVI + 3 mm.
|Figure 1: (A) TVI (pink) along with 3 mm margin (orange); (B) high dose PTV (3 mm margin to TVI); (C) dose distribution of high dose PTV|
Click here to view
It is also important to utilize appropriate motion management strategy like breath hold techniques, gating, tracking, marker placement, etc. ASTRO recommends a dose of 30–35 Gy in five fractions to the tumor with a boost dose up to 40 Gy to TVI. As per AGITG and TROG recommendations, a dose of 40 Gy in five fractions (BED10: 72 Gy, BED3: 147 Gy) is recommended, with as much dose to the PTV as possible. However, care should be taken to achieve the dose constraints of organs at risk such as duodenum, stomach, and bowel. [Figure 1(C)] shows dose distribution (color wash) of PTV.
| Conclusion|| |
SBRT in BRPC has emerged as an exciting and effective modality offering a ray of hope in this subset of patients when combined with systemic therapy and surgery. Though body of level I evidence is weak currently, it is expected that trials will show better results in this cohort of patients. Promising results are awaited with stereotactic treatment and are expected with use of particle beam therapy. The future could also see the exploration of biomarker and how it can be inculcated in these treatment paradigms. Precise contouring, good image guidance, strict quality assurance, and multi-disciplinary spatial cooperation are crucial for its success. High BED, smaller margins, short duration of treatment, and strategic sequencing are the key to better outcomes.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Barugola G, Partelli S, Crippa S, Butturini G, Salvia R, Sartori N, et al
. Time trends in the treatment and prognosis of resectable pancreatic cancer in a large tertiary referral centre. HPB (Oxford) 2013;15:958-64.
Siegel R, Naishadham D, Jemal A Cancer statistics, 2013. CA Cancer J Clin 2013;63:11-30.
Katz MHG, Pisters PWT, Evans DB, Sun CC, Lee JE, Fleming JB, et al
. Borderline resectable pancreatic cancer: The importance of this emerging stage of disease. J Am Coll Surg 2008;206:833-46; discussion 846-848.
Tempero MA, Malafa MP, Al-Hawary M, Asbun H, Bain A, Behrman SW, et al
. Pancreatic adenocarcinoma, version 2.2017, NCCN Clinical Practice Guidelines in oncology. J Natl Compr Canc Netw 2017;15:1028-61.
Lloyd S, Chang BW New possibilities and potential benefits for local control in locally recurrent pancreatic cancer. J Gastrointest Oncol 2013;4:340-2.
Ghaly M, Gogineni E, Saif MW The evolving field of stereotactic body radiation therapy in pancreatic cancer. Pancreas (Fairfax) 2019;3:9-14.
Mokdad AA, Minter RM, Zhu H, Augustine MM, Porembka MR, Wang SC, et al
. Neoadjuvant therapy followed by resection versus upfront resection for resectable pancreatic cancer: A propensity score matched analysis. J Clin Oncol 2017;35:515-22.
Yeo CJ, Cameron JL, Lillemoe KD, Sitzmann JV, Hruban RH, Goodman SN, et al
. Pancreaticoduodenectomy for cancer of the head of the pancreas. 201 patients. Ann Surg 1995;221:721-31; discussion 731-3.
Zhan HX, Xu JW, Wu D, Wu ZY, Wang L, Hu SY, et al
. Neoadjuvant therapy in pancreatic cancer: A systematic review and meta-analysis of prospective studies. Cancer Med 2017;6:1201-19.
Available from: https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf. Accessed May 2, 2020.
Koong AC, Le QT, Ho A, Fong B, Fisher G, Cho C, 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.
Polistina F, Costantin G, Casamassima F, Francescon P, Guglielmi R, Panizzoni G, et al
. Unresectable locally advanced pancreatic cancer: A multimodal treatment using neoadjuvant chemoradiotherapy (gemcitabine plus stereotactic radiosurgery) and subsequent surgical exploration. Ann Surg Oncol 2010;17:2092-101.
Mahadevan A, Jain S, Goldstein M, Miksad R, Pleskow D, Sawhney M, et al
. Stereotactic body radiotherapy and gemcitabine for locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys 2010;78:735-42.
Mahadevan A, Miksad R, Goldstein M, Sullivan R, Bullock A, Buchbinder E, et al
. Induction gemcitabine and stereotactic body radiotherapy for locally advanced nonmetastatic pancreas cancer. Int J Radiat Oncol Biol Phys 2011;81:e615-22.
Herman JM, Chang DT, Goodman KA, Dholakia AS, Raman SP, Hacker-Prietz A, 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.
Phase III FOLFIRINOX (mFFX) +/- SBRT in Locally Advanced Pancreatic Cancer (ongoing trial). Available from: https://clinicaltrials.stanford.edu/browse-all-trials.html?ctid= NCT01926197. [Last accessed on 26 May 2021].
de Geus SWL, Eskander MF, Kasumova GG, Ng SC, Kent TS, Mancias JD, et al
. Stereotactic body radiotherapy for unresected pancreatic cancer: A nationwide review. Cancer 2017;123:4158-67.
Tchelebi LT, Lehrer EJ, Trifiletti DM, Sharma NK, Gusani NJ, Crane CH, et al
. Conventionally fractionated radiation therapy versus stereotactic body radiation therapy for locally advanced pancreatic cancer (CRiSP): An international systematic review and meta-analysis. Cancer 2020;126:2120-31.
Chuong MD, Springett GM, Weber J, Klapman J, Vignesh S, Hodul PJ, et al
. Induction gemcitabine-based chemotherapy and neoadjuvant stereotactic body radiation therapy achieve high margin-negative resection rates for borderline resectable pancreatic cancer. J Radiat Oncol 2012;1:273-81.
Chuong MD, Springett GM, Freilich JM, Park CK, Weber JM, Mellon EA, 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.
Mellon EA, Hoffe SE, Springett GM, Frakes JM, Strom TJ, Hodul PJ, 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.
Katz MHG, Shi Q, Meyers JP, Herman JM, Choung M, Wolpin BM, et al
. Alliance A021501: Preoperative mFOLFIRINOX or mFOLFIRINOX plus hypofractionated radiation therapy (RT) for borderline resectable (BR) adenocarcinoma of the pancreas. JCO2021;39(3_suppl):377-377.
Palta M, Godfrey D, Goodman KA, Hoffe S, Dawson LA, Dessert D, et al
. Radiation therapy for pancreatic cancer: Executive summary of an ASTRO clinical practice guideline. Pract Radiat Oncol 2019;9:322-32.
Oar A, Lee M, Le H, Hruby G, Dalfsen R, Pryor D, et al
. Australasian Gastrointestinal Trials Group (AGITG) and Trans-Tasman Radiation Oncology Group (TROG) guidelines for pancreatic stereotactic body radiation therapy (SBRT). Pract Radiat Oncol 2020;10:e136-46.
[Table 1], [Table 2], [Table 3]