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Table of Contents
COMMENTARY
Year : 2019  |  Volume : 2  |  Issue : 1  |  Page : 19-21

Resurgence of role of radiotherapy in neoadjuvant treatment of pancreatic cancer


Department of Radiation Oncology, Kokilaben Dhirubhai Ambani Hospital, Mumbai, India

Date of Web Publication26-Jun-2019

Correspondence Address:
Dr. Kaustav Talapatra
Department of Radiation Oncology, Kokilaben Dhirubhai Ambani Hospital, Four Bungalows, Andheri (W), Mumbai 400 053
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JCO.JCO_23_18

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  Abstract 

Borderline resectable pancreatic cancer (BRPC) is a clinically distinguished malignancy. With limited role of aggressive surgical intervention, neoadjuvant treatment is warranted. Various studies and their meta-analysis addressing this issue have shown limited benefit. However, recently two prospective multiple randomized trials have evaluated benefit of neoadjuvant chemoradiotherapy in BRPC with a positive clinical response. This article gives a brief insight into these studies and discusses future prospects for role of radiation in neoadjuvant setting in pancreatic cancer.

Keywords: Neoadjuvant chemoradiotherapy, pancreatic cancer, stereotactic body radiotherapy


How to cite this article:
Vadgaonkar RA, Talapatra K. Resurgence of role of radiotherapy in neoadjuvant treatment of pancreatic cancer. J Curr Oncol 2019;2:19-21

How to cite this URL:
Vadgaonkar RA, Talapatra K. Resurgence of role of radiotherapy in neoadjuvant treatment of pancreatic cancer. J Curr Oncol [serial online] 2019 [cited 2019 Jul 20];2:19-21. Available from: http://www.journalofcurrentoncology.org/text.asp?2019/2/1/19/261472



According to 2008–2012 Surveillance, Epidemiology, and End Results (SEER) database, incidence of pancreatic cancer (PC) was 12.4 per 100,000 population per year.[1] The only curative treatment for this malignancy is surgery. However, it is observed that only 20%–25% of tumors appear to be amenable to upfront surgical resection,[2] and tumors with a limited amount of arterial encasement are now being designated as borderline resectable (BR) and these tumors could be eventually resected after downstaging. Although there is no universally accepted criteria for borderline resectable pancreatic cancer (BRPC), various definitions have been proposed in literature.[3],[4],[5],[6] BRPC is characteristically different from resectable PC in terms of requirement of more complex surgical procedure, higher risk of positive surgical margins, and association of occult distant metastases.[7] Also, the role of aggressive surgical resection is questionable in BRPC due to associated increased morbidity and mortality, and limited clinical benefit.[7] Hence, a neoadjuvant treatment followed by surgical excision deemed a theoretical advantage. However, multiple studies and their meta-analysis have evaluated this approach with disappointing clinical outcomes.[8],[9] A meta-analysis performed by Festa et al.[10] has clearly concluded that downstaging of BRPC after neoadjuvant chemoradiotherapy (CTRT) is uncommon with radiological complete/partial response observed in only 16% patients and this strategy should be used to spare surgical intervention in patients with progressive disease. Poor outcomes in these studies could be because of limited patient enrolment, use of less effective chemotherapy in neoadjuvant setting, and older radiotherapy techniques. Now, with recent advancement in radiotherapy technique and availability of more effective chemotherapy, improved outcomes can be expected in this population. This issue was recently been addressed in two multicenter, randomized trials.

A phase II/III study from Korea was conducted with an intention to randomize 110 patients with BRPC to gemcitabine-based neoadjuvant CTRT (54 Gy) followed by surgery or upfront surgery followed by CTRT.[11] Of the 50 evaluable enrolled patients, 27 were randomly assigned to neoadjuvant CTRT arm and 23 to upfront surgery arm. The overall survival (OS) at 2 years was 34.0% with a median survival of 16 months. Both OS at 2 years and median survival were significantly better in the neoadjuvant CTRT group than in the upfront surgery group (40.7%, 21 months vs. 26.1%, 12 months; hazard ratio [HR] = 1.495 [95% confidence interval = 0.66–3.36]; P = 0.028). R0 resection rate was also significantly higher in the neoadjuvant CTRT arm than upfront surgery (n = 14, 51.8% vs. n = 6, 26.1%, P = 0.004). Hence, the study was terminated prematurely after recruiting 50% of the targeted accrual. No difference was observed in pattern of recurrence between two groups (88.2% vs. 88.9%, P = 1.000) and most of the recurrences were systemic with the liver being the most frequent site (41.2% vs. 66.7%).

Preliminary results of another phase III, randomized multicenter trial were presented in ASCO 2018.[12] The study evaluated the role of neoadjuvant CTRT (n = 119, 36 Gy in 15 fractions with gemcitabine 1000mg/m2) versus immediate surgery (n = 127), both followed by adjuvant gemcitabine. OS and R0 resection were significantly better in preoperative CTRT arm (median 17.1 vs. 13.5 months, HR = 0.71, P = 0.047; and 65% vs. 31%, P < 0.001, respectively). No significant difference was observed between resection rates (P = 0.15), grade ≥3 adverse events (P = 0.17). A subgroup analysis of patients who actually underwent a resection showed a median OS of 16.8 for immediate surgery group and 29.9 months for preoperative CTRT group (P < 0.001).

The early result of these studies by showing a significant survival benefit for preoperative CTRT opened a new insight into the management of this potentially incurable malignancy. Various reasons can be drawn for this improvement in survival in preoperative CTRT group; observed benefit can be because of use of early systemic therapy to eradicate micrometastases as evidenced by decrease in tumor burden of the primary tumor on the adjacent lymph node, downstaging of PC to improve R0 resection with optimal selection of patients for surgery, and appropriate use of standard surgical procedure.

Although clinical benefit was clearly evidenced by results of these two important randomized studies in PC, following issues need to be addressed further. Survival of BRPC patients vary not only with respect to involvement of particular vessel with worst outcome observed for superior mesenteric artery invasion but also with degree of vascular invasion.[8],[13] Hence, using modern-day radiotherapy treatment planning, role of differential doses with a higher prescription to critical regions needs to be determined. Appropriate chemotherapy regimen need to be investigated further as recent study from France has shown better median survival for adjuvant combined chemotherapy with FOLFIRINOX versus gemcitabine (54 vs. 35 months) with manageable toxicities.[14] Various models have also shown that hypofractionation and high-radiation dose are associated with apoptosis of endothelial cells.[15] Although multiple prospective and retrospective studies have shown benefit of stereotactic body radiotherapy (SBRT) with acceptable toxicities,[16],[17] now it is time to establish a concrete role of SBRT in neoadjuvant setting. With the understanding of immune response, DNA damage, and apoptosis, hypofractionation or SBRT is likely to find pivotal phase in management of PC. Currently ongoing phase II randomized trial evaluating FOLFIRIONOX-based neoadjuvant chemotherapy with or without SBRT prior to surgery will answer these questions in near future.[18]


  Conclusion Top


Initial results of recent trials addressing the management of BRPC by using preoperative chemoradiotherapy have shown a meaningful improvement in clinical outcomes. The results are encouraging for incorporation of radiotherapy in the neoadjuvant management of PC. As there is a renewed interest in role of radiation in neoadjuvant setting, more evidence are expected to emerge in near future.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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National Cancer Institute SEER. Cancer Stat Facts: Pancreas cancer. Bethesda, MD: National Cancer Institute. Available from: http://seer.cancer.gov/statfacts/html/pancreas.html. [Last accessed on 24 Oct 2018].  Back to cited text no. 1
    
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Varadhachary GR, Tamm EP, Abbruzzese JL, Xiong HQ, Crane CH, Wang H, et al. Borderline resectable pancreatic cancer: Definitions, management, and role of preoperative therapy. Ann Surg Oncol 2006;13:1035-46.  Back to cited text no. 3
    
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Callery MP, Chang KJ, Fishman EK, Talamonti MS, William Traverso L, Linehan DC. Pretreatment assessment of resectable and borderline resectable pancreatic cancer: Expert consensus statement. Ann Surg Oncol 2009;16:1727-33.  Back to cited text no. 4
    
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Abrams RA, Lowy AM, O’Reilly EM, Wolff RA, Picozzi VJ, Pisters PW. Combined modality treatment of resectable and borderline resectable pancreas cancer: Expert consensus statement. Ann Surg Oncol 2009;16:1751-6.  Back to cited text no. 5
    
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National Comprehensive Cancer Network. Pancreatic adenocarcinoma (version 1.2017; February 24, 2017). Available from: https://www.nccn.org/professionals/physician_gls/PDF/pancreatic.pdf. [Last accessed on 24 Oct 2018].  Back to cited text no. 6
    
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Russo S, Ammori J, Eads J, Dorth J. The role of neoadjuvant therapy in pancreatic cancer: A review. Future Oncol 2016;12:669-85.  Back to cited text no. 7
    
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Gillen S, Schuster T, Meyer Zum Büschenfelde C, Friess H, Kleeff J. Preoperative/neoadjuvant therapy in pancreatic cancer: A systematic review and meta-analysis of response and resection percentages. PLoS Med 2010;7:e1000267.  Back to cited text no. 8
    
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Andriulli A, Festa V, Botteri E, Valvano MR, Koch M, Bassi C, et al. Neoadjuvant/preoperative gemcitabine for patients with localized pancreatic cancer: A meta-analysis of prospective studies. Ann Surg Oncol 2012;19:1644-62.  Back to cited text no. 9
    
10.
Festa V, Andriulli A, Valvano MR, Uomo G, Perri F, Andriulli N, et al. Neoadjuvant chemo-radiotherapy for patients with borderline resectable pancreatic cancer: a meta-analytical evaluation of prospective studies. JOP 2013;14:618-25.  Back to cited text no. 10
    
11.
Jang JY, Han Y, Lee H, Kim SW, Kwon W, Lee KH, et al. Oncological benefits of neoadjuvant chemoradiation with gemcitabine versus upfront surgery in patients with borderline resectable pancreatic cancer: A prospective, randomized, open-label, multicenter phase 2/3 trial. Ann Surg 2018;268:215-22.  Back to cited text no. 11
    
12.
Tienhoven Geertjan Van. Preoperative CTRT vs. immediate surgery for resectable and borderline resectable pancreatic cancer (PREOPANC-1): A randomized, controlled, multicenter phase III trial. J Clin Oncol 2018;36(18_supp). DOI: 10.1200/JCO.2018.36.18_suppl.LBA4002).  Back to cited text no. 12
    
13.
Yamada S, Fujii T, Sugimoto H, Nomoto S, Takeda S, Kodera Y, et al. Aggressive surgery for borderline resectable pancreatic cancer: Evaluation of national comprehensive cancer network guidelines. Pancreas 2013;42:1004-10.  Back to cited text no. 13
    
14.
Conroy T, Hammel P, Hebbar M, Abdelghani MB, Wei AC, Raoul J-L, et al. Unicancer GI PRODIGE 24/CCTG PA.6 trial: A multicenter international randomized phase III trial of adjuvant mFOLFIRINOX versus gemcitabine (gem) in patients with resected pancreatic ductal adenocarcinomas. J Clin Oncol 2018;36(18_suppl). DOI: 10.1200/JCO.2018.36.18_suppl.LBA4001.  Back to cited text no. 14
    
15.
Garcia-Barros M, Paris F, Cordon-Cardo C, Lyden D, Rafii S, Haimovitz-Friedman A, et al. Tumor response to radiotherapy regulated by endothelial cell apoptosis. Science 2003;300:1155-9  Back to cited text no. 15
    
16.
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.  Back to cited text no. 16
    
17.
Robin TP, Goodman KA. Radiation therapy in the management of pancreatic adenocarcinoma: Review of current evidence and future opportunities. Chin Clin Oncol 2017;6:28.  Back to cited text no. 17
    
18.
Katz MHG, Ou FS, Herman JM, Ahmad SA, Wolpin B, Marsh R, et al.; Alliance for Clinical Trials on Oncology. Alliance for clinical trials in oncology (ALLIANCE) trial A021501: Preoperative extended chemotherapy vs. Chemotherapy plus hypofractionated radiation therapy for borderline resectable adenocarcinoma of the head of the pancreas. BMC Cancer 2017;17:505.  Back to cited text no. 18
    




 

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