Hypofractionated ablative radiotherapy for locally advanced pancreatic cancer

Journal of Radiation Research, Vol. 57, No. S1, 2016, pp. i53–i57 doi: 10.1093/jrr/rrw016 Advance Access Publication: 29 March 2016 Supplement – ICRR highlights Hypofractionated ablative radiotherapy for locally advanced pancreatic cancer Christopher H. Crane The University of Texas MD Anderson Cancer Centre, USA *Corresponding author: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Centre, 1515 Holcombe Blvd, Unit 97, Houston, TX, USA. Tel: 713 563-2340; Fax: 713 563-2366; E-mail: Received December 1, 2015; Revised January 20, 2016; Accepted January 23, 2016 A B S T R AC T The role of radiation in locally advanced unresectable pancreatic cancer (LAPC) is controversial. Randomized trials evaluating standard doses of chemoradiation have not shown a significant benefit from the use of consolidative radiation. Results from non-randomized studies of 3–5-fraction stereotactic body radiotherapy (SBRT) have been similar to standard chemoradiation, but with less toxicity and a shorter treatment time. Doses of SBRT have been reduced to subablative levels for the sake of tolerability. The benefit of both options is unclear. In contrast, ablative doses can be delivered using an SBRT technique in 15–28 fractions. The keys to the delivery of ablative doses are computed tomography (CT) image guidance and respiratory gating. Higher doses have resulted in encouraging long-term survival results. In this review, we present a comprehensive solution to achieving ablative doses for selected patients with pancreatic tumors by using a combination of classical, modern and novel concepts of radiotherapy: fractionation, CT image guidance, respiratory gating, intentional dose heterogeneity, and simultaneous integrated protection. KE YWOR DS: IGRT, ablative, SBRT, pancreatic cancer, locally advanced, respiratory gating I N T RO D U C T I O N The role of radiation in locally advanced unresectable pancreatic cancer (LAPC) is controversial. There have been five trials that have evaluated the role of standard chemoradiation after chemotherapy in the treatment of LAPC. The trial that has had the greatest impact on clinical practice thus far is the LAP 07 trial. Preliminary data from the LAP 07 trial revealed no clear benefit from consolidative chemoradiation following chemotherapy [1]. Results from the trial were presented at ASCO 2013 and showed no benefit to the use of consolidative chemoradiation after 4 months of gemcitabine-based chemotherapy compared with 6 months of chemotherapy alone. Issues regarding the off-protocol use of chemoradiation, compliance in the chemoradiation arm, and radiation therapy quality assurance require further clarity when the full manuscript is published. These results, coupled with the introduction of more active systemic regimens, have led to a shift at most academic centers to the much more selective use of consolidative chemoradiation. Four other randomized trials have compared chemotherapy with chemoradiation [2–5]. Results have been mixed: two trials modestly favored a chemotherapy approach [3, 4], whereas the other two trials modestly supported an initial chemoradiation strategy [2, 5]. The Fédération Francophone de Cancérologie Digestive and Société Française de Radiothérapie Oncologique (FFCD–SFRO) showed superior survival of gemcitabine alone to a poorly tolerated experimental chemoradiation regimen (60 Gy to large fields with cisplatin and 5FU) that had not been tested in a Phase I or II trial [3]. The only other recent trial to compare initial chemotherapy with chemoradiation was conducted by the Eastern Cooperative Oncology Group (ECOG 4201). This trial compared gemcitabine-based chemoradiation followed by weekly gemcitabine with gemcitabine alone. A median survival benefit was seen in the chemoradiation arm. This benefit came at the cost of increased gastrointestinal toxicity [5]. A number of US cooperative group trials evaluating gemcitabine-based chemotherapy in advanced pancreatic cancer have included patients with locally advanced disease without planned radiotherapy. Median survival durations of between 9.1 and 9.9 [6–8] months have been achieved in these subsets of patients, compared with between 12 and 14.3 months in the LAP07 and FFCD–SFRO trials. The reason for this difference is unclear. Collectively, what these randomized trials illustrate most clearly is the substantial degree to which standard therapies are limited in their effectiveness. Specifically, they offer no hope of longterm survival. © The Author 2016. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/bync/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact • i53 i54 • C. H. Crane The rationale for the further study of the use of radiation therapy in LAPC is based on clinical and autopsy data indicating that 30% or more of patients die from complications related to local disease progression. As median survival durations improve in patients with locally advanced pancreatic cancer, local progression of disease will probably more commonly limit long-term survival. Better options for local tumor control than 50.4 Gy or low-dose SBRT (25–33 Gy in 5 fractions) are needed. LOCA L T UM OR CO NT ROL I N LO CA LLY AD VA N CE D PA N CR E AT IC CA NC E R Patients with pancreatic cancer want to live longer, and most of all they want some hope of cure. Although the natural history of pancreatic cancer is dominated by the development of metastatic disease, local tumor progression contributes significantly to morbidity and mortality. Locoregional progression is common, and it is clear that a subset of patients do not ever develop metastatic disease, and some patients with metastatic disease die from local tumor progression. A recent rapid autopsy series from Johns Hopkins reported that 28% of patients with locally advanced pancreatic cancer had no evidence of metastases at the time of death, and SMAD4 loss correlated with widespread distant metastatic disease [9]. We reported a similar rate of local progression–related death, as well as a correlation of SMAD4 expression with the pattern of disease related to death, in a Phase II trial of 69 patients with locally advanced pancreatic cancer that evaluated cetuximab-based chemotherapy followed by chemoradiation (50.4 Gy in 28 fractions). The median survival of 19.2 months was long enough to evaluate late local tumor progression (20% at 15 months, increased to 65% at 2 years). Local tumor progression was the dominant cause of death after 15 months [10]. The median survival in nearly all studies of locally advanced pancreatic cancer is too short to evaluate the highest-r (...truncated)