Editorial Opinion
Ablative Radiotherapy for Patients With Inoperable Pancreas Cancer—
Ready for Prime Time?
David P. Horowitz, MD; Karyn Goodman, MD, MS; Lisa A. Kachnic, MD
The use of radiotherapy in treating inoperable pancreatic can-
cer is a controversial topic, with conventionally fractionated
irradiation (1.8-2.0 Gy/fraction) combined with concurrent che-
motherapy demonstrating equivocal survival results in 5 phase
3 randomized clinical trials.1-5
The contemporary LAP07
Related article page 735
trial, in contrast to the older
randomized trials, used smaller radiation fields that were lim-
ited to gross disease plus margin (54 Gy in 1.8 Gy fractions) in
combination with capecitabine following 4 months of
gemcitabine chemotherapy with or without erlotinib.3 While
median overall survival was not improved by the addition of
conventional chemoradiotherapy (16.5 vs 15.2 months; P = .08),
the use of chemoradiotherapy was associated with signifi-
cantly reduced rates of local disease progression (32% vs 46%;
P = .03), longer time without receiving chemotherapy (6.1 vs
3.7 months; P = .02), and a trend toward improved progression-
free survival (hazard ratio, 0.78; P = .06). This lack of overall
survival benefit from long-course conventional radiation,
coupled with technological improvements in the planning and
delivery of radiation, has led to the use of stereotactic body
radiotherapy (SBRT) in select patients with inoperable pan-
creas cancer.
There is evidence across several solid tumor types, includ-
ing early-stage non–small-cell lung cancer, that the use of SBRT
(large conformal radiation dose delivered more than 1-5 frac-
tions) with image guidance has favorable local control and over-
all survival outcomes compared with historical convention-
ally fractionated radiation regimens.6 The hypothesis is that
these higher doses lead to increased local control, which then
translates into improved overall survival. Retrospective analy-
sis suggests that radiation dose escalation to inoperable pan-
creatic tumors may improve overall survival when a biologi-
cally effective dose (BED) of more than 70 Gy is achieved.7-9
However, this BED is substantially higher than the approxi-
mate BED of 55 Gy that is achieved with the current 25- to 33-Gy
5-fraction pancreas SBRT regimens. Nevertheless, escalating the
SBRT dose further remains challenging, mostly because of the
intimate association of pancreatic tumors with radiosensitive
luminal organs, such as the stomach and bowel.9 Moreover, if
we extrapolate from the lung cancer literature, a BED of 100 Gy
will need to be delivered to achieve an ablative effect, or more
than 90% durable local control, in pancreatic cancers.10
There are 2 emerging strategies to deliver such ablative ra-
diation doses to the pancreas. The first is daily adaptive plan-
ning using novel magnetic resonance linear accelerators. This
technology allows for a visualization of the pancreas tumor and
the critical surrounding normal tissues while the patient is ly-
ing on the treatment table. The radiation oncology physician
and physics team are able to create a daily plan that maxi-
mizes the dose to the pancreas and minimizes the excessive
radiation dose to the nearby critical organs, such as the duo-
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denum, stomach, and small/large intestines. Early retrospec-
tive data using this approach report a 49% 2-year survival rate,
median survival of 20.8 months, and no grade 3 toxicity in pa-
tients who received a BED of 70 Gy or greater.9 This tech-
nique, stereotactic magnetic resonance–guided adaptive ra-
diation therapy, is being evaluated in a prospective, phase 2
multi-institutional study (NCT03621644) that prescribes 50 Gy
in 5 fractions (BED of 100 Gy). For institutions that do not have
access to a magnetic resonance imaging accelerator, a second
approach for ablative radiation delivery is computed
tomography–based image-guided hypofractionation (higher
than the standard 1.8- to 2-Gy daily doses), which delivers more
than 15 to 25 fractions using intensity-modulated radiation and
motion management.
In this issue of JAMA Oncology, Reyngold and colleagues11
describe the use of 67.5 Gy in 15 or 75 Gy in 25 hypofraction-
ated treatment regimens (BED of 98 Gy) in their retrospective
single-institution cohort of 119 patients with locally ad-
vanced unresectable pancreatic cancer. The dose and fraction-
ation scheme were chosen based on the proximity of the tu-
mor to the stomach or bowel (a 25-fraction regimen was used
for tumors <1 cm from the gastrointestinal track and 15 frac-
tions for tumors >1 cm away), and radiation was adminis-
tered after induction chemotherapy. A total of 86.5% of pa-
tients received mFOLFIRINOX or gemc itabine/nab-
paclitaxel, and a median of 4 months of induc tion
chemotherapy was given before radiotherapy. At a median fol-
low-up of 24.5 months, median overall survival was 26.8
months, which compares favorably with the 15.2 to 16.5 months
described in the 2 arms of the randomized LAP07 trial,3 as well
as the results from a multi-institutional prospective phase 2
trial of 5-fraction SBRT that gave a total dose of 33 Gy.12 These
encouraging survival results were accompanied by low toxic-
ity rates; no grade 4 to 5 toxicity was observed, and only an
8% grade 3 gastrointestinal hemorrhage rate was noted, in
which 8 of 10 patients were receiving concurrent anticoagu-
lation. While these single-institution results are promising, pre-
vious data from the same institution that used a convention-
ally fractionated radiation of 50.4 to 56 Gy after 3 to 4 months
of induction chemotherapy in 134 patients with locally ad-
vanced cancer, of whom only 25% received FOLFIRINOX, dem-
onstrated 1- and 2-year overall survival rates of 85% and 47%,
respectively.13 Compared with the findings of multiple ran-
domized clinical trials, these results highlight the need to evalu-
ate the effect of a treatment approach outside of a highly spe-
cialized tertiary care center.
Contradicting the traditional dogma of radiation oncol-
ogy, which sought to give homogeneous radiation doses and
reduce hotspots within the treatment target, the stereotactic,
ablative technique used by Reyngold and colleagues11 gave in-
tentionally inhomogeneous doses with significant hotspots
within the target volume to achieve sharp dose gradients that
(Reprinted) JAMA Oncology May 2021 Volume 7, Number 5 687
 Opinion Editorial

spare normal tissues. A high central tumor dose was also as-
sociated with improved progression-free survival. However,
these sharp dose gradients still place normal tissues very close
to potentially injurious doses of radiation, and the results re-
ported must be interpreted cautiously before being widely ad-
opted, in keeping with recommendations from the American
Society of Radiation Oncology clinical practice guidelines for
pancreatic cancer.14 Verification of the association between the
target and organs at risk before treatment, and use of adap-
tive planning as needed, as briefly described in this article11 and
elsewhere, is highly operator dependent.15 At least as impor-
tant as the technical planning capabilities for highly confor-
mal, ablative radiation treatment, which has rapidly been ad-
opted for treating primary and metastatic tumors, is the ability
to accurately localize the correct target and deliver treatment
safely. Whether such techniques can be applied outside of a
single center must be studied in a prospective manner.
Beyond questions about the generalizability of the tech-
niques used in this cohort study, a future multicenter trial must
address other issues. Most notably is the type and duration of
chemotherapy used. While more than 85% of the partici-
pants in this study received mFOLFIRINOX or gemcitabine/
nab-paclitaxel, the median duration of induction therapy was
only 4 months. Additionally, there was substantial variability
of the use of adjuvant and salvage chemotherapy, with scant
details provided. A randomized trial of 6 months of mFOL-
FIRINOX or gemcitabine/nab-paclitaxel followed by BED-
driven ablative radiotherapy (50 Gy in 5 fractions, 67.5 Gy in
15 fractions, or 75 Gy in 25 fractions) would help to answer this
important question. Given the negative findings of the LAP07
trial, the onus is on the radiation oncology community to dem-
onstrate that our technically exquisite capabilities translate into
treatments that finally move the needle for inoperable pan-
creatic cancer.

ARTICLE INFORMATION
Author Affiliations: Department of Radiation
Oncology, Columbia University Irving Medical
Center, New York, New York (Horowitz, Kachnic);
Columbia University Herbert Irving Comprehensive
Cancer Center, New York, New York (Horowitz,
Kachnic); Department of Radiation Oncology, Icahn
School of Medicine at Mount Sinai, New York, New
York (Goodman).
Corresponding Author: Lisa A. Kachnic, MD,
Department of Radiation Oncology, Columbia
University Irving Medical Center, 622 W 168th
Street, New York, NY 10032 (lak2187@cumc.
columbia.edu).
Published Online: March 11, 2021.
doi:10.1001/jamaoncol.2021.0028
Conflict of Interest Disclosures: Dr Kachnic
reports honoraria from UpToDate. Dr Goodman
reported serving on the advisory board for
RenovoRx. No other disclosures were reported.
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