Research

JAMA Oncology | Brief Report

Association of Ablative Radiation Therapy With Survival Among Patients

With Inoperable Pancreatic Cancer
Marsha Reyngold, MD, PhD; Eileen M. O’Reilly, MD; Anna M. Varghese, MD; Megan Fiasconaro, MSc;
Melissa Zinovoy, MD; Paul B. Romesser, MD; Abraham Wu, MD; Carla Hajj, MD; John J. Cuaron, MD;
Richard Tuli, MD, PhD; Lara Hilal, MD; Danny Khalil, MD, PhD; Wungki Park, MD; Ellen D. Yorke, PhD;
Zhigang Zhang, PhD; Kenneth H. Yu, MD, MSc; Christopher H. Crane, MD

Editorial page 687

IMPORTANCE Surgical resection has been considered the only curative option for patients Supplemental content
with pancreatic cancer. Nonoperative local treatment options that can provide a similar
benefit are needed. Emerging radiation techniques that address organ motion have enabled
curative radiation doses to be given in patients with inoperable disease.
OBJECTIVE To determine the association of hypofractionated ablative radiation therapy
(A-RT) with survival for patients with locally advanced pancreatic cancer (LAPC) treated with
a novel radiation planning and delivery technique.

DESIGN, SETTING, AND PARTICIPANTS This cohort study included 119 consecutive patients
treated with A-RT between June 2016 and February 2019 and enrolled in a prospectively
maintained database. Patients were treated with a standardized technique within a large
academic cancer center regional network. All patients with localized, unresectable, or
medically inoperable pancreatic cancer with tumors of any size and less than 5 cm luminal
abutment with the primary tumor were eligible.

INTERVENTIONS Ablative RT (98 Gy biologically effective dose) was delivered using standard
equipment. Respiratory gating, soft tissue image guidance, and selective adaptive planning
were used to address organ motion and limit the dose to surrounding luminal organs.

MAIN OUTCOMES AND MEASURES The primary outcome was overall survival (OS). Secondary
outcomes included incidence of local progression and progression-free survival.

RESULTS Between 2016 and 2019, 119 patients (59 men, median age 67 years) received A-RT,
including 99 with T3/T4 and 53 with node-positive disease, with a median carbohydrate
antigen 19-9 (CA19-9) level greater than 167 U/mL. Most (116 [97.5%]) received induction
chemotherapy for a median of 4 months (0.5-18.4). Median OS from diagnosis and A-RT were
26.8 and 18.4 months, respectively. Respective 12- and 24-month OS from A-RT were 74%
(95% CI, 66%-83%) and 38% (95% CI, 27%-52%). Twelve- and 24-month cumulative
incidence of locoregional failure were 17.6% (95% CI, 10.4%-24.9%) and 32.8% (95% CI, Author Affiliations: Department of
21.6%-44.1%), respectively. Postinduction CA19-9 decline was associated with improved Radiation Oncology, Memorial Sloan
Kettering Cancer Center, New York,
locoregional control and survival. Grade 3 upper gastrointestinal bleeding occurred in 10 New York (Reyngold, Zinovoy,
patients (8%) with no grade 4 to 5 events. Romesser, Wu, Hajj, Cuaron, Tuli,
Hilal, Crane); David M. Rubenstein
CONCLUSIONS AND RELEVANCE This cohort study of patients with inoperable LAPC found that Center for Pancreatic Cancer
A-RT following multiagent induction therapy for LAPC was associated with durable Research, New York, New York
locoregional tumor control and favorable survival. Prospective randomized trials in patients (Reyngold, O’Reilly, Varghese, Park,
Yu, Crane); Department of Medical
with LAPC are warranted. Oncology, Memorial Sloan Kettering
Cancer Center, New York, New York
(O’Reilly, Varghese, Khalil, Park, Yu);
Department of Epidemiology and
Biostatistics, Memorial Sloan
Kettering Cancer Center, New York,
New York (Fiasconaro, Zhang);
Department of Medical Physics,
Memorial Sloan Kettering Cancer
Center, New York, New York (Yorke).
Corresponding Author: Christopher
H. Crane, MD, Department of
Radiation Oncology, Memorial
Sloan-Kettering Cancer Center,
JAMA Oncol. 2021;7(5):735-738. doi:10.1001/jamaoncol.2021.0057 1275 York Ave, New York, NY 10065
Published online March 11, 2021. (cranec1@mskcc.org).

(Reprinted) 735
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 Research Brief Report Association of Ablative Radiation Therapy With Survival Among Patients With Inoperable Pancreatic Cancer
P
ancreatic cancer is a leading cause of cancer death in
the US.1 For patients with localized disease, surgery and
systemic therapy provide the best opportunity for du-
rable cancer control. Resection with negative margins is asso-
ciated with the best outcomes,2 but is often hindered by mes-
enteric vessel involvement. Long-term survival associated with
incompletely resected and unresected tumors has not sur-
passed a median of 12 months and 2-year rate of 20%. In ran-
domized trials, conventional doses of radiation therapy (RT)
as a consolidation strategy after gemcitabine for unresected
tumors do not improve patient survival.3-5 Multiagent chemo-
therapy regimens have since been shown to be superior to
gemcitabine. However, the importance of local tumor control
remains, and is illustrated by the survival limitation in pa-
tients with localized tumors who cannot have surgery com-
pared with those who can. Recent technological advance-
ments and innovative solutions for managing internal organ
motion have enabled safe RT dose escalation. Early reports of
dose escalation to an ablative threshold in small cohorts sug-
gested that controlling the primary tumor can improve
survival. 6,7 We report mature data on a 119-patient, uni-
formly treated cohort with regard to ablative RT (A-RT) as well
as diagnostic, therapeutic, and supportive care pathways.
Methods
Consecutive patients with localized unresectable and medi-
cally inoperable pancreatic ductal adenocarcinoma (PDAC) who
received definitive A-RT at Memorial Sloan Kettering Cancer
Center regional network June 2016 to February 2019 were in-
cluded. Tumors of any size and less than 5 cm luminal abut-
ment were eligible for A-RT. A database of baseline clinical and
treatment characteristics, outcomes, and adverse events (AEs)
was prospectively maintained at 3- and 6-month intervals. The
Memorial Sloan Kettering institutional review board ap-
proved the study, and all participants provided written in-
formed consent.
Ablative RT simulation, planning, and delivery were car-
ried out according to the standardized protocol as previously
described8 (Supplement). Briefly, fractionation schemes in-
cluded 75 Gy in 25 fractions (biologically effective dose
[BED] = 97.5 Gy) for tumors less than 1 cm from stomach or in-
testines, and 67.5 Gy in 15 fractions (BED = 97.88 Gy) for tu-
mors of 1 cm or further. Treatments were delivered on Varian
linear accelerators with RPM system for respiratory motion
management and daily cone-beam computed tomography
(CBCT) for image guidance.
Locoregional and distant progression were based on RE-
CIST 1.1 criteria. Adverse events were scored by Common Ter-
minology Criteria for Adverse Events (version 4.0). Statistical
methods are detailed in eMethods the Supplement.
Results
One hundred and nineteen consecutive nonmetastatic pa-
tients with PDAC were treated with definitive intent June 2016
736 JAMA Oncology May 2021 Volume 7, Number 5 (Reprinted)
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Key Points
Question Does irradiation dose escalation to doses known to cure
other cancers improve local tumor control and survival for patients
with localized pancreatic cancer?
Findings Ablative radiation therapy after induction chemotherapy
in 119 patients with locally advanced unresectable pancreatic
cancer was associated with a 2-year local tumor progression rate of
only 32.8% and a 2-year overall survival rate of 38% from the time
of irradiation.
Meaning Hypofractionated ablative radiation therapy was
associated with durable control of the primary tumor leading to
favorable survival outcomes.
to February 2019 (eTable 1 in the Supplement). Overall, 99
(83%) had radiographic T3/T4 disease, and 51 (49%) were node-
positive. One hundred and sixteen (97.5%) received induc-
tion chemotherapy, consisting of mFOLFIRINOX (fluoroura-
cil, oxaliplatin, irinotecan, leucovorin) (n = 66), gemcitabine/
nab-paclitaxel (n = 37), or other (n = 13) for a median of 4
months (0.5 months-13 months). Ablative RT consisted of 75
Gy in 25 fractions (n = 96) or 67.5 Gy in 15 fractions (n = 23) with
concurrent fluoropyrimidine (n = 107) or other (n = 4) chemo-
therapy.
At a median follow-up of 18.4 months from A-RT and 24.5
months from diagnosis, 55 patients had died. Median progres-
sion-free survival (PFS) and overall survival (OS) from the time
of A-RT were 6.3 months (95% CI, 5.26-8.78) and 18.2 months
(95% CI, 16.3-26.8), respectively. Median PFS and OS from di-
agnosis were 13.2 months (95% CI, 11.4-15.7) and 26.8 months
(95% CI 21.7-35.7), respectively. The 12- and 24-month OS from
the time of A-RT were 74% (95% CI, 66%-83%) and 38% (95%
CI, 27%-52%), respectively (Figure 1). The 12- and 24-month
cumulative incidence of locoregional progression (LRP) were
17.6% (95% CI, 10.4%-24.9%) and 32.8% (95% CI, 21.6%-
44.1%), respectively. Twenty-five patients were alive without
radiographic evidence of progression at the time of manu-
script preparation. Of 103 patients with data on subsequent sys-
temic chemotherapy, 19 started maintenance therapy and 53
received salvage chemotherapy during the follow-up period.
The association of baseline characteristics with OS, PFS,
and LRP are shown in eTable 2 in the Supplement. Notably,
postinduction reduction in carbohydrate antigen 19-9 (CA19-9)
compared with baseline was associated with improved PFS
(HR, 1.36; 95% CI, 1.08-1.71; P = .009) and LRP (HR, 1.86; 95%
CI, 1.55-2.25; P < .001) on univariate analysis. Using the most
optimal cut point for CA19-9 by the maximal χ2 method, 1-year
LRP rates were 16.5% vs 44.5% for patients achieving 80th per-
centile reduction in their CA19-9 vs others (P = .007), with a
trend for improved OS of 73% vs 66% (P = .09). On multivari-
able analysis, only postinduction CA19-9 reduction (HR, 1.33;
95% CI, 1.03-1.70; P = .03) and presence of central tumor high
dose (HR, 2.20; 95% CI, 1.12-4.30; P = .02) correlated with im-
proved PFS (Figure 2).
Grade 3 and 4 or higher A-RT-attributable AEs occurred
in 16 and 0 patients, respectively (eTable 3 in the Supple-
ment). Ten patients had upper gastrointestinal bleeding,
jamaoncology.com
 Association of Ablative Radiation Therapy With Survival Among Patients With Inoperable Pancreatic Cancer Brief Report Research

Figure 1. Overall Survival and Cumulative Incidence of Locoregional Progression

A Overall survival from the time of A-RT B Cumulative incidence of locoregional failure from the time of A-RT
1.0 1.0

Cumulative locoregional failure

Overall survival probability

0.8 0.8

0.6 0.6

0.4 0.4

0.2 0.2

0 0
0 10 20 30 40 0 10 20 30 40
Time since radiation, mo Time since radiation, mo
No. at risk No. at risk
All 119 81 23 6 All 117 73 15 2

A, Kaplan-Meier estimate of overall survival rates. B, Cumulative incidence of locoregional progression rates. A-RT indicates ablative radiation therapy.

Figure 2. Overall Survival and Cumulative Incidence of Locoregional Progression by CA19-9 Percent Change

A Overall survival by postinduction CA19-9 decrease B Cumulative incidence of locoregional failure by postinduction
CA19-9 decrease
1.0 1.0
P =.07

Cumulative locoregional failure

Overall survival probability

0.8 0.8

0.6 0.6

<80th Percentile
0.4 0.4
<80th Percentile
80th Percentile
0.2 0.2
P =.09 80th Percentile
0 0
0 10 20 30 40 0 10 20 30 40
Time since radiation, mo Time since radiation, mo
No. at risk No. at risk
<80th Percentile 19 9 3 0 <80th Percentile 19 7 1 0
80th Percentile 77 54 12 4 80th Percentile 76 48 10 1

CA19-9 indicates carbohydrate antigen 19-9.

related to anticoagulation in 8 and requiring endoscopic
interventions in 2.
Discussion
These data demonstrate that A-RT in anatomically suitable pa-
tients with LAPC was associated with durable locoregional tu-
mor control, which may have contributed to a favorable 2-year
survival of 38% from the time of A-RT. In comparison, con-
ventional RT has failed to improve OS compared with chemo-
therapy alone in randomized clinical trials.3-5 Median OS from
diagnosis has ranged from 8.6 to 15.2 months in patients re-
ceiving conventional RT after induction gemcitabine.3-5 Im-
portantly, less than 20% of patients receiving conventional RT
survived 2 or more years, resulting in lack of LC benchmarks
beyond 1 year.
Undoubtedly advances in systemic treatment and pa-
tient selection have contributed to the favorable outcomes in
this study. FOLFIRINOX and gemcitabine/nab-paclitaxel have
been important advances that have improved outcomes in the
metastatic and adjuvant settings. Meta-analysis of nonran-
domized prospective trials and retrospective studies have also
reported encouraging results in patients with localized dis-
ease treated with initial FOLFIRINOX. The effect of FOL-
FIRINOX on mOS (range, 10.0-32.7 months) is confounded by
resection rates up to 43% in these reports.9 Surgical resection
has until now been the only means of achieving long-term
survival.2,10 However, more complex surgical resections have
higher perioperative morbidity and mortality rates and infe-
rior long-term survival.11-13 Moreover, 2-year local recurrence
rates after surgery exceed 30%.14 Ablative RT may offer an al-
ternative in patients who are at higher surgical risk.
Ablative RT combines stereotactic technology for precise
RT delivery with innovative solutions for internal organ mo-
tion and radiation science-informed fractionation to achieve
an ablative dose to the target while sparing the adjacent lumi-
nal gastrointestinal tract. Incremental dose escalation using

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 Research Brief Report Association of Ablative Radiation Therapy With Survival Among Patients With Inoperable Pancreatic Cancer

this approach in 47 patients with LAPC resulted in improved
OS compared with conventional RT (36% vs 19%) at 2 years.7
A multi-institutional study of similarly ablative dosing in 24
patients delivered with magnetic resonance image-guidance,
an emerging technology with a distinct solution for organ mo-
tion management, resulted in a 2-year OS of 49%, further re-
affirming the benefit of dose escalation.6 In our study, 119 pa-
tients were selected after initial chemotherapy based on
anatomical suitability and treated uniformly with the same ab-
lative technique. Treatment was otherwise according to the
same institutional paradigm throughout the study period, with
outcomes and AEs longitudinally entered into a prospec-
tively maintained database. As such, this is the largest and most
homogeneous cohort, providing a unique opportunity to evalu-
ate the efficacy of A-RT.
Limitations
The limitations of this study include its retrospective, non-
randomized, single institution design, possible selection bias,
heterogeneity of induction chemotherapy regimen and dura-
tion, lack of a direct comparison RT group, and the possible
confounding effect of salvage chemotherapy on survival.
Ablative RT (98 Gy BED) following induction systemic
therapy for LAPC was safe and associated with durable local
tumor control, which could have contributed to a longer sur-
vival duration.

ARTICLE INFORMATION REFERENCES Oncol Biol Phys. 2016;94(4):755-765. doi:10.1016/j.

Accepted for Publication: December 7, 2020. 1. Siegel RL, Miller KD, Jemal A. Cancer statistics, ijrobp.2015.12.003

Published Online: March 11, 2021.
doi:10.1001/jamaoncol.2021.0057
Author Contributions: Dr Reyngold had full access
to all the data in the study and takes responsibility
for the integrity of the data and the accuracy of the
data analysis.
Concept and design: Reyngold, Zinovoy, Cuaron,
Tuli, Khalil, Yu, Crane.
Acquisition, analysis, or interpretation of data:
Reyngold, O'Reilly, Varghese, Fiasconaro, Zinovoy,
Romesser, Wu, Hajj, Tuli, Hilal, Khalil, Park, Yorke,
Zhang, Yu.
Drafting of the manuscript: Reyngold, O'Reilly,
Romesser, Khalil, Yu, Crane.
Critical revision of the manuscript for important
intellectual content: Reyngold, O'Reilly, Varghese,
Fiasconaro, Zinovoy, Romesser, Wu, Hajj, Cuaron,
Tuli, Hilal, Khalil, Park, Yorke, Zhang, Yu.
Statistical analysis: Reyngold, Fiasconaro, Khalil,
Park, Zhang, Crane.
Administrative, technical, or material support:
Reyngold, O'Reilly, Zinovoy, Romesser, Wu, Hajj,
Cuaron, Yorke.
Supervision: Reyngold, Tuli, Park, Crane.
Conflict of Interest Disclosures: Dr O'Reilly
reported grants from Genentech Roche,
Celgene-BMS, BioNTech, BioAtla, AstraZeneca,
Arcus, Silenseed, and personal fees from CytomX
Therapeutics, Rafael Therapeutics, Polaris, Merck,
AstraZeneca, Ipsen, Sobi, and Celgene outside the
submitted work. Dr Romesser reported grants and
personal fees from EMD Serono and nonfinancial
support from Elekta during the conduct of the
study. Dr Wu reported grants from CivaTech
Oncology, Inc; and personal fees from AstraZeneca
outside the submitted work. Dr Yorke reported
grants from the National Institutes of Health during
the conduct of the study. No other disclosures were
reported.
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