Seminars in Oncology 46 (2019) 19–27

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Seminars in Oncology
journal homepage: www.elsevier.com/locate/seminoncol

Neoadjuvant Treatment for Pancreatic Cancer

Alexander G. Raufi, MD a,∗, Gulam A. Manji, MD, PhD a, John A. Chabot, MD b, Susan E. Bates, MD a
a
The Division of Medical Oncology, Columbia University Medical Center, New York, NY
b
The Department of Surgery, Columbia University Medical Center, New York, NY

a r t i c l e i n f o a b s t r a c t

Article history: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with limited effective therapeu-
Received 11 December 2018 tic options and exceedingly high mortality rates. Currently, cure can only be achieved through resection,
Accepted 11 December 2018
however the vast majority of patients present with advanced disease for which upfront surgery is not
an option. In an effort to improve surgical candidacy, neoadjuvant chemotherapy, with or without ra-
Keywords: diation therapy, is often used in an effort to downstage borderline resectable and locally advanced tu-
Pancreatic Cancer mors, and some argue for its use even in patients with resectable tumors. Underlying this thinking is the
Neoadjuvant therapy recognition that pancreatic cancer is simultaneously both a locally invasive and systemic disease, even
Resectable in patients without evidence of metastasis on imaging. Current evidence to date is largely retrospec-
Borderline resectable
tive, but suggests that neoadjuvant therapy can increase R0 (pathologically negative margin) resection
Locally advanced
rates and improve overall survival. The standard approach to neoadjuvant treatment involves choosing
between the two most active combination regimens for metastatic disease, namely modified FOLFIRNOX
and gemcitabine/nab-paclitaxel. Nonrandomized data indicate that these regimens can yield resection
rates up to 68% and 36%, in borderline resectable and locally advanced PDAC, respectively. Furthermore,
randomized data in patients with resectable PDAC treated with gemcitabine-based neoadjuvant therapy
suggests that despite an approximate 10% drop in resection rates, there is a significant improvement in
median overall survival. Herein, we will discuss the rationale for neoadjuvant therapy, current and for-
mer treatment regimens, common issues faced by clinicians when using these combinations, and several
ongoing clinical trials.
© 2018 Elsevier Inc. All rights reserved.

Contents

Background. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
Rationale for neoadjuvant therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
Data supporting neoadjuvant therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
Defining resectable, borderline resectable, and locally advanced pancreatic cancer and treatment effect . . . . . . . . . . . . . . . . . . . . . 20
Trials with neoadjuvant therapy in patients with resectable disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
Trials with neoadjuvant therapy in patients with borderline resectable disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Trials with neoadjuvant therapy in patients with locally advanced disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Currently used regimens for neoadjuvant chemotherapy in patients with BR or LA disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
FOLFIRINOX. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Gemcitabine/nab-paclitaxel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
Gemcitabine/docetaxel/capecitabine (GTX). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
Complexities of neoadjuvant therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
Ongoing trials with neoadjuvant therapy in patients with resectable, BR, or LA pancreatic cancer . . . . . . . . . . . . . . . . . . . . . . . . . . 25
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
Supplementary materials. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
∗
Corresponding author. Columbia University, 161 Fort Washington Avenue at W.
165th Street, New York, NY 10032. E-mail address: agr2139@cumc.columbia.edu (A.G. Raufi).

https://doi.org/10.1053/j.seminoncol.2018.12.002
0093-7754/© 2018 Elsevier Inc. All rights reserved.

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20 A.G. Raufi, G.A. Manji and J.A. Chabot et al. / Seminars in Oncology 46 (2019) 19–27
Background
The aggressive nature of pancreatic ductal adenocarcinoma
(PDAC) makes it a particularly challenging disease to treat. At the
time of diagnosis, approximately 9% of cases will have localized
disease and 29% regional disease; but in total only 15%–20% will
be deemed resectable [1]. Pancreaticoduodenectomy, developed by
Allen Whipple at Columbia University, is the primary procedure
performed for patients with resectable tumors of the pancreatic
head, where over 65% of pancreatic cancer is discovered [2]. It is a
technically challenging operation, given the proximity of the pan-
creas to major vascular structures, and it carries substantial opera-
tive and postoperative risks. Unfortunately, even with a successful
R0 resection (pathologically negative margin), neither pancreatico-
duodenectomy nor distal pancreatectomy, can guarantee a cure and
rates of recurrence approach 80% [3].
Rationale for neoadjuvant therapy
1. To increase R0 resection rates by reducing tumor bulk and
involvement of nearby structures.
2. To downstage disease.
3. To decrease surgical complexity.
4. To give patients suffering from weight loss or biliary ob-
struction time to improve their performance status for
surgery.
5. To ensure that all patients receive chemotherapy.
6. To allow emergence of resistant, already present metastatic
disease, if such exists.
7. To treat locally invasive disease before resection, as surgery
may alter perfusion in the area.
8. To treat micrometastatic disease earlier, at the time of diag-
nosis.
There are several compelling reasons to consider neoadjuvant
therapy (Text Box). Since surgical resection represents the only
treatment modality that can lead to cure, increasing resectability
of borderline resectable (BR) and locally advanced (LA) tumors has
been a major focus of recent trials. In addition, by decreasing tu-
mor bulk and vessel involvement, neoadjuvant therapy may fulfill
another goal, it may also increase R0 resection rates, which unsur-
prisingly is associated with improved survival [4]. It is widely rec-
ognized that pancreatic cancer is both a locally invasive and sys-
temic disease in the majority of patients at presentation, which is
in part supported by the fact that, despite complete resection and
adjuvant therapy, disease recurs in the majority of patients and
5-year survival rates approach 30% [5–9]. Therefore, neoadjuvant
therapy offers an opportunity to treat micrometastatic disease ear-
lier, which can be particularly relevant in cases of prolonged sur-
gical recovery. Significant delays in initiating adjuvant therapy are
not uncommon and approximately 20% of patients are unable to
recover sufficiently following surgery to receive any adjuvant ther-
apy [10].
The two most frequently used neoadjuvant regimens are
mFOLFIRINOX (5-FU, leucovorin, irinotecan and oxaliplatin) and
gemcitabine/nab-paclitaxel. While the choice of one versus the
other depends on several factors, there is good evidence that ei-
ther of these “modern” regimens outperforms older combinations,
or single agent therapy [11,12].
Data supporting neoadjuvant therapy
The increasing focus on neoadjuvant options is supported pri-
marily by data from small, single institution trials and several large
meta-analyses (Table 1). In one of the largest meta-analyses per-
formed to-date, Gillen et al pooled data from 111 neoadjuvant tri-
als conducted between 1966 and 2009 [13]. In total, 4,394 patients
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with a diagnosis of PDAC were included and were grouped into
two cohorts: resectable and nonresectable disease. Of those pa-
tients initially diagnosed with nonresectable disease, 46.9% under-
went surgical exploration after neoadjuvant therapy and 69.9% of
these were able to undergo successful resection, with an R0 re-
section rate of 79.2%. The authors estimated a median overall sur-
vival (mOS) for these patients of 20.5 months, which mirrors that
of patients with resectable disease at diagnosis. A major drawback
of this study was that the analysis was not done by intention-to-
treat which, if performed, would reduce potential bias in treat-
ment effect (survival bias), since clearly not all patients proceed
to surgery. In 2017, D’Angelo et al performed one of the first meta-
analyses to report survival using ITT analysis [14]. Twelve prospec-
tive neoadjuvant studies with both resectable and either border-
line resectable and locally advanced PDAC (BR/LA disease), pub-
lished between 2008 and 2015, were included and the authors
reported a resection rate of 65%, and notably, a similar mOS of
22.78 months. More recently, Versteijne et al performed a meta-
analysis on pooled data from 38 trials, again using ITT analysis,
and included a total of 3,484 patients diagnosed with resectable or
BR pancreatic cancer [15]. They reported no meaningful difference
in mOS for patients with resectable disease treated with upfront
surgery versus neoadjuvant therapy (17.14 v 18.2 months) however,
there was a difference in mOS, favoring neoadjuvant therapy over
upfront surgery, in patients with BR disease (19.2 v 12.8 months).
R0 resection rates favored those receiving neoadjuvant therapy, in
both resectable (85% v 71.4%) and BR disease (88.6% v 63.9%). Sim-
ilar results were also reported in a large meta-analysis by Suker et
al (see below), who examined outcomes with neoadjuvant FOLFIRI-
NOX in 315 patients from 11 studies, and reported that 25% of pa-
tients were effectively downstaged and able to undergo resection
[16].
In 2017, Mokdad et al published a unique retrospective study
utilizing propensity score matched analysis to investigate the role
of neoadjuvant therapy in patients with early stage pancreas can-
cer. The authors queried the National Cancer Database for patients
with stage I or II PDAC who underwent surgery between 2006 and
2012. A total of 2,005 patients treated with neoadjuvant therapy
followed by surgery were matched with 6,015 patients who under-
went upfront resection and the authors reported a median overall
survival difference of 5 months (26 v 21 months) favoring those
who received neoadjuvant therapy. Although this study was lim-
ited by inherent selection bias, as the neoadjuvant therapy group
was populated with only those patients who tolerated neoadjuvant
therapy, it demonstrates the utility of neoadjuvant therapy as a se-
lection strategy for management of patients with early stage dis-
ease [17]. A major challenge to the interpretation of these studies
is the varying definitions of resectable, BR, and LA disease; a prob-
lem that has only recently been addressed in the NCCN guidelines.
Defining resectable, borderline resectable, and locally advanced
pancreatic cancer and treatment effect
Prior to 2010, no universally adopted criteria defining BR or LA
pancreatic cancer existed and definitions varied considerably from
study to study. In an effort to rectify this problem the NCCN for-
mally adopted a set of guidelines based on criteria established by
an expert consensus group (Table 2) [18,19]. Although this has im-
proved clinical trial reporting, it has not eliminated all interin-
stitutional differences impacting decisions regarding resectability.
For example, variability remains in imaging methods and inter-
pretation. In 2012, Katz et al reviewed 122 cases of BR pancre-
atic cancer imaged after neoadjuvant therapy; 84 (69%) had sta-
ble disease, 15 (12%) had a partial response, and 23 patients (19%)
had progressive disease [20]. Although only one patient (0.8%)
had his/her disease downstaged to resectable status by imaging,
 A.G. Raufi, G.A. Manji and J.A. Chabot et al. / Seminars in Oncology 46 (2019) 19–27 21

Table 1
Meta-analyses supporting a neoadjuvant therapy strategy.

Study Patient population Data Comment

Gillen et al. (2010) • Pooled data from 111 neoadjuvant trials
[13] conducted between 1966 and 2009
• 4,394 patients with PDAC grouped into
two cohorts: resectable and
nonresectable disease
D’Angelo et al. • Pooled data from 12 prospective
(2017) [14] neoadjuvant studies published between
2008 and 2015
• 624 patients with resectable, BR, and LA
PDAC
Versteijne et al. • Pooled data from 38 trials
(2018) [15] • 3,484 patients with resectable or BR
PDAC
Suker et al. (2016) • Pooled data from 11 studies of
[16] neoadjuvant FOLFIRINOX
• 315 patients with LA PDAC
Mokdad et al., • Retrospective study of National Cancer
(2017) [17] Database between 2006 and 2012
• Utilized propensity score matched
analysis to investigate role of
neoadjuvant therapy in stage I or II PDAC
who underwent surgery
• 2,005 patients treated with neoadjuvant
therapy followed by surgery matched
with 6,015 patients with upfront
resection
Abbreviations: mOS, median overall survival; ITT, intention-to-treat; BR, borderline resectable; LA, locally advanced; PDAC, pancreatic ductal adenocarcinoma
• Amongst patients initially diagnosed with
nonresectable disease who underwent
neoadjuvant therapy:
→ 46.9% underwent surgical exploration
→ 69.9% had successful resection
→ 79.2% had R0 resection
• Estimated mOS = 20.5 months
• ITT analysis
• Resection rate = 65%
• Similar mOS of 22.78 months
• ITT analysis
• Resectable disease
→ Similar mOS for upfront surgery (17.4
months) v neoadjuvant therapy (18.2
months)
→ R0 rates favored neoadjuvant therapy
(85% v 71.4%)
• BR disease
• mOS favored neoadjuvant therapy (19.2
months) over upfront surgery, (12.8
months)
• R0 rates favored neoadjuvant therapy
(88.6 v 63.9%)
• 25% of patients effectively downstaged
and able to undergo resection
• Estimated mOS = 24.2 months
• Median overall survival of 26 months
with neoadjuvant therapy v 21 months
with upfront resection
• Estimated mOS of 20.5 months, mirrors
that of patients with resectable disease
at diagnosis
• Major drawback that analysis not done
by ITT which would reduce potential bias
in treatment effect (survival bias), since
not all patients proceed to surgery
• One of the first meta-analyses to report
survival using ITT analysis
• Focused solely on prospective trials
• One of the largest ITT meta-analysis
performed to date
• Focused on solely on LA PDAC
• Limited by inherent selection bias, as
neoadjuvant therapy group populated
with those patients who tolerated
neoadjuvant therapy
• Demonstrates the utility of neoadjuvant
therapy as a selection strategy for
management of patients with early stage
disease

Table 2
Classification for of pancreatic cancer involving the head or uncinated process (NCCN/AHPBA/SSO/SSAT).

Resectable Borderline resectable Locally advanced/Unresectable

SMV/PV No abutment/encasement or ≤180° contact without vein contour Abutment/encasement (≥1800 ), reconstructible Not reconstructible
irregularity
SMA No abutment/encasement Abutment (≤180°) Encasement (≥180°)
CHA No abutment/encasement Abutment or short-segment encasement Long-segment encasement
Celiac trunk No abutment/encasement No abutment/encasement Abutment

SMV, superior mesenteric vein; PV, portal vein; SMA, superior mesenteric artery; CHA, common hepatic artery.

85 patients (66%) underwent pancreatectomy with 81/85 (95%)
achieving an R0 resection, illustrating how inaccurate current
imaging techniques are at predicting disease status postneoadju-
vant therapy. To mitigate these discrepancies and facilitate patient
selection for surgery, structured reporting strategies have been de-
veloped, but have yet to be widely adopted [21]. Ultimately, the
question of what a surgeon feels comfortable with will continue to
vary, and will likely continue to impact treatment decisions [22–
24].
Trials with neoadjuvant therapy in patients with resectable disease
Whether patients with resectable disease should undergo
neoadjuvant treatment remains highly controversial. While there
are compelling reasons to treat (Text Box), there is a risk that some
patients will not only fail to benefit but progress to unresectable
disease. This “failure rate” has been reported to be as high as 16%
[25]. To date, no large randomized phase III control trial compar-
ing neoadjuvant therapy to upfront surgery in resectable pancre-
atic cancer has been published; however, several small trials sug-
gest the merit of this strategy (Table 3). A nonrandomized study of
neoadjuvant gemcitabine plus cisplatin given to 28 patients with
resectable disease found that 93% remained resectable and 25/28
(89%) completed pancreaticoduodenectomy with an R0 resection
rate in 20/25 (80%) [26]. At 26.5 months, the mOS in this trial
was significantly higher than seen a decade earlier with the same
agents [27]. A similar 27.2 month mOS was reported in 2014 by
O’Reilly et al combining gemcitabine and oxaliplatin [28].
A currently unresolved question in resectable pancreatic can-
cer treatment is whether or not the addition of neoadjuvant ra-
diation to chemotherapy improves outcomes. Several early phase
clinical trials have studied the tolerability and efficacy of com-
bining radiation and chemotherapy in this setting (Table 3). Two
studies randomized patients to upfront surgery or neoadjuvant

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22 A.G. Raufi, G.A. Manji and J.A. Chabot et al. / Seminars in Oncology 46 (2019) 19–27

Table 3
Neoadjuvant clinical trials for patients with resectable pancreatic cancer.

Trial N Therapy Resection rate (%) R(0) Resection rate (%) Median survival
Palmer et al. (2007) [27] 50 A: Gemcitabine 1 g/m2 every 7 days for 43 days A: 9/24 (38) A: 6/9 (75) A: 9.9 months
B: Gemcitabine 1 g/m2 + cisplatin 25 mg/m2 every 7 days B: 18/26 (70) B: 12/18 (75) B: 16.6 months
(omitting day 22 or days 15 and 36 [revised schedule])
Heinrich et al. (2008) [26] 28 Gemcitabine 1 g/m2 + cisplatin 50 mg/m2 biweekly for 4 25/28 (89) (20/25) 80 26.5 months
cycles
O’Reilly et al. (2014) [28] 38 Gemcitabine 1 g/m2 + oxaliplatin 80 mg/m2 biweekly for 4 27/38 (71) 20/27 (74) 27.2 months
cycles
Golcher et al. (2015) [29] 66 A: Surgery A: 23/33 (70) A: 16/23 (70) A: 14.4 months
B: Gemcitabine 300 mg/m2 + cisplatin 30 mg/m2 days 1, 8, B: 19/33 (58) B: 17/19 (89) B: 17.4 months
22, 29 with RT
Casadei et al. (2015) [30] 38 A: Surgery A: 15/20 (75) A: 5/15 (33) A: 19.5 months
B: Gemcitabine 1 g/m2 days 1, 8, every 21 days x 2 cycles B: 11/18 (61) B: 7/11 (64) B: 27.5 months
followed by gemcitabine 50 mg/m2 twice weekly for a
total of 6 weeks + RT

Table 4
Neoadjuvant clinical trials for patients with borderline resectable pancreatic cancer.

Trial N Therapy Resection rate (%) R(0) Resection rate (%) Median survival
2 2
Motoi et al. (2013) [31] 35 Gemcitabine 1,0 0 0 mg/m days 1 and 8 with S-1 40 mg/m BID 30/35 (86) 26/30 (87) 19.7 months
for 14 days every 21 days x 2 cycles
Landry et al. (2010) 21 A: Gemcitabine 500 mg/m2 weekly for 6 weeks with RT A: 3/10 (30) Not reported A: 19.4 months
[32]
2
B: Gemcitabine 175 mg/m on days 1, 5, 29, and 33, cisplatin 20 B: 2/11 (18) B: 13.4 months
mg/m2 on days 1–5 and 29–32, 5-FU 600 mg/m2 on days 1–5
and 29–32 followed by radiation with continuous infusion 5-FU
225 mg/m2 for 6 weeks
Kim et al. (2013) [33] 68 Gemcitabine 1 g/m2 on days 1, 8, 15 + oxaliplatin 85 mg/m2 on 43/68 (63) 36/43 (84) 18.2 months
days 1, 15 every 21 days for 2 cycles with RT, 30 Gy
∗
Katz et al. (2016) [34] 22 modified FOLFIRINOX (85 mg/m2 of oxaliplatin, 180 mg/m2 of 15/22 (68) 14/15 (93) 21.7 months
irinotecan hydrochloride, 400 mg/m2 of leucovorin calcium, and
2,400 mg/m2 of 5-FU) followed by 5.5 weeks of external-beam
RT (50.4 Gy) concurrently with capecitabine 825 mg/m2 BID
Murphy et al. (2018) 48 FOLFIRINOX (85 mg/m2 oxaliplatin, 400 mg/m2 bolus 5-FU on day 32/48 (66) 31/32 (97) 37.7 months
[35] 1, then 2,400 mg/m2 continuous infusion for 46 hours.
Leucovorin calcium, 400 mg/m2 , and irinotecan hydrochloride,
180 mg/m2 ) x8 cycles. Upon restaging, patients with resolution
of vascular involvement received RT (5 Gy × 5) with
capecitabine. Patients with persistent vascular involvement
received RT with 5-FU or capecitabine.
van Tienhoven et al. 246 A: Surgery A: 91/127 (72) A: 28/91 (31) A: 13.5 months
(2018) [36]
B: 15 times of 2.4 Gray (Gy) combined with gemcitabine, 1,0 0 0 B: 72/119 (60) B: 45/72 (63) B: 17.1 months
mg/m2 on days 1, 8, and 15, preceded and followed by a cycle of
gemcitabine
∗
Trial included patients with resectable disease.

therapy with chemo-RT suggested better overall survival with
neoadjuvant therapy, notwithstanding lower resection rates were
reported in this group. Results from the two studies were simi-
lar: 70%–75% of those assigned to upfront surgery compared with
57.5%–61% of those assigned to the neoadjuvant arm underwent
resection [29,30]. Thus, among patients with resectable disease,
neoadjuvant therapy does not significantly reduce resection rates,
but with a highest reported mOS of 27.5 months, the addition of
RT to chemotherapy does not appear to significantly outperform
chemotherapy alone. As noted above, patient populations in these
studies are often not comparable and the question of neoadjuvant
therapy for resectable disease remains far from settled.
Trials with neoadjuvant therapy in patients with borderline
resectable disease
The role of neoadjuvant chemotherapy for the treatment of bor-
derline resectable pancreatic cancer has also been investigated in
several phase II clinical trials, many of which have focused on
the addition of RT to chemotherapy (Table 4) [31–33]. Katz et al
reported the results of the Alliance for Clinical Trials in Oncol-
ogy Trial A021101, a prospective, multicenter, single-arm trial in
which patients were treated with neoadjuvant modified FOLFIRI-
NOX with RT [34]. Using current NCCN classifications, 22 patients
with BR disease were selected and treated with four cycles of mod-
ified FOLFIRINOX followed by 5.5 weeks of external-beam radiation
therapy concurrently with capecitabine prior to surgery. The au-
thors reported that despite significant ≥ grade 3 (64%), 15 (68%)
patients were able to undergo pancreatectomy with an R0 resec-
tion in 14/15 (93%). The mOS for these patients was 21.7 months
from time of registration, supporting further study of this regimen
in a phase III trial. Another single arm phase II trial with 8 cycles
of neoadjuvant FOLFIRINOX followed by RT given to 48 patients
with BR pancreatic cancer showed similar findings. [35]. Among
the 32 patients who underwent resection, 31/32 (97%) achieved an
R0 resection and the overall mOS was 37.7 months. The random-
ized phase III PREOPANC trial, which compared upfront surgery to
neoadjuvant combination gemcitabine and RT in patients with re-
sectable and BR disease, was presented at the 2018 ASCO Meeting
[36]. The study demonstrated superiority of neoadjuvant chemoRT
with a mOS of 17.1 months compared to 13.5 months in those re-
ceiving surgery alone (P = 0.074). Furthermore, although the re-
section rate in the preoperative arm was lower than that of the
surgery arm (60% v 72%), the R0 resection rate was substantially

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 A.G. Raufi, G.A. Manji and J.A. Chabot et al. / Seminars in Oncology 46 (2019) 19–27 23

Table 5
Neoadjuvant clinical trials for patients with locally advanced pancreatic cancer.

Trial N Therapy Resection R(0) Resection Median

rate (%) rate (%) survival
Herman et al. (2015) [37] 49 Gemcitabine (1,0 0 0 mg/m2 ) x3 doses followed by RT (33.0 Gy) 4/49 (8) 4/4 (100) 13.9 months
Ikeda et al. (2013) [39] 60 S-1 80 mg/m2 BID with RT (50.4 Gy) in 28 fractions over 5.5 weeks 2/60 (3) Not reported 16.2 months
Marthey et al. (2015) [43] 77 Folfirinox oxaliplatin (85 mg/m2 ), leucovorin (400 mg/m2 ), irinotecan 28/77 (36) 25/28 (89) 22 months
(180 mg/m2 ), 5-FU (400 mg/m2 bolus with a 46-hour continuous
infusion of 2.4 g/m2 ) every 2 weeks
Sherman et al. (2015) [38] 45 GTX capecitabine (1500 mg/m2 , days 1–14), gemcitabine (750 mg/m2 , 40/45 (89) 28/40 (70) 29 months
days 4 and 11) and docetaxel (30 mg/m2 , days 4 and 11) followed by
GX/RT if extensive arterial involvement

higher (63% v 31%). A follow-up Alliance study, A021501, is cur-
rently ongoing for BR disease, randomizing 134 patients to re-
ceive FOLFIRINOX with or without stereotactic body frame radia-
tion therapy (SBRT). The added value of RT in the BR setting has
been difficult to discern; notably the Alliance study was recently
suspended following interim analysis.
Trials with neoadjuvant therapy in patients with locally advanced
disease
ment was delivered every 2 weeks until disease progression, pa-
tient refusal, unacceptable toxicity, or consolidation therapy with
external radiotherapy/surgery. While no complete responses were
reported, partial responses, based on RECIST (Response Evaluation
Criteria in Solid Tumors) criteria, were noted in 22/77 (28%) pa-
tients, and 43/77 (56%) patients had stable disease. In total, 28/77
(36%) patients underwent a surgical resection with a reported R0
resection rate of 89% (25/28). Notably, 24/28 (86%) subjects were
treated with external radiotherapy prior to surgery and the mOS
for all patients enrolled on this trial was 22 months.

A large proportion of patients diagnosed with PDAC are found

to have unresectable LA disease. Although by definition these pa-
tients have no evidence of metastatic spread, treatment strategies
have focused on the use of systemic chemotherapy alone. Conver-
sion to BR or resectable disease has traditionally been exceedingly
rare, however, several studies have reported more promising re-
sults (Table 5) [37,38]. A Japanese trial investigating S-1 (a combi-
nation of tegafur, gimeracil, and oteracil potassium) combined with
RT in 60 patients with LA PDAC demonstrated favorable responses
and tolerability [39]. In this trial, 16 (27%) patients achieved a
partial response but only two (3%) patients had disease that was
downstaged and eventually resected.
In 2012, Hosein et al published the results of a retrospective
series evaluating the role of full-dose neoadjuvant FOLFIRINOX in
18 patients with locally advanced PDAC [40]. Although this trial
did include several patients with borderline resectable disease, it
represents the first published data including North American pa-
tients with LA PDAC treated with FOLFIRINOX. At maximum re-
sponse or tolerability, 7/18 (39 %) were considered resectable and
went to surgery. More recently, Blazer et al published a retro-
spective study on 43 patients with BR and LA PDAC treated with
modified FOLFIRINOX [41]. Overall the regimen was well toler-
ated, and of those who were initially diagnosed with LA disease
based on NCCN guidelines, resection was accomplished in 11 of
25 (44%) cases. Of these patients, 10/11 (91%) had an R0 resec-
tion. The median OS had not been reached at the time of publi-
cation. In 2015, Nanda et al performed a single institution retro-
spective study that included 29 patients with LA pancreatic cancer
who were also treated with modified FOLFIRINOX with or without
additional chemoRT prior to surgery [42]. Among these patients,
41.3% were able to undergo surgery and 83% achieved an R0 re-
section. One-year PFS was 49.2% and OS was 65.5% while the mOS
for this cohort was 18.6 months. These results have been further
validated in several prospective studies described below. The high
R0 rates suggest that while chemotherapy may not convert locally
advanced disease to a resectable state, when it does, the response
can be profound.
Radiation therapy has also been utilized to aid chemotherapy in
down staging of LA disease. Marthey et al reported a prospective
phase II study in 77 patients with LA PDAC treated with full dose
FOLFIRINOX with or without neoadjuvant radiation therapy [43].
Patients were enrolled at 11 French medical centers where treat-
Currently used regimens for neoadjuvant chemotherapy in
patients with BR or LA disease
FOLFIRINOX
The two preferred regimens for treating patients with BR or
LA PDAC are modified FOLFIRINOX and gemcitabine/nab-paclitaxel.
The rationale for using these combinations is based on data gath-
ered in the metastatic setting. The activity of FOLFIRINOX was ini-
tially validated by Conroy et al who, in 2011, published their land-
mark findings of a median survival of 11.1 months with this com-
bination compared to 6.8 months with gemcitabine alone [44]. Pa-
tients in the FOLFIRINOX group had higher rates of toxicity com-
pared to gemcitabine and in the United States most clinicians
have found it more toxic than originally reported. This has re-
sulted in preferential use of modified regimens, with dose-reduced
irinotecan or omission of the bolus portion of the 5-FU infusion.
These “modified FOLFIRINOX” (mFOLFIRINOX) regimens with vary-
ing drug doses and intensity (Table 6) have been studied in both
the metastatic and the neoadjuvant settings, but have never been
directly compared to the original full dose regimen [40,41,45].
Given that the goals of chemotherapy in the metastatic and neoad-
juvant setting are different, with the former to slow and control
disease and the latter to shrink and eradicate micrometastatic dis-
ease, different therapeutic strategies should be acknowledged. Be-
cause of the steep dose response curve for cytotoxic chemother-
apy, we cannot assume that modifying FOLFIRINOX in all patients
will provide comparable benefit. Without data to the contrary, in
considering FOLFIRINOX for neoadjuvant therapy, physicians should
strive for full and on-schedule dosing.
However, there is evidence that mFOLFIRINOX may be suffi-
cient for neoadjuvant therapy. Suker et al, reviewed 11 studies with
315 treatment-naive patients who received FOLFIRINOX as first-line
therapy for LA PDAC, finding that approximately one-quarter of pa-
tients were able to undergo surgical resection after treatment with
an R0 resection rate of 75% and mOS of 24.2 months [16]. Impor-
tantly, two of these studies used dose-modified FOLFIRINOX yet
reported an mOS of 21.2 months (Mahaseth et al, which did not
give bolus 5-FU [46]) and 26 months (Sadot et al, which adminis-
tered chemotherapy at 80% dose intensity [47]). Furthermore, pre-
liminary data from the PRODIGE 24/CCTG PA.6 trial, presented at

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24 A.G. Raufi, G.A. Manji and J.A. Chabot et al. / Seminars in Oncology 46 (2019) 19–27

Table 6
Modified FOLFIRINOX dosing regimens.

Trial N Therapy Dose (MG/M2) Resection R(0) Resection Median survival

rate (%) rate (%)
Mahaseth et al. (2013) [46]∗ 24 Oxaliplatin 85 42 83.3 17.8 months
Irinotecan 180
5-FU CIV 2,400
Marthey et al. (2015) [43] 77 Oxaliplatin 85 36 89 22 months
Irinotecan 180
5-FU bolus 400
5-FU CIV 2,400
Nanda et al. (2015) [42] 29 Oxaliplatin 85 41.3 83 18.6 months
Irinotecan 180
5-FU CIV 2,400
Sadot et al. (2015) [47] 101 Oxaliplatin 68 31 55 25 months
Irinotecan 144
5-FU bolus 320
5-FU CIV 1,920
Blazer et al. (2015) [41] 39 Oxaliplatin 85 51.1 86.4 18 months
Irinotecan 165
5-FU CIV 2,400
Katz et al. (2016) [34] 22 Oxaliplatin 85 68 93 21.7 months
Irinotecan 180
5-FU CIV 2,400
Stein et al. (2016) [49]∗ 31 Oxaliplatin 85 41.9 100 26.6 months
Irinotecan 135
5-FU bolus 300
5-FU CIV 2,400
Conroy et al. (2018) [48]∗∗ 247 Oxaliplatin 85 N/A N/A 54 months
Irinotecan 180 (reduced to 150 after patient #162)
5-FU CIV 2,400

Abbreviations: 5-FU, 5-fluorouracil; CIV, continuous intravenous infusion.

∗
Trial included patients with borderline resectable and locally advanced (BR/LA) as well as metastatic disease—reported here are the results of the BR/LA cases.
∗∗
mFOLFRINOX given as adjuvant therapy.

the 2018 ASCO conference, revealed the striking activity of modi-
fied FOLFIRINOX in the adjuvant setting [48]. Several phase II stud-
ies also lend support to the notion that modified FOLFIRINOX may
have significant efficacy in both the metastatic and neoadjuvant
settings (Table 6) [49]. Nonetheless, studies are needed to deter-
mine best dose and schedule for modified FOLFIRINOX.
Gemcitabine/nab-paclitaxel
Gemcitabine plus nab-paclitaxel (Abraxane) is the regimen con-
sidered to most closely approximate the activity of FOLIRINOX
in metastatic PDAC. Its role in pancreatic cancer was established
by a large phase III trial that randomized 861 patients with
metastatic PDAC to either the combination of gemcitabine and nab-
paclitaxel or gemcitabine alone and demonstrated an improvement
in median overall survival of 8.5 months from the gemcitabine
plus nab-paclitaxel combination compared to 6.7 months for sin-
gle agent gemcitabine [50]. Because gemcitabine/nab-paclitaxel
is well tolerated, and has been studied in patients over 70
years of age with slightly worse performance status, this com-
bination has rapidly been adopted in the community. Further-
more, unlike FOLFIRINOX, this regimen can be easily combined
with other agents, and many investigators are currently com-
bining the gemcitabine/nab-paclitaxel platform with other ther-
apies in an effort to further improve outcomes. Examples in-
clude addition of: (1) the immune checkpoint inhibitor nivolumab
(NCT02309177); (2) the matrix degrading hyaluronidase PEGPH20,
(NCT02715804); (3) the anti-IGF-1R/anti-ErbB3 bispecific mon-
oclonal antibody MM-141 (NCT02399137); (4) the multitarget-
ing heparan sulfate mimetic, necuparanib (NCT01621243); (5) the
selective inhibitor of nuclear export selinexor (NCT02178436);
(6) the inhibitor of notch-mediated signaling and transcrip-
tion demcizumab (NCT02289898); and (7) the hormone in-
hibitor enzalutamide (NCT02138383). Of note, the majority of
these studies are being conducted in the metastatic setting,
and several have reported negative findings, MM-141 [51]; necu-
paranib [52]; and demcizumab [53], leaving the combination of
gemcitabine/nab-paclitaxel as the only proven combination to
date.
In the neoadjuvant setting, only single institution experiences
have been reported. In 2016, Ielpo et al reported on 25 patients
with resectable and BR PDAC defined according to the NCCN guide-
lines who received neoadjuvant gemcitabine/nab-paclitaxel [54].
The resection rate among all patients was 68% (17/25 patients),
and 73% (8/11 patients) among those with BR disease; the R0
resection rate was 100% in all resectable cases. Among patients
who underwent surgery, mOS was 21 months and mDFS was 19
months.
Gemcitabine/docetaxel/capecitabine (GTX)
Investigators at Columbia University first described the 3-drug
regimen GTX for use in the PDAC in 2004 and this combination has
subsequently been tested in the neoadjuvant setting [55]. Sherman
et al described 45 patients with LA pancreatic cancer (American
Joint Committee on Cancer stage III) who were treated with 6 cy-
cles of neoadjuvant GTX [38]. Among the 34 patients with arte-
rial involvement, 29 (85%) patients underwent subsequent resec-
tion, with 20/29 (69%) patients achieving an R0 resection. All 11
patients with venous-only involvement underwent resection. The
median OS among those with arterial involvement was 29 months
and in those with venous involvement, the median OS had not
been reached at the time of publication (>42 months). A follow-up
analysis failed to reveal any presenting parameters capable of pre-
dicting response to neoadjuvant treatment with this regimen [56].
From a health economic perspective, GTX is significantly less costly
when compared to gemcitabine/nab-paclitaxel or FOLFIRINOX but
has yet to become widely adopted.

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 A.G. Raufi, G.A. Manji and J.A. Chabot et al. / Seminars in Oncology 46 (2019) 19–27 25

Table 7
Selected ongoing neoadjuvant clinical trials.

Trial Number Phase Target Therapy Primary endpoints

planned population
NCT02839343 134 II BR A: mFOLFIRINOX Overall survival
B: mFOLFIRINOX + RT
NCT02676349 90 II BR A: mFOLFIRINOX R0 resection rate
B: mFOLFIRINOX + RT
NCT03199144 70 II BR Nab-paclitaxel + gemcitabine + RT Overall survival
NCT03099265 28 II BR mFOLFIRINOX + SBRT R0 resection rate
NCT02723331 50 II R/BR Nab-paclitaxel and gemcitabine + SBRT R0 resection rate
NCT02125136 168 II BR/LA A: Nab-paclitaxel + gemcitabine Conversion rate
B: Nab-paclitaxel + gemcitabine followed by FOLFIRINOX
NCT02562716 112 II R A: mFOLFIRINOX Overall survival
B: Nab-paclitaxel + gemcitabine
NCT02305186 56 Ib/II R/BR Neoadjuvant CRT + pembrolizumab Safety and number of TILs
per HPF
NCT02749136 44 II BR mFOLFIRINOX PFS at 1 year

Abbreviations: R, resectable; BR, borderline resectable; LA, locally advanced; TILS, tumor infiltrating lymphocytes; HPF, high-power field; PFS, progression-free survival;
NAB-PACLITAXEL, nanoparticle albumin-bound paclitaxel (Abraxane).

Complexities of neoadjuvant therapy domized or real-world comparative data are desperately needed.
Until such data are available, treatment practices will vary.
The above studies demonstrate the many complexities sur-
rounding neoadjuvant trials in pancreatic cancer. Trials performed
Ongoing trials with neoadjuvant therapy in patients with resectable,
to date have often been underpowered and performed at sin-
BR, or LA pancreatic cancer
gle institutions and comparing results between trials is difficult
given the variability in treatment regimens, dosing, and lack of
Ongoing phase II clinical trials incorporating patients with bor-
uniform metrics defining resectable, BR, and LA disease. Tolerabil-
derline resectable pancreatic cancer will hopefully shed light on
ity of FOLFIRINOX is a prime example of this issue. Studies per-
optimal neoadjuvant regimens in this setting (Table 7). Several
formed in Europe typically have used one standard dosing regimen
investigate the role of newer neoadjuvant combinations such as
of FOLFIRINOX whereas those performed in the United States have
FOLFIRINOX or gemcitabine/nab-paclitaxel with or without RT.
often modified and dose reduced this combination. It remains un-
For example, the phase II Alliance A021501 (NCT02839343) trial,
clear what effect, if any, significant dose reductions have on out-
which is currently underway in the United States, randomizes pa-
comes. As discussed above, while reports of modified versions of
tients with BR pancreatic cancer to either neoadjuvant treatment
FOLFIRINOX have suggested little impact of dose reduction, large
with mFOLFIRINOX × 8 cycles or mFOLFIRINOX × 7 cycles + 5 days
randomized studies may contest these findings in the neoadjuvant
of RT followed by FOLFOX x 4 cycles. The PANDAS-PRODIGE44
setting, where maximum efficacy is needed. In addition, many tri-
study (NCT02676349), which opened in France in 2016, also com-
als under-report performance status of patients, which plays an
pares neoadjuvant mFOLFIRINOX to mFOLFIRINOX with RT. In this
important role in patient selection, especially with FOLFIRINOX or
study, patients with BR disease are randomly selected for treat-
radiation therapy. Another factor impacting interpretation and gen-
ment with neoadjuvant mFOLFIRINOX with or without preopera-
eralizability of these studies is the fact that many have been per-
tive chemoRT with capecitabine. There are also multiple single-
formed at single institutions with significant experience in treating
arm trials combining gemcitabine and nab-paclitaxel with SBRT.
patients with pancreatic cancer. This hampers the ability to apply
These include the CKPancreas (NCT03199144) trial, open in Luxem-
these results to real world practice.
bourg; and a University of Colorado trial (NCT02723331) which is
Determining the role of radiation therapy has been a complex
enrolling both resectable and BR PDAC. The phase III NEOLAP trial
issue and due to changes in technology, data from early trials can-
(NCT02125136) will intensify therapy by following nab-paclitaxel
not be easily extrapolated. Unfortunately, few trials directly com-
and gemcitabine with FOLFIRINOX in patients with BR or LA tu-
pare chemotherapy to chemoRT in the neoadjuvant setting and
mors. In addition, the SWOG 1505 (NCT02562716) trial, which
those that do are often underpowered to detect statistically sig-
has completed accrual, directly compares neoadjuvant mFOLFIRI-
nificant differences. Conventional external beam radiation therapy
NOX to gemcitabine plus nab-paclitaxel in resectable disease.
(EBRT) is rapidly being replaced by SBRT, which provides pre-
Lastly, an interesting randomized multicenter phase Ib/II study
cise delivery of radiation while sparing surrounding normal tis-
(NCT02305186) is underway and will assess the safety and the im-
sues. Two recent retrospective case series evaluated outcomes in
munological effects of chemoRT in combination with immunother-
patients with either BR or LA disease who received SBRT in the
apy (pembrolizumab) in patients with resectable or BR pancreatic
neoadjuvant setting. The first, reported data from Moffitt Cancer
cancer.
Center where a total of 159 patients were treated with chemother-
apy for 2–3 months followed by SBRT (25–30 Gy) [57]. The esti-
mated mOS was 19.2 months for BRPC patients and 15.0 months Conclusions
for LA PDAC patients (P = 0.402). In the second study, performed at
Johns Hopkins University, 88 patients (14 patients with BR and 74 Despite recent ground-breaking advances in the field of on-
patients with LA PDAC) were treated with neoadjuvant chemother- cology as a whole, considerable gains are needed for patients
apy followed by SBRT (25–33 Gy) [58]. Of the 19 (22%) patients diagnosed with pancreatic cancer. There is mounting evidence
who underwent surgery following SBRT, 84% had an R0 resection. that neoadjuvant therapy is able to not only downstage tumors
The mOS of resected patients was 20.2 months. While many in- and increase resectability, but also treats micrometastatic cancer
vestigators consider SBRT valuable in the neoadjuvant setting, ran- earlier in the disease course. Currently, there are considerable

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exclusivamente. No se permiten otros usos sin autorización. Copyright ©2021. Elsevier Inc. Todos los derechos reservados.
26 A.G. Raufi, G.A. Manji and J.A. Chabot et al. / Seminars in Oncology 46 (2019) 19–27
challenges for clinicians presented with cases of BR or LA pancre-
atic cancer and much of this stems from inexact data. This disease
requires a multidisciplinary approach to optimize outcomes. The
groundwork to studying neoadjuvant therapy for this patient
population depends on clear staging and imaging guidelines and
well designed, properly powered, phase III control trials. Until
more convincing evidence arises, regimens with proven activ-
ity in the metastatic setting, such as modified FOLFIRINOX and
gemcitabine/nab-paclitaxel, will remain the treatment of choice
for this patient population.
Conflict of interest
No known conflicts of interest for Raufi, Chabot and Bates.
Dr. Manji has received research funding for a clinical trial from
Plexxikon, MERCK, Roche/Genentech. Research funding has also
been received from MERCK and Roche/Genentech.
Supplementary materials
Supplementary material associated with this article can be
found, in the online version, at doi:10.1053/j.seminoncol.2018.12.
002.
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