Clinical Review & Education

Review

Therapeutic Advances in Localized Pancreatic Cancer

Susan Tsai, MD, MHS; Douglas B. Evans, MD

IMPORTANCE It is estimated that pancreatic cancer (PC) will become the second leading

cause of cancer-related death in the United States by 2030.

OBSERVATIONS Clinical and preclinical data support the understanding that PC metastases
occur early in the pathogenesis of this disease, even before the primary tumor can be detected.
This has important implications for the clinical management of patients with localized PC, as
surgery alone is unlikely to be curative for most patients. The delivery of postoperative adjuvant
therapy is problematic in this disease because of the magnitude of the operation needed to
remove the primary tumor, which can affect patient recovery and delay (sometimes indefinitely)
the delivery of systemic therapy. For these reasons, the use of chemotherapy and/or
chemoradiation prior to surgery (neoadjuvant therapy) is increasingly recognized as the
preferred strategy for treatment sequencing. Neoadjuvant therapy is recommended for patients
with borderline resectable PC and, at some centers, neoadjuvant therapy has been extended to
patients with resectable PC as well. Importantly, therapeutic advances in multidrug systemic
therapy and radiation therapy have already been adopted in the neoadjuvant setting where
treatment toxicity will not be compounded by surgical recovery. In addition, the use of localregional therapies in highly selected patients with locally advanced PC, following a prolonged
period of induction systemic therapy, will be an area of intense scrutiny. Future improvements in
diagnostic biomarkers may allow for real-time sequencing of multimodality therapy for individual
patients based on a more accurate and timely assessment of treatment response.
CONCLUSIONS AND RELEVANCE Neoadjuvant treatment sequencing allows patients to receive
multimodality therapy in a manner that prioritizes early exposure to systemic therapy to
maximize the treatment of micrometastatic disease in an immune-competent host prior to
surgical intervention. Patients who complete all intended neoadjuvant therapy, including
surgery, experience an overall survival benefit that is unmatched by a surgery-first approach.

Author Affiliations: The Pancreatic

Cancer Program, The Medical
College of Wisconsin, Milwaukee;
Department of Surgery, The Medical
College of Wisconsin, Milwaukee.

JAMA Surg. doi:10.1001/jamasurg.2016.1113

Published online June 8, 2016.

Corresponding Author: Susan Tsai,

MD, MHS, Department of Surgery,
The Medical College of Wisconsin,
9200 W Wisconsin Ave, Milwaukee,
WI 53226 (stsai@mcw.edu).

ancreatic cancer (PC) is a rising public health threat and is anticipated to account for more than 48 000 cancer-related
deaths by 2030, a death rate that will be surpassed only by
lung cancer.1 In contrast to the improvements seen in the oncologic
treatments of many solid-organ cancers, the survival of patients with
PC has remained largely unchanged over the past 3 decades.2 Significant advances in surgical technique have resulted in decreased perioperative morbidity and mortality after pancreatic resection, but this
has not improved the median overall survival of patients with localized
operable PC.3 In fact, one of the proposed reasons for the lack of improvement in survival among operated on patients has been the increased use of surgery in patients previously considered high risk or
inoperable.3 Thus, gains in preoperative staging, including improved
radiographic detection of metastatic disease, must be weighed against
the use of surgery in high-risk patients with more advanced local tumors and medical comorbidities. Regardless of the reason, a median
survival of 24 months for patients treated with a surgery-first approach
with or without adjuvant therapy is unacceptable.3 Based on the observation that most patients who undergo successful surgery will develop systemic recurrence, a growing number of clinicians and scienjamasurgery.com

tists now support the hypothesis that most patients with PC have
systemic disease at the time of diagnosis, even in the absence of radiographic evidence of distant metastases.4-6 One of the most revolutionary changes in the management of PC has been a greater appreciation
for the early metastatic potential of PC; tumor biology has important
implications for treatment sequencing.7-9 Treatment strategies have
evolved to prioritize early systemic therapy for patients with localized
PC. In this review, we highlight the rationale for neoadjuvant treatment
sequencing, identify new diagnostic biomarkers in development, and
examine alternative therapeutic modalities, which are increasingly
incorporated into the treatment of patients with PC.

Treatment Sequencing for Patients

With Localized Pancreatic Cancer
As with most other solid tumors, treatments for patients with PC are
stage specific. Current staging is defined by objective radiologic classification of the extent of disease largely through the use of com(Reprinted) JAMA Surgery Published online June 8, 2016

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Clinical Review & Education Review

Therapeutic Advances in Localized Pancreatic Cancer

Table 1. Definitions of Clinical Stage: Comparison of MCW

vs NCCN Staging Criteriaa
MCW

NCCN Version 2.2015

Question What is the benefit of neoadjuvant therapy for localized

pancreatic cancer?

SMA,
celiac

No abutment

No abutment

Hepatic
artery

No abutment

No abutment

SMV-PV

50% narrowing of
SMV, PV, or SMV-PV

No tumor contact or 180 contact

without vein contour irregularity

Findings In this review, neoadjuvant treatment sequencing was

found to be associated with improved surgical selection by
identifying patients with aggressive disease biology who are at
high risk for early disease progression and, therefore, not likely to
benefit from surgical resection. The median overall survival of
patients who complete neoadjuvant therapy and surgery is
approximately 36 months compared with 24 months for patients
treated with a surgery-first approach.

Stage
Resectable

Borderline Resectable
SMA

180 (abutment)

180 (abutment)

Celiac

180 (abutment)

180 (abutment); >180 without

involvement of the aorta and amenable
to celiac resection (HA-GDA not
involved)b

Hepatic
artery

Abutment or short
segment encasementc

Contact without extension to celiac or

HA bifurcationc

SMV-PV

>50% narrowing of
SMV, PV, SMV/PV, or
short-segment
occlusionc

Contact >180 or contour irregularity

or thrombosis and reconstruction
possible (suitable proximal and distal
targets)c

Other

CT scan findings
suspicious but not
diagnostic of
metastatic disease

Tumor contact with the inferior vena

cava

Locally Advanced
SMA,
celiac

>180(encasement)

>180 (encasement); Tumor contact

with first jejunal SMA branchd

SMV-PV

Occlusion without
option for
reconstruction

Unreconstructable SMV/PV; Contact

with most proximal draining jejunal
branch to SMVd

Abbreviations: CT, computed tomography; GDA, gastroduodenal artery;

HA, Hepatic artery; MCW, Medical College of Wisconsin; NCCN, National
Comprehensive Cancer Network; PV, portal vein; SMA, superior mesenteric
artery; SMV, superior mesenteric vein.
a

Adapted with permission from Wolters Kluwer Health Inc.10

Also considered locally advanced, refer to NCCN guidelines.

Amenable to reconstruction.

Unresectable.

puted tomographic imaging (Table 1).11 Contrast-enhanced multiplanar computed tomography provides highly accurate assessments
of tumor-vessel associations, which can be used to reproducibly define the clinical stage of PC. Classification of resectable, borderline
resectable (BLR), and locally advanced PC has been defined by consensus guidelines and are essential to the development of stagespecific treatment plans.12,13 Although computed tomography and
other cross-sectional imaging studies are extremely accurate at defining the extent of the primary tumor, the detection of metastatic
disease continues to be challenging. At least 10% to 20% of patients with PC will have radiographically occult metastases at the time
of laparoscopy or laparotomy14,15; this number may be higher in some
centers throughout the world.16-18 Furthermore, within 6 months
of successful surgery, up to 60% of patients with PC experience disease relapse, as reported in the CONKO-001 (Charit Onkologie 001)
Study, a landmark randomized trial that compared adjuvant gemcitabine with observation in patients with resected PC.19 In addition, more than 76% of patients who undergo surgical resection of
the primary tumor will develop distant metastatic disease as the first
evidence of disease recurrence.5,6
Owing to the high probability of disease relapse, consensus
guidelines recommend systemic therapy for all patients with localE2

Key Points

Meaning Patients with pancreatic cancer may benefit from

neoadjuvant therapy to identify patients with pancreatic cancer
who will most benefit from surgical resection and avoid surgical
morbidity in those patients in whom surgery provides no
oncologic benefit.

ized PC.12 The current challenge for patients with localized PC is the
treatment of clinically/radiographically occult metastases, which are
present in most patients who are eligible for surgical resection. There
are 2 logical approaches to address the presence of micrometastatic disease: deliver systemic therapy in either the postoperative
(adjuvant) or preoperative (neoadjuvant) period. Multiple randomized clinical trials have assessed the benefit of adjuvant chemotherapy or chemoradiation and have consistently demonstrated an
overall improvement in median survival with adjuvant therapy (median overall survival, approximately 24 months) as compared with
surgery alone.19-22 However, it is important to recognize 2 critical limitations of this approach. First, adjuvant trials had an inherent selection bias because they excluded patients who experienced significant surgical morbidity or mortality, rendering them ineligible for trial
eligibility at 8 to 12 weeks after surgery. Overall 90-day mortality after pancreatectomy has been reported to be as high as 7.4% and procedure-related complications can occur in more than 30% of
patients.23,24 Therefore, the survival durations reported in adjuvant trials following pancreatectomy are superior to what can be
achieved in general practice as such trials included only a subset of
all patients who underwent surgery with curative intent. Second,
completion of adjuvant therapy can be challenging even when successfully initiated in the postoperative setting. In the CONKO-001
trial, 90% of patients (168/186) received a single dose of therapy,
87% (138/161) received 1 cycle of therapy, and only 62% of patients
(111/179) were able to complete all 6 cycles of gemcitabine.25 Outside the context of a clinical trial, analysis of the Surveillance, Epidemiology, and End Results Program database suggests that approximately 50% of eligible patients received adjuvant therapy
following major pancreatic resection for cancer.26 Given the limited feasibility of delivering adjuvant therapy and the increased toxicity of more effective contemporary systemic therapies, alternative treatment sequencing strategies have evolved.

Rationale for Neoadjuvant Treatment Sequencing

In contrast to an adjuvant approach, chemotherapy and chemoradiation may be more reliably delivered to patients being considered for curative surgery in the neoadjuvant setting. In 2 neoadjuvant trials, chemoradiation was completed by 84 of 85 patients

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Therapeutic Advances in Localized Pancreatic Cancer

(99%) and chemotherapy followed by chemoradiation was completed by 79 of 90 patients (88%).27,28 In addition, neoadjuvant
therapy affords a 2- to 30-month window in which patients with unfavorable tumor biology who are at risk for developing metastatic
disease progression can be identified prior to surgery. Among the
10% to 30% of patients who develop disease progression, neoadjuvant treatment sequencing prevents an operative intervention
(that would have no oncologic benefit) without any delay in exposure to additional/alternative systemic therapy, which is an important consideration in this era of improved multiagent chemotherapy. Initial concerns regarding the safety and feasibility of
neoadjuvant therapy have been largely unfounded. Foremost was
the concern that patients with potentially operable PC may develop local disease progression, which would prevent potentially curative surgical resection; the window of opportunity for surgery
could be lost. Such concerns regarding local disease progression have
not been realized,27-29 For example, among 176 patients who were
enrolled in 2 clinical trials, less than 1% of eligible patients were found
to have isolated local disease progression at the time of restaging
after neoadjuvant therapy (before planned surgery).27,28 In a contemporary experience from our institution, only 4 of 246 patients
(1.6%) were found to have local disease progression after neoadjuvant therapy; all 4 patients were assessed as having BLR disease at
the time of diagnosis.29 In addition, concerns over the toxicity of neoadjuvant therapy and the effect of treatment-related adverse effects on operative morbidity and mortality were not observed.27,28,30
The incidence of pancreatic fistula, the most frequent serious complication associated with pancreatectomy, is reduced after neoadjuvant therapy as the treated pancreas becomes more firm in response to chemoradiation.31-33 An analysis of the National Surgical
Quality Improvement Program database demonstrated no differences in 30-day mortality and morbidity rates among patients
treated with neoadjuvant therapy as compared with patients who
received surgery first.34 Furthermore, the addition of radiation may
have important implications as several series have reported decreased rates of positive margins (R1 or R2) and node-positive disease following neoadjuvant therapy.31-33 Most importantly, among
patients who are able to complete all intended neoadjuvant therapy
and surgery, median overall survival is improved by almost 12 months
(34-45 months vs 22-26 months) as compared with a surgery-first
approach.3,27,28,35
Attempts at the prospective comparison of neoadjuvant
therapy with a surgery-first approach have been unsuccessful.16,17
It is not surprising that such clinical trials have failed to meet
accrual targets, as patients and referring physicians are, in general,
unwilling to participate in clinical trials (phase II or III) that involve
randomization to 2 noticeably different treatment arms. Traditionally, randomized clinical trials usually share a common backbone of
therapy (often considered the most effective therapy) on which a
novel therapy is added to 1 arm. The difference between arms is
viewed (by the patient) as small and often the unique drug or
novel therapy in the experimental arm can only be accessed
through the trial mechanism. For patients with localized, operable
PC, the difference between immediate surgery and neoadjuvant
therapy is viewed as too great; patients assume that their physician must know which is better and, therefore, decline to participate. However, there are multiple advantages to using neoadjuvant treatment sequencing in clinical trial design, including
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identification of patients with micrometastatic disease (avoidance

of stage misclassification) and the ability to observe radiographic,
biochemical, and histologic responses to therapy (not possible in
the adjuvant setting). For these reasons, neoadjuvant therapy is
an attractive backbone for future studies of multimodality therapy
in localized PC. Neoadjuvant treatment sequencing also allows for
the expansion of window-of-opportunity trials to patients with
operable PC (who have an intact immune system in the absence of
surgery-induced immune suppression) and gets around the problem of delivering complicated multiagent systemic therapy (5fluorouracil, oxaliplatin, irinotecan, and leucovorin [FOLFIRINOX]
and gemcitabine doublets/triplets) to patients challenged by postsurgical recovery.

Treatment Sequencing for Localized Pancreatic Cancer

Multiple investigators have reported results after treating patients
with neoadjuvant therapy (Table 2). Overall, comparison of singleinstitutional series is complicated by variability in the staging definitions, chemotherapeutic agents, and radiation therapy plans.41
With an intention-to-treat analysis (including all patients in whom
neoadjuvant therapy is initiated), median overall survivals range from
23 to 33 months.38,42 No specific preoperative regimen has been universally recommended and may vary by institution and ongoing clinical trials. At our institution, clinical trial enrollment is strongly encouraged. When this is not possible, neoadjuvant treatment of
resectable PC incorporates systemic gemcitabine and external
beam radiation therapy (Figure, A). This regimen is a slight modification of the neoadjuvant treatment schema reported by Evans and
colleagues,27 which resulted in a median survival of almost 3 years
in those patients who completed all therapy to include surgery.
Available clinical trials in this country are evaluating the use of
FOLFIRINOX and gemcitabine/nab-paclitaxel given prior to surgery (clinicaltrials.gov Identifier: NCT02243007).43 At our institution, clinical trial development for patients with resectable PC has
emphasized molecular profiling of the fine-needle aspiration specimen as a guide to the choice of systemic therapy given prior to operation (clinicaltrials.gov Identifier: NCT01726582).44 Emerging clinical trials will likely favor systemic therapy followed by chemoradiation
in an effort to deliver all intended nonsurgical therapy prior to operation; the delivery of adjuvant therapy to patients who have also
received neoadjuvant treatment (especially with contemporary
therapies) is quite difficult even by an experienced physician team
at a high-volume cancer center.
Patients with BLR PC are fundamentally different from those
with resectable disease owing to a higher risk for harboring radiographically occult distant metastatic disease1,2; the highest risk for
a positive margin of resection due to tumor-artery abutment3; and
the need for a more complex operation usually involving vascular
resection and reconstruction. For these reasons, at some institutions, neoadjuvant therapy for patients with BLR PC includes both
systemic therapy and chemoradiation. Chemoradiation has been
thought to be particularly important to facilitate a margin-negative
resection for those patients with arterial abutment. At our institution, 2 months of neoadjuvant chemotherapy is given followed by
chemoradiation prior to considering surgery (Figure, B). This general treatment schema has been the foundation of treatment sequencing for those patients with BLR PC who are treated either in
or out of a clinical trial.
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Therapeutic Advances in Localized Pancreatic Cancer

Table 2. Selected Large Series of Neoadjuvant Therapy for Localized PC

Source

Design

No. of
Patients

Completed All
Neoadjuvant Therapy
and Surgery, No. (%)

Neoadjuvant Therapy

R0 Resection,
No. (%)

Median OS of Patients
Completing All
Intended Therapy, mo

R PC
Evans et al,27
2008

Phase II

86

Gemcitabine, 400 mg/m2, with

30-Gy radiation

73 (84)

68 (94)

34

Varadhachary
et al,28 2008

Phase II

90

Gemcitabine, 750 mg/m2; cisplatin,

30 mg/m2; and 30-Gy radiation

62 (69)

62 (100)

31

Christians
et al,35 2016

Single-institution
retrospective

69

Most received gemcitabine,

400 mg/m2, and 5040-Gy radiation

60 (87)

58 (97)

45

Katz et al,36
2012

Single-institution
retrospective

122

Gemcitabine-based chemotherapy
and 5040-Gy radiation

85 (66)

80 (95)

33

Motoi et al,37
2013

Phase II

Gemcitabine, 1000 mg/m2; S-1,

40 mg/m2

30 (85)

31 (86)

20

BLR PC

38

35

Rose et al,
2014

Single-institution
retrospective

64

Gemcitabine, 1000 mg/m and

docetaxel, 80 mg/m2 5040-Gy
radiation

31 (48)

27 (87)

Not met at median

follow-up of 21.6 mo

Varadhachary
et al, 39 2015

Phase II

22

FOLFIRINOX and 50.4-Gy radiation

15 (68)

13 (93)

NA

Phase II

268

R: 162 (99);
BLR: 42 (98)

5-y survival; R: 57%;

BLR: 34%

R and BLR
Takahashi
et al,40 2013

Gemcitabine, 1000 mg/m2, and

50-Gy radiation

207 (77)

Abbreviations: BLR, borderline resectable; FOLFIRINOX, fluorouracil, leucovorin, irinotecan and oxaliplatin; NA, not available; OS, overall survival; PC, pancreatic
cancer; R, resectable.

Figure. Sequencing of Neoadjuvant Therapy for Resectable and Borderline Resectable Pancreatic Cancer Outside of the Context of a Clinical Trial
(Trial Usually Preferred)
A Resectable pancreatic cancer

Dual-phase
CT staging;
CA19-9
Diagnosis
with EUS/FNA

Weekly gemcitabine and external-beam radiation

therapy 50.4 Gy in 28 fractions, M-F

Restaging
CT; CA19-9

Surgery

Restaging
CT;CA19-9

Adjuvant therapy
for 4 mo

Borderline resectable pancreatic cancer

Dual-phase
CT staging;
CA19-9
Diagnosis
with EUS/FNA

Induction
chemotherapy
for 2 mo

Restaging
CT; CA19-9

Gemcitabine-based
chemoradiation
50.4 Gy in
28 fractions, M-F

Surgery

Restaging
CT;CA19-9

Adjuvant
therapy
for 4 mo

Future clinical trials will likely incorporate all intended systemic therapy and
chemoradiation prior to surgery, for reasons that span both host/tumor biology
and practical considerations. The delivery of postoperative adjuvant therapy is
difficult and, in some patients of advanced age, made more difficult with
induction therapy prior to surgery. With improved techniques for the rapid
assessment of treatment response, we may enter an exciting time in the

management of localized pancreatic cancer that allows for the application of

tumor/patient-specific systemic therapy (with or without chemoradiation)
followed by the selective application of surgery to responding patients.
CA indicates carbohydrate antigen; CT, computed tomography;
EUS, endoscopic ultrasonography; FNA, fine-needle aspiration; M-F, Monday
through Friday.

Importance of Assessing Treatment Response

gemcitabine/nab-paclitaxel, have been associated with 30% to 40%

response rates among patients with more advanced disease, the
many patients with localized PC are likely to have minimal to modest radiographic changes in tumor size even in the setting of clinical
benefit and a normalization of CA19-9.14,36,45,46 This is likely owing
to the dense stromal component of PC, which remains radiographically unchanged even when histologic response is significant.47 Moreover, even in those tumors that demonstrate a decrease in overall

The assessment of treatment response is critically important and in

patients with localized PC, defining treatment response to therapy
can be particularly challenging. At the Medical College of Wisconsin, treatment response is assessed using 3 critically important criteria: performance status; cross-sectional imaging ; and serum biomarkers such as carbohydrate antigen (CA) 19-9. 10 Although
contemporary chemotherapy regimens, such as FOLFIRINOX and
E4

Restaging
CT; CA19-9

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Therapeutic Advances in Localized Pancreatic Cancer

size/largest diameter, the relationship of the tumor to adjacent blood

vessels generally does not change. A change in clinical stage, reflecting a change in local tumor-vessel anatomy, in response to neoadjuvant therapy rarely occurs.36 Therefore, the use of restaging
imaging should primarily be performed to (1) identify local or distant disease progression, which would alter clinical management,
and (2) facilitate operative planning. Importantly, careful attention
to radiographic findings allows for a detailed preoperative plan, especially when vascular reconstruction is anticipated. Vascular resections at the time of pancreatectomy should occur as planned
events rather than an emergent response to vascular injury. Unexpected vascular injuries can compromise the completeness of the
resection, resulting in a positive margin.48,49
Improvement in performance status and a decline in CA19-9 levels are used as surrogate markers of response under the assumption that extrapancreatic micrometastatic disease has likely responded to therapy if the condition of the patient improves and the
level of CA19-9 declines. Although most patients experience a decline in CA19-9 levels in response to neoadjuvant therapy, 14% of patients (27/194) had an increase in CA19-9 levels, and among these
patients, metastatic disease was detected in 56% (15/27).50 Therefore, clinicians should have a low threshold for expanding the diagnostic workup (magnetic resonance imaging of liver or positron emission tomography) prior to surgery in patients who have a rising
CA19-9 level after neoadjuvant therapy. In fact, as additional biomarkers beyond CA19-9 become available, dynamic changes in biomarker response to neoadjuvant therapy may be able to more accurately predict the anticipated benefit from surgery. This will be
especially important in those patients of advanced age or defined
medical comorbidities in whom surgery may be of increased risk.

Advances in Therapeutics
Following the success of FOLFIRINOX and gemcitabine/nabpaclitaxel in the management of metastatic PC, there has been renewed enthusiasm for drug development in PC. A unique advantage of neoadjuvant as compared with adjuvant clinical trials is the
ability to assess treatment efficacy in the resected specimen (pathologic response) following induction therapy.47 Neoadjuvant trials may
provide an opportunity to assess both pathologic response and dynamic monitoring of biomarker response to treatment, which may
in turn facilitate smaller adaptive clinical trial designs. Herein, we highlight a few novel developments within each aspect of multimodality therapy for patients with localized PC.

Systemic Therapy
Following the experience of FOLFIRINOX and gemcitabine/nabpaclitaxel in the metastatic setting, a growing number of programs
have explored the use of these regimens for the management of patients with localized disease, especially those with BLR PC.45,46 Early
experience with neoadjuvant FOLFIRINOX demonstrated that this
therapy can be administered safely and can be associated with a significant pathologic response.30 The initial report of neoadjuvant
FOLFIRINOX and chemoradiation included 18 patients with BLR PC,
of which 12 (67%) completed all neoadjuvant therapy and surgery.30
Of note, only 2 (17%) of the 12 patients were found to have nodepositive disease, and all 12 patients had negative (R0) margins. Simijamasurgery.com

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larly, in another series of 47 patients with BLR and locally advanced

PC, neoadjuvant FOLFIRINOX with or without radiation therapy was
associated with an 85% (40/47) resection rate and only 14 of 40
patients (35%) had node-positive disease.51 The Alliance A021101
Trial investigated the use of 4 cycles of preoperative FOLFIRINOX
followed by 50.4 Gy of radiation therapy with concurrent capecitabine in patients with BLR PC.52 Reported at the 2015 American Society of Clinical Oncology meeting, 15 of the 22 patients (68%)
completed all neoadjuvant therapy and surgery, and 2 of 22 patients (9%) had a pathologic complete response. A follow-up
study using a randomized phase II design is being developed to
specifically examine the benefit of chemoradiation. In addition,
neoadjuvant therapy with gemcitabine/nab-paclitaxel is also being
studied in a prospective randomized clinical phase II study comparing perioperative gemcitabine/nab-paclitaxel vs adjuvant gemcitabine/nab-paclitaxel in patients with resectable PC (NEONAX Trial;
clinicaltrials.gov Identifier: NCT02047513).53

Radiation Therapy
As the survival durations of patients with localized PC increase, local
disease control may become a more significant clinical concern. Local
recurrence rates after surgery have been reported to range from 20%
to60%andtheincorporationofchemoradiationtoaugmentlocalcontrol seems logical.54,55 Conventional chemoradiation regimens that
involve 3-dimensional conformal radiation have been enhanced by
techniques that improve radiation dose escalation such as intensitymodulated radiation therapy or stereotactic body radiation (SBRT). In
particular,interestinSBRThasdevelopedbecauseoftheshorterlength
of treatment (5 days vs 28 days). Initial reports of single-fraction SBRT
(25 Gy) in locally advanced PC was met with little enthusiasm owing
to the increased rates of late gastrointestinal toxicities.56 Other studies that used fractionated SBRT reported similar rates of local control
with comparable toxicity with intensity-modulated radiation therapy
in patients with locally advanced PC.57,58 The extrapolation of SBRT to
the neoadjuvant setting has been reported by 2 centers.57,59 In a retrospective report of 73 patients with BLR PC, 3 cycles of gemcitabine/
taxotere/xeloda chemotherapy was followed by 5 fractions of SBRT to
include25Gytothegrosstumorvolumeand35Gytotheareaoftumorvesselabutment.57 Followingneoadjuvanttherapy,31ofthe73patients
(42%) underwent resection. R0 resections were achieved in 30 of 31
patients (97%) but only 20 of 31 tumors (65%) were node negative;
a number lower than other reports with neoadjuvant therapy. Four patientswhodidnotundergosurgeryexperiencedlate-grade3toxicities;
3hadgastrointestinalbleedingthatrequiredembolizationand1patient
had failure to thrive and required feeding tube placement. Of the 31 patients who underwent resection, 7 (23%) had complications including
wound infection (n = 2), wound dehiscence (n = 1), and anastomotic
leak (n = 4). Another group has reported on pathologic response following SBRT for both locally advanced and BLR PC.59 Gemcitabinebased chemotherapy or FOLFIRINOX was delivered to 11 patients followed by SBRT to a dose of 24 Gy in 1 fraction or 36 Gy in 3 fractions.
An R0 resection was achieved in 10 of the 11 patients and 3 patients had
complete pathologic responses. There was 1 perioperative mortality
related to postoperative bleeding and pancreatic fistula. In addition,
2 patients developed delayed pseudoaneurysms, which were attributed to the SBRT and occurred at 4.5 to 6.6 months following surgery.
Both required embolization and 1 patient died secondary to complications related to the embolization. Proponents of SBRT extol the expe(Reprinted) JAMA Surgery Published online June 8, 2016

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Therapeutic Advances in Localized Pancreatic Cancer

ditiousdeliveryofhigh-doseradiation,whichminimizestheoveralltime
taking therapy and may facilitate a longer period of systemic chemotherapy. As the experience with SBRT matures, it will be important to
characterize the incidence of late toxicities, surgical complications, and
the ability to achieve local control before it can be accepted as equivalent to standard-fractionation intensity-modulated radiation therapy.

or long-term survival. However, it is important to remember that such

responding patients will likely realize a significant survival benefit even
without surgery, as they have been preselected based on response
to induction therapy. Therefore, it is critically important that surgery
be applied only to carefully selected patients using objective criteria
and not because other therapies have been exhausted and the medical team is unsure of what to do next.

Surgery in the Setting of Locally Advanced

Pancreatic Cancer
Given the improved response rates seen with current systemic therapies, patients who were previously thought to have nonsurgical disease are being reconsidered for surgery. Such patients have often received a lengthy course (4 months) of systemic therapy, often
followed by chemoradiation, and are then found to have a good performance status with a low or normalized serum level of CA19-9.60
Following such extended therapy, patients without disease progression have 3 options; a treatment break (rarely preferred by the asymptomatic patient with a normalized CA19-9 level), maintenance chemotherapy, or surgery. Surgery is often considered because there are
few other attractive options, complete histologic responses are rare
with systemic therapy and chemoradiation, and surgical resection of
the primary tumor is thought to offer the only option for possible cure

The limited and clinically insignificant gains in survival for patients

with localized PC over the past 3 decades have been due, in large
part, to the application of a local therapy (surgery) to a systemic disease. In contrast to a surgery-first strategy, neoadjuvant treatment
sequencing will ensure the receipt of systemic therapy by all patients and improve the discrimination between patients who will and
will not benefit from surgery. With growing acceptance, neoadjuvant therapy will be the backbone for most future studies of multimodality therapy in localized PC, which will increasingly incorporate novel investigational drug therapies and evolving techniques
and fractionation schemes for the delivery of radiation therapy.

burden of thyroid, liver, and pancreas cancers in the

United States. Cancer Res. 2014;74(11):2913-2921.

ARTICLE INFORMATION
Accepted for Publication: March 11, 2016.
Published Online: June 8, 2016.
doi:10.1001/jamasurg.2016.1113.
Author Contributions: Drs Tsai and Evans had full
access to all of the data in the study and take
responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design: Both authors.
Drafting of the manuscript: Both authors.
Statistical analysis: Evans.
Administrative, technical, or material support: Tsai.
Conflict of Interest Disclosures: None reported.
Funding/Support: We acknowledge the support
of the We Care Fund for Medical Innovation and
Research, the Ronald Burklund Eich Pancreatic
Research Fund, and the Lockton Fund for
Pancreatic Cancer Research from the Department
of Surgery at the Medical College of Wisconsin. Dr
Tsai acknowledges support from the institutional
research grant 86-004-26 from the American
Cancer Society.
Role of the Funder/Sponsor: The funders had
no role in the design and conduct of the study;
collection, management, analysis, and
interpretation of the data; preparation, review, or
approval of the manuscript; and decision to submit
the manuscript for publication.
Additional Contributions: We thank Wendy Behrs
for assistance with manuscript preparation. She did
not receive compensation. The Pancreatic Cancer
Program at the Medical College of Wisconsin is
grateful for the courageous patients and families
who have formed the basis of our experience and
reinforce the importance of multimodality care.
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