S u r g e o n - L e d C l i n i c a l Tr i a l s

in Pancreatic Cancer
a,b c,
Akhil Chawla, MD , Cristina R. Ferrone, MD *

KEYWORDS
 Pancreatic cancer  Clinical trials  Chemotherapy  Radiation

KEY POINTS
 Pancreatic cancer
 Clinical trials
 Neoadjuvant therapy
 Chemotherapy
 Radiation

BACKGROUND

With an increase in systemic options available for metastatic pancreatic cancer, there
has recently been a rise in key clinical trials focused on localized pancreatic cancer.
Many of these reports have been practice-defining and have altered the design of sub-
sequent clinical trials. The results have raised key questions for clinical trial investiga-
tors to clarify the future standard of care. The utilization of multi-agent chemotherapy
regimens in the localized disease setting has sparked cooperative group and interna-
tional collaborations in an effort to better understand the optimal regimen in the neo-
adjuvant and adjuvant disease settings. In addition, sophisticated techniques in
radiation oncology, including the increasing familiarity with hypofractionated radiation,
have boosted its use in the perioperative setting. Key to many of these trials has been
the utilization of imaging criteria to define eligibility criteria, which aim to increase the
level of quality control and standardization. However, we have learned that therein lies
a significant amount of subjectivity in interpretation between each classification,
requiring an increased sophistication in terms of trial design. This review highlights
key clinical trials in localized pancreatic cancer over the past decade, with an
emphasis on surgeon-led efforts to highlight the significant investigations that have ul-
timately paved the way for future prospective studies in pancreatic cancer.

a
Division of Surgical Oncology, Department of Surgery, Northwestern Medicine Regional
Medical Group, Northwestern University Feinberg School of Medicine, 676 N. St. Clair St., Suite
650Chicago, IL 60611, USA; b Robert H. Lurie Comprehensive Cancer Center, Chicago, IL, USA;
c
Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
* Corresponding author. Wang 460, 15 Parkman Street, Boston, MA 02114.
E-mail address: [email protected]

Surg Oncol Clin N Am 32 (2023) 143–151

https://doi.org/10.1016/j.soc.2022.08.001 surgonc.theclinics.com
1055-3207/23/ª 2022 Elsevier Inc. All rights reserved.
144 Chawla & Ferrone

ADJUVANT TRIALS IN PANCREATIC CANCER

The establishment of standard combination chemotherapy regimens such as fluoro-

uracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) and gemcitabine with
albumin-bound paclitaxel (nab-paclitaxel) in the localized disease space have
stemmed from key multi-institutional randomized clinical trials performed in the met-
astatic disease setting.1,2 These trials ultimately led to a broad acceptance of well-
defined multi-agent combination chemotherapy regimens in metastatic pancreatic
cancer due to increased efficacy when compared with single-agent therapy. The
increased experience managing the multi-agent chemotherapy-induced toxicity has
subsequently also improved. The significant improvement in the survival of patients
with metastatic pancreatic ductal adenocarcinomas (PDAC) prompted the switch
from single-agent therapy3–5 to multi-agent therapy.6–10

European Study Group for Pancreatic Cancer (ESPAC)-4 Trial

The landmark ESPAC-4randomized phase III trialestablished the first standard multidrug
adjuvant therapy regimen for pancreatic cancer.6 In this multi-center trial led by the Eu-
ropean Study Group for Pancreatic Cancer, 732 patients were randomized from six coun-
tries to either gemcitabine with capecitabine or gemcitabine treatment alone within
12 weeks of surgery. The primary endpoint of this trial was overall survival (OS) with the
intent to treat the population of patients who received at least one cycle of adjuvant ther-
apy. Patients randomized to gemcitabine with capecitabine were found to have a median
OS of 28.0 months compared with 25.5 months in the gemcitabine alone arm (hazard ratio
[HR] 0.82; 95% confidence interval [CI] 0.68–0.98; P 5 0$032). Importantly, patients who
received combination therapy had overall good tolerability of the dual-agent regimen,
with an acceptable level of toxicity using a dose reduction protocol.6

Adjuvant Therapy for Patients With Resected Pancreatic Cancer (APACT) Trial
The APACT trial evaluated gemcitabine and nab-paclitaxel in the adjuvant setting. The
phase III multicenter trial randomized 866 patients to receive the combined adjuvant
regimen or to receive adjuvant gemcitabine alone. After a median follow-up of
38.5 months, gemcitabine and nab-paclitaxel did not improve disease-free survival
(DFS) compared with the gemcitabine group (19.4 vs 18.8 months, HR 0.88; 95%CI:
0.73–1.06; P 5 .1824), which was the primary endpoint of the study. Importantly, DFS
in this study was independently assessed, as opposed to investigator assessed, with
hopes to decrease investigator bias due to lack of imaging reliability for recurrent dis-
ease. These results had initially only been presented in abstract form.11 Recently, the
updated 5-year analysis was reported for this study. The OS, a secondary endpoint in
the trial, which did not reach statistical significance in the original report, was confirmed
to be improved with the combination regimen when compared with gemcitabine alone.
The median OS in the gemcitabine and nab-paclitaxel arm was 41.8 months, compared
with 37.7 months (HR 0.80; 95% CI: 0.678–0.947; P 5 .0091). Although the results of this
study are slowly gaining traction in clinical practice, this study served to establish gem-
citabine and nab-paclitaxel as an adjuvant regimen option in pancreatic cancer.12

Unicancer Partenariat de Recherche en Oncologie Digestive (PRODIGE)

24/Canadian Cancer Trials Group (CCTG) PA.6 Trial
The Unicancer PRODIGE 24/CCTG PA.6 trial led by the Partenariat de Recherche en
Oncologie Digestive intergroup and the Canadian Cancer Trials Group established
modified FOLFIRNOX (mFOLFIRINOX) as the standard adjuvant chemotherapy
regimen for pancreatic cancer patients with good performance status.13 In this
 Surgeon-Led Clinical Trials in Pancreatic Cancer 145

multi-institutional phase III European Trial, eligible patients restricted to a postopera-

tive CA 19-9 serum level of less than 180 U/m were randomized to receive 6 months of
adjuvant mFOLFIRINOX or adjuvant gemcitabine within 3 to 12 weeks of surgical
resection.13 The primary endpoint for the trial was DFS. After a median follow-up of
69.7 months, patients treated in the mFOLFIRINOX arm showed a 5-year DFS rate
of 26.1% versus 19.0% in the gemcitabine arm (HR 0.66; 95% CI 0.54–0.82;
P 5 .0001). Medial OS in the mFOLFIRINOX arm was 53.5 months in comparison to
35.5 months in patients who received adjuvant gemcitabine (HR 0.68; 95% CI 0.54–
0.85; P 5 .0009).14 Favorable survival outcomes were seen in both arms of this trial
when compared with prior adjuvant gemcitabine trials likely because of the eligibility
restriction of good performance status and low CA 19 to 9 levels. In addition, patients
in the gemcitabine arm who recurred are likely to have benefited from contemporary
treatment regimens at the time of disease progression.
These landmark adjuvant therapy trials highlight the value of combination chemo-
therapy in the adjuvant disease setting for patients with the surgically resected disease
if their performance status allows them to tolerate their associated toxicities.

NEOADJUVANT CHEMOTHERAPY TRIALS

Experience in terms of efficacy and toxicity of mFOLFIRINOX and gemcitabine-based

combination regimens has allowed investigators to evaluate combination regimens in
the neoadjuvant setting. The utilization of combination systemic therapy in the adjuvant
setting has been shown to improve DFS and OS in the above-described landmark tri-
als.6,12,13 However, approximately half of the patients who undergo pancreatic resection
are unable to complete intended adjuvant chemotherapy.15,16 Treatment with preoper-
ative chemotherapy may lead to enhanced rates of tolerability for patients, particularly
when compared with patients receiving multi-agent regimens after recovering from
pancreatic surgery.17 Therefore, there has been an increased emphasis on the utilization
of neoadjuvant and perioperative combination therapies in localized pancreatic cancer.

Study Group of Preoperative Therapy for Pancreatic Cancer (PREP)-02/Japanese

Study Group of Adjuvant Therapyfor Pancreatic Cancer (JSAP)05 Trial
The Japanese PREP-02/JSAP05 trial, which began in 2013, was the first multi-
institutional randomized trial to report results on the use of perioperative chemo-
therapy. In total, 362 patients were enrolled at 57 centers over a 3-year period.18 Pa-
tients with localized pancreatic cancer without any evidence of arterial involvement
were enrolled after histologic confirmation and central randomization to either a peri-
operative therapy arm or an adjuvant therapy arm. Venous vascular involvement to any
extent was allowed. Patients (n 5 182) in the perioperative arm received two cycles of
neoadjuvant gemcitabine and S-1, an oral 5-fluorouracil derivative19 not available in
the United States, followed by an operation and adjuvant S-1 for 6 months. Patients
randomized to the adjuvant therapy arm (n 5 180) received 6 months of adjuvant
S-1. Preoperative therapy improved OS to 36.7 months compared with 28.8 months
in the adjuvant therapy arm (HR 0.72; P 5 .015).20 These results were among the first
prospective randomized data to show that preoperative chemotherapy leads to nodal
downstaging; patients in the perioperative arm were found to have nodal metastases
in 59.6% of patients compared with 81.5% of patients in the adjuvant therapy arm. In
addition, neoadjuvant chemotherapy therapy did not lead to any difference in surgical
outcomes including morbidity, operative time, intraoperative bleeding, rate of reoper-
ation, or operative mortality. Although this study was the first randomized multi-
institutional trial to show the benefit of perioperative therapy, by design, patients in
146 Chawla & Ferrone

the perioperative arm received two extra months of systemic therapy, when compared
with the adjuvant arm. Therefore, this trial did not definitively address the optimal
sequencing of therapy in resectable pancreatic cancer.

Southwestern Oncology Group (SWOG) S1505 Trial

The Southwest Oncology Group’s 1505 trial evaluated two standard multi-agent peri-
operative chemotherapy regimens. Patients with resectable pancreatic cancer by Na-
tional Comprehensive Cancer Network (NCCN)/Intergroup criteria,21,22 and confirmed
via a post hoc central radiologic eligibility review were eligible. In total, 147 patients
were randomized to perioperative mFOLFIRINOX therapy or therapy with periopera-
tive gemcitabine and nab-paclitaxel. Patients received 12 weeks of neoadjuvant ther-
apy, followed by an operation, and 12 weeks of adjuvant therapy.
After central radiologic review, 43 patients were ultimately excluded leaving 103
eligible patients for analysis.23 Statistical analysis for the primary endpoint included
OS with a “pick the winner” design, stratified by performance status. The trial failed
to meet the pre-specified threshold and there was no difference in median OS be-
tween the two multi-agent regimens.16 The median OS of patients treated with mFOL-
FIRINOX was 22.4 months and 23.6 months for those treated with gemcitabine and
nab-paclitaxel.16 Of 103 eligible patients who underwent neoadjuvant therapy, 26
dropped out due to progression of disease and treatment toxicity.23 Of the 77 patients
who went to the operating room, 73 underwent a curative-intent resection. A margin-
negative resection was achieved in 85% of these cases. However, only 60% were able
to begin their adjuvant therapy after recovering from the operation, with less than half
of the patients in each arm completing all protocol-defined therapy.16,23
Taken together, the results of the SWOG S1505 trial did not yield a clear direction
regarding a superior multi-agent neoadjuvant regimen. However, there were key les-
sons that were recognized from the trial results. Confirming what has been shown in
previously reported single-arm phase II studies,7,8,24 the SWOG S1505 results corrob-
orate high rates of therapy completion using multi-agent chemotherapy, with 84% to
85% of patients completing all preoperative chemotherapy. However, with 36% of all
patients not undergoing an operation due to disease progression during neoadjuvant
chemotherapy,23 increased equipoise has been raised regarding the efficacy of the
neoadjuvant strategy for all patients with technically resectable disease. Another
key takeaway from this trial involved the need for a prospective radiologic review.
Nearly a third of patients enrolled in the SWOG S1505 were determined to be ineligible
after post hoc central radiology review, underscoring the importance of integrating a
prospective central radiologic eligibility review into trial design.

Alliance A021806 Trial

The ALLIANCE A021806 trial randomizes patients with resectable pancreatic cancer
to perioperative or adjuvant chemotherapy. This phase III randomized controlled trial
seeks to elucidate the role of neoadjuvant chemotherapy in patients with resectable
pancreatic cancer. Patients with resectable pancreatic cancer based on the NCCN/
Intergroup definition are eligible for the study. The protocol includes a preregistration
phase which involves a prospective central radiologic eligibility review for confirmation
of resectable disease status. Patients are then randomized to a Perioperative Arm or
an Adjuvant Arm. The Perioperative Arm includes treatment with eight cycles of neo-
adjuvant mFOLFIRINOX treatment, followed by surgical resection, and four cycles of
adjuvant mFOLFIRINOX. The Adjuvant Arm includes upfront surgery followed by 12
cycles of adjuvant mFOLFIRINOX. Restaging scans are performed every 2 months
in both arms of the study.
 Surgeon-Led Clinical Trials in Pancreatic Cancer 147

The primary endpoint for this trial is 2-year OS. Secondary endpoints include DFS,
margin-negative resection rate, locoregional recurrence rate, and distant recurrence
rate. Importantly, this trial will directly assess the tolerability of mFOLFIRINOX therapy
in the perioperative versus the adjuvant setting with the dose-intensity of chemo-
therapy delivered as well as adverse events in each arm evaluated as a secondary
endpoint. Built-in is the key quality of life correlatives that will serve to better elucidate
how patients may tolerate each strategy. Currently, there is no level one phase III ev-
idence to guide the clear use of neoadjuvant mFOLFIRINOX treatment of resectable
pancreatic cancer. Although institutional bias exists, there is significant variability in
national practice patterns. Therefore, the ALLIANCE A021806 trial aims to establish
a new standard of care for patients with resectable disease.

RADIATION TRIALS

Radiation therapy continues to be controversial in the management of pancreatic

adenocarcinoma. Furthermore, the total dose and dosing schedule to achieve the
optimal outcome continue to be under investigation.

PREOPANC-1 Trial
The most recent phase III trial involving radiation therapy for patients with resectable
and borderline PDAC is the PREOPANC-1 study from the Netherlands.25 This study
involved 16 centers and randomized 246 patients with either resectable or borderline
pancreatic cancer to receive preoperative chemoradiotherapy, which consisted of
three cycles of gemcitabine, with the second cycle combined with radiotherapy, fol-
lowed by an operation and four cycles of adjuvant gemcitabine or to an immediate
operation and six cycles of adjuvant gemcitabine. Median OS by intention to treat
was 16.0 months in patients treated with preoperative chemoradiotherapy and
14.3 months in patients treated with immediate surgery (hazard ratio, 0.78; 95% CI,
0.58–1.05; P 5 .096). The R0 resection rate was 71% (51 of 72) in patients who
received preoperative chemoradiotherapy and 40% (37 of 92) in patients assigned
to an immediate operation (P < .001). Preoperative chemoradiotherapy was associ-
ated with a significantly better DFS, locoregional failure-free interval, rate of pathologic
lymph nodes, perineural invasion, and venous invasion. Survival analysis of patients
who underwent tumor resection and started adjuvant chemotherapy showed
improved survival with preoperative chemoradiotherapy (35.2 v 19.8 months;
P 5 .029). The proportion of patients who suffered serious adverse events was 52%
versus 41% (P 5 .096). After a median follow-up of 27 months the intent to treat anal-
ysis did not show an OS difference and the predefined subgroup of patients with sus-
pected resectable PDAC showed no significant difference in OS or DFS. However,
after a median follow-up of 59 months, neoadjuvant gemcitabine-based chemoradio-
therapy followed by surgery and adjuvant gemcitabine improved OS compared with
upfront surgery and adjuvant gemcitabine in patients with borderline resectable
pancreatic cancer (5-year OS 20.5% vs 6.5%).25

Alliance A021501
The Alliance for Clinical Oncology Trial A021501, a recently completed randomized
phase II trial, enrolling 134 patients with biopsy-confirmed pancreatic ductal adeno-
carcinoma that meets centrally reviewed anatomic criteria on imaging for the border-
line resectable disease were randomized to receive either eight cycles of
mFOLFIRINOX or seven cycles of mFOLFIRINOX followed by stereotactic body radi-
ation therapy (33–40 Gy in five fractions). Patients without evidence of disease
148 Chawla & Ferrone

progression following preoperative therapy underwent pancreatectomy and, if able,

received four additional cycles of postoperative modified fluorouracil, leucovorin, iri-
notecan, and oxaliplatin (mFOLFOX). The primary endpoint is an 18-month OS rate
of patients enrolled in each of the two treatment arms. This has not yet been pub-
lished. An interim analysis of the margin-negative resection rate within each arm
was performed which mandated the closure of the radiation arm. Although the radia-
tion arm did not show an improvement in the margin negative resection rates, the trial
was not powered to evaluate the benefit of radiation in the overall treatment of pancre-
atic adenocarcinoma. Therefore, definitive conclusions cannot be made regarding the
utility of radiation treatment in this disease.
Despite improvement in local control rates,25 there continues to be institutional,
regional, and international biases evaluating the role of radiation in the care of patients
with borderline and locally advanced pancreatic adenocarcinoma. Two Phase II clin-
ical trials conducted at the Massachusetts General Hospital for borderline and locally
advanced pancreatic cancer patients support the use of radiation in these patient
populations.7,8 Both trials enrolled 50 patients each, of whom 32 and 34 patients
went on to surgical resection in the borderline and locally advanced populations,
respectively. Most of the patients in both trials received eight cycles of neoadjuvant
FOLFIRINOX followed by 50.4 Gy of radiation with 5-fluorouracil. The margin-
negative resection rate was 97% in borderline resectable patients7 and 88% in locally
advanced patients.8 Both trials showed impressive disease-free and OS rates of
48.6 months and 64.5 months, respectively, in borderline resectable patients7 and
21.3 months and 33.0 months, respectively, in locally advanced patients.8

Locally Advanced Trials

The treatment of locally advanced diseases has improved significantly because of
more effective systemic therapies, better radiation treatments, and more aggressive
surgical approaches. Over the last decade, a larger number of patients who present
with locally advanced diseases are being considered for surgical resection. However,
the optimal preoperative treatment for locally advanced pancreatic cancer continues
to be explored.

Massachusetts General Hospital (MGH) 13-051

The MGH single institution Phase II clinical trial for locally advanced PDAC enrolled 50
patients, of whom 34 (69%) went on to surgical resection.8 Of these patients 80%
completed all 8 cycles of FOLFIRINOX, but 51% (25/49) had a grade 3 or greater
toxicity from chemotherapy. Of the 34 patients who underwent resection, 30 (88%)
had a margin-negative resection, which was the primary endpoint of the study. For
resected patients, median progression-free survival was 21.3 months and median
OS was 33.0 months.8

Neoadjuvant Chemotherapy in Locally Advanced Pancreatic Cancer (NEOLAP)

The NEOLAP Phase II trial compared the efficacy and safety of nab-paclitaxel plus
gemcitabine with nab-paclitaxel plus gemcitabine followed by FOLFIRINOX as multi-
drug induction chemotherapy regimens in locally advanced pancreatic cancer.26
Twenty-eight centers in Germany randomized 130 patients to either the nab-
paclitaxel plus gemcitabine group (64 patients) or the sequential FOLFIRINOX group
(66 patients). Surgical exploration after completed induction chemotherapy was
done in 63% (40/64) of patients and 36% were resected in the nab-paclitaxel plus
gemcitabine group, whereas 64% (42/66) patients were explored and 44% resected
in the sequential FOLFIRINOX group. After a median follow-up of 24.9 months, the
 Surgeon-Led Clinical Trials in Pancreatic Cancer 149

median OS was 18.5 months in the nab-paclitaxel plus gemcitabine group and
20.7 months in the sequential FOLFIRINOX group (HR 0.86; 95%CI 0.55–1.36;
P 5 .53). Of all the secondary endpoints evaluated, only histopathological downstag-
ing was improved in the sequential FOLFIRINOX group (ypT1/2 stage: 20/29 (69%)
versus 4/23 (17%), P 5 .0003; ypN0 stage: 15/29 (52%) versus 4/23 (17%),
P 5 .02). Although both regimens resulted in similar resection rates and OS, the
encouraging changes in the histopathologic profiles with treatment sequencing
need to be further explored.

SUMMARY

Advances in multimodality therapy have allowed pancreatic cancer patients to

continue to have improved progression-free and OS rates. Clinical trials are confirming
improved margin-negative resection rates and decreased rates of nodal involvement
resulting in encouraging OS rates. However, despite these improvements most of the
patients will continue to present distantly as their first site of recurrence.27 Internation-
ally there is consensus that patients with borderline and locally advanced pancreatic
cancer should receive neoadjuvant systemic chemotherapy. The role of radiation ther-
apy in pancreatic cancer continues to be discussed. For resectable pancreatic cancer,
the standard of care is upfront resection, and the role of neoadjuvant therapy will
hopefully be answered with the Alliance A021806 clinical trial. Improving our under-
standing of the biology of pancreatic cancer will result in improved individualized sys-
temic treatments to further raise the survival of pancreatic cancer patients.

CLINICS CARE POINTS

 Multimodality therapy is essential to optimize the treatment of patients with pancreatic

cancer.
 Neoadjuvant therapy in patients with borderline and locally advanced pancreatic ductal
adenocarcinomas has improved margin-negative resection rates and overall survival.
 The role of neoadjuvant therapy in resectable pancreatic cancer has not been clarified and
the standard of care continues to be upfront resection.

DISCLOSURE

Ferrone: Consultant for Intraop

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