This randomized controlled trial compared neoadjuvant chemoradiotherapy followed by surgery to upfront surgery followed by adjuvant therapy for patients with borderline resectable pancreatic cancer. It found that the neoadjuvant treatment approach significantly improved 2-year survival rates compared to upfront surgery. Specifically, the 2-year survival rate was 40.7% for the neoadjuvant group versus 26.1% for the upfront surgery group. The neoadjuvant approach also resulted in a higher R0 resection rate and median overall survival of 21 months compared to 12 months for upfront surgery. However, both approaches had similar recurrence rates, with most recurrences being systemic.

1. JOURNAL CLUB-
PREOPERATIVE CT+RT
IN BORDERLINE
PANCREATIC CANCER
Dr.Bhavin P.Vadodariya
05/12/2018

2. Annals of Surgery Volume XX, Number XX, Month November 2018

3. GENERAL IDEA

4. DEFINITION
Borderline tumors are best conceptualized as:
Those that involve the mesenteric vasculature to a limited extent. Those for
which resection, while possible, would likely be compromised by positive
surgical margins … in the absence of preoperative therapy.”
Katz MHG et al, Ann Surg Oncol ; E-pub Feb 23, 2013

9. COLLATERALS
Findings with a cavernous collateralization of the PV axis towards the liver
hilus as
well as a distal tumor involvement of the jejunal vein branches are
considered to be technically not resectable and do not fulfil the criteria of
BR‐PDAC, but are included in the LA‐PDAC definition.
These two latter findings (venous collateralization and jejunal branch
infiltration) are very unlikely to be converted into a resectable situation after
neoadjuvant therapy as a recanalization of venous vessels cannot be
generally expected

10. Borderline Resectable Lesions--
Criteria
MDA
2006 (Type
A)
AHPBA/SSAT/SSO
2009
NCCN
2012
Arterial Involvement:
Abutment Celiac axis √
Abutment SMA √ √ √
Abutment or encasement of short segment
CHA, typically at GDA
√ √ √
Venous Involvement:
Abutment SMV/PV with/without
impingement
√ √
Short segment occlusion of SMV, PV, or
SMV/PV confluence if reconstructable
√ √ √
‘Abutment’ <180°
‘Encasement’ >180°
Varadhachary, Ann Surg Onc, 2006
www.nccn.org, 2012 guidelines
Callery, Ann Surg Onc 2009

11. ISHIKAWA CLASSIFICATION
CIRCA 1992

12. BORDERLINE RESECTABLE PATIENTS
MD ANDERSON CLASSIFICATION
Three Categories:
Anatomy - Borderline Tumors (1/2 cases)
Biology - Equivocal Staging,CEA >500, Nodal
Condition - Marginal Performance Status
Katz MGH et al, JACS, 2008

13. Pancreatic cancer (PDAC) is one of the most aggressive solid tumor entities
and the fourth leading cause for cancer‐associated mortality in Western
countries and shows an increasing incidence which will make it the second
leading cause of cancer‐associated deaths in 2030.
Currently, only 15%–20% of all patients are candidates for upfront surgery at
the time of diagnosis, which offers the chance of long‐term survival, a
proportion that has not significantly changed during the last two decades.
 In the remaining 80%–85% of all patients, either a locally advanced or even
metastatic stage of disease is found at the initial presentation

14. AGGRESSIVE SURGERY??
For patients with borderline resectable pancreatic cancer (BRPC) and locally
advanced pancreatic cancer, some surgeons have performed aggressive
surgical treatment including major vessel resection.
However, the role of aggressive surgical treatment is questionable because
of the high morbidity, low R0 resection, and high early systemic recurrence.

15. ADVANTAGE
Early systemic treatment for undetected micrometastases
Increased R0 resection rate
Reduced pancreatic leakage.5,6

16. DISADVANTAGES
Delayed resection can reduce the chance of cure and result in an
exaggerated effect because of selection bias.
Furthermore, significant downstaging after neoadjuvant treatment is limited
and varies among previous reports owing to the lack of highly effective
treatment regimens.7,8

17. CONSENSUS STATEMNT
HACKERT
1.Patients with resectable PDAC should undergo surgical exploration and
radical resection.
2. Patients with LA-PDAC should not be considered for upfront resection,
but neoadjuvant therapy option should be evaluated, when possible included
in a clinical trial protocol.

18. CONSENSUS STATEMNT
HACKERT
In venous BR PDAC, upfront surgery should be performed and, if the
intraoperative finding matches the presumed borderline situation as defined
above, completed as an en bloc tumor removal with venous replacement.
In contrast, when suspected arterial BRPDAC is found intraoperatively to be a
true arterial involvement, no general recommendation for resection is given,
neoadjuvant
treatment with consecutive surgical re-exploration and the option for a
secondary resection is possible, as well as direct arterial resection in
exceptional cases or under study conditions

19. THE NATIONAL
COMPREHENSIVE CANCER
NETWORK (NCCN)
Recommends Neoadjuvant treatment rather than upfront surgery for BRPC,
despite lacking high-level evidence.
Owing to a lack of consensus and evidence, many surgeons still prefer
upfront surgery as a treatment for BRPC.
Therefore, in this study, They compared the outcomes of neoadjuvant
treatment followed by surgical resection with upfront surgery followed by
adjuvant treatment in BRPC.

20. LITERATURE REVIEW

21. Only Retrospective data ,This is first study- korean
PREOPANC 1 – Yet not published
Data is highly polluted with LA-PDAC
Different clinical practice patterns reflect the wide variety of protocols and
the lack of a standardized approach for neoadjuvant treatment in BR‐PDAC.

22. PRE-OPERATIVE THERAPY FOR BORDERLINE
RESECTABLE PANCREATIC CANCER
Author
Year
Regimen # Patients Resection
Rate
Median
Survival
Resected
Evans
2008
Gem/XRT 84 74% 34 M
Varadhachary
2008
Gem/Cis
Gem/XRT
96 66% 31 M
Katz
2008
Variable 84
(Type A)
38% 40 M
!
Evans DB, et al. JCO, 2008.
Varadhachary GR, et al. JCO, 2008.Katz MH, et al. J Am Coll Surg, 2008.

24.  Complete Response- 3%
Stable disease- 46%
Partial response- 29%
Progression -17%

25. PROGRESSIVE DISEASE-17%
 Patients with aggressive an unfavorable tumor biology. In this subgroup of
patients, a resection could have been performed at the time of diagnosis due
to the BR
stage of the tumor
However, they may not have had a benefit of the operation and may have
suffered from very early recurrence postoperatively, which underlines the
importance of considering the B category of the IAP consensus

26. In the case of stable disease or response, a resection was possible in two out
of three patients, including approximately 60% of R0 resections and a
median survival
time of 25.9 months,
Which is comparable to the outcome after upfront resection.
Because of the large data heterogeneity, the overall small number of
patients, and the fact that all results are based on observational studies
alone, it is not valid to draw a conclusion or give recommendation for
neoadjuvant treatment in BR‐PDAC

27. SPECIAL SITUATION
when tumors of the pancreatic body involve the basis of the CA and
do not extend towards the common hepatic artery beyond the
offspring of the gastroduodenal
artery (GDA).
In these situations, a distal pancreatectomy with CA resection under
preservation of the GDA (DP‐CAR, modified Appleby procedure) is
technically feasible.

30. A recent systematic review on 19 studies included 240 patients and
confirmed that, despite a considerable morbidity, this procedure can be
performed with a low mortality of 3.5% and results in 15 months median
survival, which increases to
18 months if resection is embedded in a multimodal therapy approach.

33. STUDY- KOREAN 2018

34. STUDY DESIGN
This randomized controlled parallel-group trial
Group 1- NACT RT f/b Surgery
Group 2- Upfront Surgery f/b Adjuvant Therapy

35. INCLUSION CRITERIA
Between 18 and 75 years of age and providing written informed consent
 Radiologic evidence of BRPC according to the 2012 NCCN guidelines,
 Histologically or cytologically proven pancreatic cancer
 No history of previous chemoradiation therapy
 Adequate bone marrow, hepatic, and renal function according to laboratory
test results.

36. EXCLUSION CRITERIA
Had undergone concomitant unplanned antitumor therapy (eg,
chemotherapy, radiotherapy, immunotherapy)
Had a concomitant or previous malignancy (except cancer that had been in
complete remission for >5 years)
Had uncontrolled systemic disease (eg, infectious disease and cardiovascular
disease).

37. TREATMENT PROTOCOL

38. NEOADJUVANT
CHEMOTHERAPY
In the neoadjuvant group, a 3-dimensional treatment plan was established
using radiotherapy-planning computed tomography (CT) before starting
chemoradiation.
Chemoradiotherapy consisted of
45 gray (Gy) in 25 fractions and 9 Gy in 5 fractions (5 times a week for a
total of 6 weeks),
plus
Intravenous gemcitabine (at 400 mg/m2 with 150 mL) of normal saline

39. NEOADJUVANT
CHEMOTHERAPY
After chemoradiation, patients underwent a 4- to 6-week rest period.
CT, PET,MRI were performed to reassess the extent of disease before
determination of surgery according to the RECIST version 1.1.
 Surgery with curative intent was performed if no distant metastasis or
progression was observed.
 The assessment was carried out at 3-month intervals, along with an
evaluation of tumor markers, including carbohydrate antigen.

40. UPFRONT SURGERY
In the upfront surgery group, surgery was performed according to the
participating surgeons’ guidelines regarding dissection of the nerve plexus
of major vessels and D2 lymph node dissection (including station 16 nodes).
The surgical extent was identical to the neoadjuvant group.
According to the depth and length of adjacent vessel invasions, the
surgeons used their discretion to decide on the optimal methods of
resection and anastomosis of vessels to achieve R0 resection.

41. UPFRONT SURGERY
After surgery, chemoradiation was performed within 8 weeks using
the same protocol as the neoadjuvant group, provided the patients’
condition was acceptable.

42. MAINTENANCE
CHEMOTHERAPY
Maintenance chemotherapy was performed within 4 t 6 weeks after
completion of surgery and chemoradiation regardless order of treatment in
both groups.
Gemcitabine at 1000 mg/m2 was administered as an intravenous infusion
over 30 to 40 minutes on days 1, 8, and 15, followed by 1 week of rest,
every 4 weeks for 4 cycles

43. OUTCOME
The primary outcome
(2-YSR)-the 2-year survival rate
The secondary outcomes
1-YSR
R0 resection rate.

44. RESULTS

50. R0,R1
Pathologically, an R1-positive margin is defined as 1 cancer
cells within 1 mm of any surface or margin (R1 <1 mm).
A clear (R0) resection margin is then defined as tumor cells 1 mm away from
any
margin or surface (R0 >1 mm).

52. ITT ANALYSIS
NACT RT Upfront SX
1 year Survival Rate 74.1% 47.8%
2 year Survival Rate 40.7% 26.1% (P=0.028)
Median Overall Survival 21 months 12 months

54. PP1 ANALYSIS
NACT RT Upfront SX
2 year Survival Rate 41.2% 41.7% (P=0.337)
Median Overall Survival 22 months 19.5 months

55. The 2-YS
75.0% vs 66.7%

56. There was no difference in the recurrence pattern between the
2 arms (P= 1.000).
The recurrence rate was 88.2% in Arm 1 and 88.9% in Arm 2.
Most recurrences were systemic with the liver being the most
frequent site of recurrence in both groups (41.2% in Arm 1 vs 66.7%
in Arm 2)

57. DSB
The safety monitoring committee decided on early termination of this
study on the basis of the statistical significance of neoadjuvant
treatment efficacy, in consideration of patient safety.

63. CONCLUSION PREOPANC 1
Preoperative chemoradiotherapy significantly improves outcome in
(borderline) resectable pancreatic cancer compared to immediate
surgery.

64. Patient Korean Trial PREOPANC 1
NACT Upfront
Surgery
P Value NACT Upfront
Surgery
P Value
Overall
Survival
21 months 12 months 0.028 17.1 months 13.5 months 0.047
Resection
Rate
70 % 78% 62% 72%
R0 Rate 82.4% 33.3% 0.010 65% 31% 0.010
Actual OS 22 months 19.5 months 0.337 29.9 months 16.8 months 0.001
ADE No difference No difference
Recurrence
rate
88.2% 88.9% 1.000 NA NA
DFS 11.2 months 7.9 months 0.010
DMFI 17.1 months 10.2 months 0.012
LRFI Not reached 11.8 months <0.001

65. DISCUSSION

66. WHY NACT IMPROVED OS
Early systemic treatment for undetected micrometastasis
R0 resection rate increment (51 vs 26 %)
Optimal selection of patients for surgery.
Aggressive resection doesn’t improve OS because of margin positivity

67. MARGINS?

68. MARGINS

69. A recent prospective randomized clinical
trial showed that only 57% of patients
underwent surgery after neoadjuvant
therapy and only 21% finished the entire
treatment protocol, even in patients with
initially resectable pancreatic cancer.
 In this study, 62.9% of BRPC patients
underwent resection after neoadjuvant
treatment and 52.2% underwent
chemoradiation after surgical resection (P
¼ 0.59), whereas 28% completed
maintenance chemotherapy.

70. DIFFICULTY
Events such as drug toxicity or disease progression can hinder the
completion of the initial treatment in pancreatic cancer.
These results illustrate the difficulties faced by clinical trials in pancreatic
cancer and thepossibility of selection bias when interpreting outcomes of
neoadjuvant treatment, especially in the retrospective study setting.

71. MORE EFFECTIVE SYSTEMIC
THERAPY
There was no difference in recurrence patterns.
The recurrence rate was 88.2% in the neoadjuvant treatment group and
88.9% in the upfront surgery group.
Most recurrences were systemic with the liver as the most common site.
More effective systemic therapy, to reduce metastasis and recurrence even
after neoadjuvant treatment followed by resection, must be investigated to
improve long-term survival.

72. DIFFERENCE IN SURVIVAL –
EXTENT OF TUMOUR
INVOLVEMENT
The survival outcome can differ markedly according to the extent of tumor
involvement and types of vessels involved.
Therefore, BRPC should not be regarded as a single entity but rather as a
spectrum of disease that needs further clarification and a standardized
definition.
Yamada et al19 reported that the median disease-free survival durations in
patients with pancreatic cancer and portal vein, hepatic artery, and superior
mesenteric artery invasion were 12.0, 7.4, and 6.7 months, respectively (P <
0. 05).

73. STANDARD RADIOLOGY
FORMAT
To overcome the heterogeneity of BRPC, several radiologic organizations
have
attempted to introduce a standardized reporting system.
Standardization can help facilitate research by using consistent staging with
respect to resectability status and allowing for comparison among
different institutions.

79. OPTIMAL TREATMENT
REGIMEN
Although the use of neoadjuvant therapy results in a higher R0 resection
rate than surgery and provides treatment for subclinical metastases, no
standardized regimen is available at this time.
Currently, the chemotherapy such as FOLFIRINOX and gemcitabine combined
with protein-bound paclitaxel (nab-paclitaxel, Abraxane) regimens are
widely used due to the relatively high response rate.
More high-level evidence is needed in selecting the appropriate treatment
regimen.

80. TAKE HOME MESSAGE
The first randomized clinical trial to investigate the oncological
benefits of neoadjuvant treatment in BRPC.
Neoadjuvant treatment, rather than upfront surgery, should be
considered for patients with BRPC.
Future studies are needed to identify more effective systemic
treatments that control local disease and reduce systemic metastasis
after treatment.

81. THANK YOU