1) Several studies provide evidence supporting the use of neoadjuvant therapy for resectable pancreatic cancer. The PREOPANC-1 trial found no survival benefit for neoadjuvant chemoradiotherapy compared to upfront surgery in resectable pancreatic cancer. However, the Prep-02/JSAP-05 and PACT-15 trials found significantly improved survival with neoadjuvant chemotherapy compared to upfront surgery. 2) Guidelines such as ESMO and NCCN provide classifications for resectability and recommend considering neoadjuvant therapy for resectable pancreatic cancer with certain high-risk features or comorbidities. 3) Potential advantages of neoadjuvant therapy include managing micro

1. NEOADJUVANT THERAPY IN PANCREATIC CANCER
BODERLINE AND RESECTABLE
DR SUJAN SHRESTHA
MCh, RESIDENT
TUTH, IOM

2. Evolution of adjuvant therapy in pancreatic cancer
DR SUJAN SHRESTHA
MCh, RESIDENT
TUTH, IOM

3. IS THERE BENEFIT OF ADJUVANT THERAPY?
IF YES, IS IT ADJUVANT CHEMO OR CHEMORAD?
IF CHEMO, WHICH CHEMOTHERAPY?
……………………………..?
THE ANSWER TODAY WILL BE THE OUTDATED PAST FOR FOR BETTER TOMORROW

4. ESPAC 1
February 1994 and June 2000.

5. • Standard care for patients with resectable pancreatic cancer should
consist of curative surgery followed by adjuvant systemic
chemotherapy. (YES) (5FU + LEUCOVORIN)
• Adjuvant chemoradiotherapy not only fails to benefit patients but
also reduces survival when it is given before chemotherapy. (NO)
CONCLUSION

6. July 1998 and December 2004
PURELY GERMAN STUDY

7. Adjuvant gemcitabine for 6 months compared with
observation resulted in increased overall survival as
well as disease-free survival. These findings support
the use of gemcitabine in this setting.
CONCLUSION

8. ESPAC 1 = 5FU AND LEUCOVORIN IS GOOD
CONKO1 = GEMCITABINE IS GOOD
ESPAC 3 = OK LET'S COMPARE BOTH

9. 2003 to 2007
ESPAC 3

10. Adjuvant gemcitabine was recommended as the
treatment of choice in pancreatic cancer patients
following upfront resection.
CONCLUSION

11. Nov 10, 2008, and Sept 11, 2014
ESPAC 4

12. ESPAC-4 indicate that adjuvant gemcitabine plus
capecitabine is the new standard of care.
CONCLUSION

13. France and Canada
April 2012 through October 2016

14. Modified FOLFIRINOX regimen led to significantly longer
disease-free survival and overall survival than adjuvant
chemotherapy with gemcitabine. The incidence of toxic effects
was higher with the modified FOLFIRINOX regimen than with
gemcitabine therapy.
CONCLUSION

15. FROM 6 MONTHS WITHOUT SURGERY
FOR 17 MONTHS IN EARLY ADJUVANT
30 MONTHS TILL END OF ESPAC 4

16. (a)No venous spread,
(b) contact <180° with no
stenosis,
(c) contact <180° with stenosis,
(d) teardrop sign,
(e) venous encasement >180°
CLASSIFICATION OF VENOUS RELATIONSHIP

17. CRITERIA DEFINING RESECTABILITY STATUS AT DIAGNOSIS
NCCN Guidelines Version 2.2021

18. (a)No arterial spread,
(b) arterial contact <180°,
(c) arterial contact >180°, with or without caliber
irregularity
CLASSIFICATION OF ARTERIAL RELATIONSHIP

19. CRITERIA DEFINING RESECTABILITY STATUS AT DIAGNOSIS
NCCN Guidelines Version 2.2021

20. ESMO
FOLLOW THE GREEN

21. High-risk features
• Very highly elevated CA 19-9
• Large primary tumors,
• Large regional lymph nodes,
• Excessive weight loss,
• Extreme pain.
NCCN 2021

22. NCCN 2021

24. BRIEF SUMMARY
ESMO
-ALL BODERLINE RESECTABLE
NCCN
-RESECTABLE WITH HIGH-RISK FEATURES
-ALL BODERLINE
-ALL LOCALLY ADVANCE WITH GOOD PERFORMANCE
STATUS
WHAT DO THE GUIDELINES SAY?

25. Preoperative Therapy in Patients
Borderline Resectable and Locally Advanced Pancreatic
Cancer
BURDEN OF BODERLINE AND LOCALLY ADVANCE TUMORS
PANCREATIC CANCER
METASTATIC
BODERLINE AND LOCALLY ADVANCE
RESECTABLE
50%
30-40%
10-20%
PROBLEMS:
• DIFFICULT FOR RO RESECTION
• (BRUCHLER SAYING) RESECTABILITY CRITERIA DEPENDS UPON SURGEON
• ARE USUALLY POOR BIOLOGY WITH POOR OUTCOME EVEN AFTER RO RESECTION
SPECTRUM OF PANCREATIC CANCER PATIENT

26. Preoperative Therapy in Patients Borderline
Resectable
WHY TO GIVE NEOADJUVANT THERAPY FOR BR AND LAPC?
• Tumor regression and more likely RO resection
• Avoid futile operation for progressive disease
• Treatment of micro metastasis
• May improve overall and disease-free survival compared to upfront surgery +- vascular
resection

27. Problem:
• Tissue confirmation is mandatory by EUS- BIPOSY or ERCP- BRUSH CYTOLOGY
• CA19-9 ( Non dependable value in jaundice patient and Lewis antigen negative patient)
• Mandatory diagnostic laparoscopy before and after NEO (36% showed metastatic
disease) +-
• Mandatory stenting in jaundice patient ( modified FOLFIRINOIX requires bilirubin <1.5
normal)
Preoperative Therapy in Patients Borderline
Resectable

28. Response and Restaging After Induction Chemotherapy
Radiographic Response NEOADJUVANT (3 CYCLES) CECT PANCREATIC PROTOCOL
RECIST CRITERIA
CT SCAN UNABLE TO DIFFERENTIATE FIBROSIS OR TUMOR

29. Biochemical Response
Response and Restaging After Induction Chemotherapy
CA19-9 is currently the only approved biomarker for pancreatic cancer to evaluate
response to preoperative chemotherapy.
IF CA19-9 shows a decrease of more than 30–50%, or normalization, in response to
preoperative therapy, it is associated with a higher rate of R0-resection and improved
overall survival
Boone BA, et al. Serum CA 19-9 response to neoadjuvant therapy is associated with outcome in pancreatic
adenocarcinoma. Ann Surg Oncol. 2014

30. Response and Restaging After Induction Chemotherapy
Histopathologic Response
PREOPANC trial. J Clin Oncol. 2020
GOOD HISTOLOGICAL RESPONSE ASSOCIATED WITH BETTER DFS AND MOS

31. So, we went through different aspects of neoadjuvant therapy in BRPDAC
So, what are level 1 evidences supporting these claims of neoadjuvant role in PC?
Preoperative Therapy in Patients Borderline
Resectable

32. Preoperative Therapy in Patients Borderline
Resectable
Feb, 2020

33. PREOPANC TRIAL
Randomized phase III trial in 16 centers
Patients were randomly assigned 1:1 to preoperative chemoradiotherapy or immediate
surgery.
PREOPERATIVE CHEMORADIOTHERAPY
STAGING LAPROSCOPY
CHEMORT( 2.5CGY /15 FRACTIONS + GEMCITABINE 3 COURSE)
CT EVALUATION WITHIN 4 WKS OF LAST DOSE OF CRT
SURGERY
4 CYCLE OF GEMCITABINE
UPFRONT SURGERY
STAGING LAPROSCOPY ON SURGEON’S DESCRETION
SURGERY
ADJUVANT CHEMO GEMCITABINE 6 CYCLES

34. PREOPANC TRIAL

35. PREOPANC TRIAL

36. PREOPANC TRIAL

37. Preoperative Therapy in Patients Borderline
Resectable
KOREAN BODERLINE PANCREATIC CANCER NEOADJUVANT TRIAL
Jin-Young Jang et, al.
Annals of surgery, 2018

38. Patients were randomly assigned 1:1 to preoperative chemoradiotherapy or immediate
surgery.
PREOPERATIVE CHEMORADIOTHERAPY
CHEMORT(45GY /25 FRACTIONS + GEMCITABINE )
CT EVALUATION after 4 WKS OF LAST DOSE OF CRT
SURGERY
GEMCITABINE
UPFRONT SURGERY
SURGERY
ADJUVANT CHEMORADIATION GEMCITABINE
KOREAN BODERLINE PANCREATIC CANCER NEOADJUVANT TRIAL

39. Pathological Findings and Tumor Responses of Patients Undergoing
Surgery

40. In the intention-to-treat analysis,
the 2-YSR and median survival
were significantly better in the
neoadjuvant chemoradiation than
the upfront surgery group [40.7%, 21
months vs 26.1%, 12 months,
hazard ratio 1.495 (95% confidence
interval 0.66–3.36), P 1⁄4 0.028].
KOREAN BODERLINE PANCREATIC CANCER NEOADJUVANT TRIAL
Conclusion: This is the first prospective randomized controlled trial on the
oncological benefits of neoadjuvant treatment in BRPC. Compared to upfront
surgery, neoadjuvant chemoradiation provides oncological benefits in patients with
BRPC.

41. ONGOING NEOADJUVANT TRIALS (RCT) FOR BRPC

42. TILL NOW
PREOPANC TRIAL AND KOREAN TRIAL PROVIDES LEVEL 1 EVIDENCES FOR
USE OF NEOADJUVANT CRT IN BODERLINE RESECTABLE PANCREATIC CANCER
LET US WAIT FOR MORE ROBUST EVIDENCES FROM ONGOING TRIAL
Preoperative Therapy in Patients Borderline
Resectable

44. Preoperative Therapy in Resectable pancreatic
cancer
Advantages of of Neoadjuvant chemotherapy in resectable PDAC
COMPLIANCE TO CHEMOTHERAPY
FRAIL PATIENT
COMORBID PATIENT
COMPLEX SURGERY
(PANCREATICODUODENECTOMY)
POSTOP COMPLICATIONS
• POPF
• PPH
• WOUND RELATED COMPLICATIONS
• OTHER SYSTEMIC COMPLICATIONS
ONLY 50-70 % WILL INITIATE ADJUVANT THERAPY
ONLY 50% WILL COMPLETE THE REGIMEN
VERY FEW WILL COMPLETE INTENTED REGIMEN (modification on standard regimen)
SO, WITH NEO THERAPY IT ENSURE EVERY PATIENT GETS CHEMOTHERAPY

45. Preoperative Therapy in Resectable pancreatic
cancer
Advantages of of Neoadjuvant chemotherapy in resectable PDAC
Managing Micrometastatic Disease
Resectable cancer surgery Adjuvant Recurrence
Local
Distant (70%)
Explanation
• Systemic disease by nature
• Micrometastais (not picked up by scan and eye)

46. Managing Micrometastatic Disease
Preoperative Therapy in Resectable pancreatic
cancer

47. Preoperative Therapy in Resectable pancreatic
cancer
Advantages of of Neoadjuvant chemotherapy in resectable PDAC
Test of Biology: Allow Emergence of Occult Metastatic
Disease
Resectable cancer surgery Adjuvant
Early Recurrence
20%
Could we have prevented futile operation on these poor tumor biology patient
Neoadjuvant Progression on scan Poor biology
Prevention of futile
nontherapeutic operation

48. Preoperative Therapy in Resectable pancreatic
cancer
Advantages of of Neoadjuvant chemotherapy in resectable PDAC
Test of Performance Status Before Major Surgery
Consider neoadjuvant chemotherapy in patients with a performance status or comorbidity profile not currently
appropriate, but potentially reversible for a major abdominal operation (PREHABILITAION)
ASCO clinical practice guideline update. 201
Decrease Surgical Complexity
2019

49. Decrease Surgical Complexity
OBJECTIVE
• Postoperative complications.
• upfront resection or pancreatectomy following NAT
753patient
s
The rate of CR-POPF was 3.6-fold lower in patients receiving NAT vs upfront resection (13 [3.8%]
vs 56 [13.8%]; P < .001).
Neoadjuvant therapy may be associated with a significant reduction in the rate of
CR-POPF.
CONCLUSION
Preoperative Therapy in Resectable pancreatic
cancer
Advantages of of Neoadjuvant chemotherapy in resectable PDAC

50. Preoperative Therapy in Resectable pancreatic
cancer
Advantages of of Neoadjuvant chemotherapy in resectable PDAC
Improve Resection Margin and Lymph Node Status
MORE RELEVANT FOR NEOCHEMORADIOTHERAPY
Intact vascular supply better drug delivery
Well- oxygenated tissues with intact blood supply may enhance the effectiveness of
drug delivery and reduce hypoxia-related resistance to chemoradiation and
radiation-related toxicity
Ngo-Huang A, Parker NH, Wang X, et al. Langenbecks Arch Surg.
2017.

51. Potential Disadvantages with a Neoadjuvant Approach
Preoperative Therapy in Resectable pancreatic
cancer
Complications Related to Invasive Procedures
Need for tissue biopsy EUS related complications
• 1% overall complications
• 0.02% mortality
Wang KX, Ben QW, Jin ZD, et al. : a systematic review. Gastrointest Endosc.
2011.
Need for biliary drainage For starting chemotherapy bilirubin level should be less than 50 micromole/l
Preoperative biliary drainage associated with postoperative infectious complications
DROP TRIAL
Complication associated with PTBD and ERCP

52. Potential Disadvantages with a Neoadjuvant Approach
Preoperative Therapy in Resectable pancreatic
cancer
Low Rate of Complete or Significant Radiological or Pathologic
Response
Complete pathological response of 3.9–7% and a radiological response of about
30% of the patients may be expected during neoadjuvant chemotherapy.
Cloyd JM, Wang H, Egger ME, et al. JAMA Surg.
2017
Therapeutic Toxicity
Progression on neoadjuvant
Counteracted by concept of poor biology

53. What are the evidences for neoadjuvant in resectable pancreatic cancer?
Preoperative Therapy in Resectable pancreatic
cancer

54. Preoperative Therapy in Patients Resectable
PDAC
Feb, 2020

55. PREOPANC TRIAL
Randomized phase III trial in 16 centers
Patients were randomly assigned 1:1 to preoperative chemoradiotherapy or immediate
surgery.
PREOPERATIVE CHEMORADIOTHERAPY
STAGING LAPROSCOPY
CHEMORT( 2.5CGY /15 FRACTIONS + GEMCITABINE 3 COURSE)
CT EVALUATION WITHIN 4 WKS OF LAST DOSE OF CRT
SURGERY
4 CYCLE OF GEMCITABINE
UPFRONT SURGERY
STAGING LAPROSCOPY ON SURGEON’S DESCRETION
SURGERY
ADJUVANT CHEMO GEMCITABINE 6 CYCLES

56. PREOPANC TRIAL

57. PREOPANC TRIAL

58. A predefined subgroup analysis showed superior OS after
preoperative chemoradiotherapy for borderline resectable PDAC and
no significant difference for resectable PDAC.
No survival benefit on resectable pancreatic cancer
PREOPANC TRIAL
Preoperative Therapy in Resectable pancreatic
cancer

59. Randomized phase II/III trial of neoadjuvant chemotherapy with gemcitabine and
S-1 versus upfront surgery for resectable pancreatic cancer (Prep-02/JSAP-05)
(Prep-02/JSAP-05) trial
Preoperative Therapy in Resectable pancreatic
cancer

60. (Prep-02/JSAP-05) trial

61. (Prep-02/JSAP-05) trial
Conclusions: This phase III study demonstrated the significant survival
benefits of NAC-GS treatment. Therefore, the results indicated that
neoadjuvant chemotherapy could be a new standard for patients with resectable

62. PACT-15 TRIAL
LANCET, 2018
ITALIAN TRIAL

63. SURGERY GEMCITABINE
SURGERY PEXG( CISPLATIN,EPIRUBICIN,GEMCITABINE,CAPACITABINE)
PEXG SURGERY PEXG
PACT-15 TRIAL

64. PACT-15 TRIAL

65. PACT-15 TRIAL
55% OF 3 YRS OS WITH NEO

66. PACT-15 TRIAL
Interpretation Our results provide evidence of the
efficacy of neoadjuvant chemotherapy in
resectable pancreatic ductal adenocarcinoma. Since
the trial began, the standard of care for adjuvant therapy has altered, and
other chemotherapy regimens developed. Thus, we decided to not continue
with the phase 3 part of the PACT-15. We are planning a phase 3 trial of this
approach with different chemotherapy regimens.

67. PREOPANC 1
PACT -15
JSAP-05
NO
YES
PIPELINE
Preoperative Therapy in Resectable pancreatic
cancer

69. Guidelines
• ESMO
• NCCN
Classification of resectability
• NCCN
Advantages of neoadjuvant
• Micrometastasis
• Test of biology
• Compliance
• More r0 and lymphnode yield
• Less popf
Disadvantages
• Biopsy
• Stent
• Progression
• Toxicity
Evidences for borderline ( USUALLY RADIOTHERAPY IS ADDED)
• Preopanc (NCRT + SURGERY + ACT)
• KOREAN (NCRT + SURGERY + ACRT)
• PIPELINE TRIAL
= ESPAC 5
FOUR GROUPS
• SURGERY + ADJUVANT
• NCRT + SURGERY + ADJUVANT
• NCT GEM BASED + SURGERY + ADJUVANT
• NCT M FOLFIRINOX + SURGERY + ADJUVANT
= PANDAS PRODIGE 44 TRIAL
• NCT (MFOLFOX) VS NCRT (MFOLFOX)
EVIDENCES FOR RESECTABLE ( USUALLY ONLY NEOADJUVANT
CHEMO) (ALSO ALWAYS ONE ARM WITH SURGERY FIRST AS
SURGERY FIRST IS STANDARD AT PRESENT)
• PREOPANC NO
• PREP 02 OR JSAP 5 TRIAL (SURGERY + S1 VS NCT (GEM)
+SURGERY+ S1)
• PACT 15 TRIAL (3 GROUPS )
= SURGERY + GEM
= SURGERY + PEXG
= PEXG + SURGERY + PEXG
PIPELINE
PANACHEO PRODIGE 44 TRIAL
3 GROUPS
1. MODIFIED FOLFIRINOX NCT
2. MODIFIED FOLFOX NCT
3. UPFRONT SURGERY

70. THANK YOU