1. Neoadjuvant Therapy for Pancreatic Cancer
Mark M. Zalupski, M.D University of Michigan
Ascension Michigan GI Conference Multidisciplinary Management of the GI Cancer Patient
March 30, 2019

2. Disclosures – None Off Label Use - Yes

3. Definition of neoadjuvant treatment
Pancreas Cancer – Background, Multi-modality and Adjuvant Therapy
Neoadjuvant Trials
Ongoing Efforts and Conclusions

4. What is neoadjuvant treatment?
“Treatment given as a first step to shrink a tumor before the main treatment, which is usually surgery”
1st treatment sometime called induction
Can be chemotherapy and/or radiation
Use often has defined value in post-op setting
Main treatment = curative intent = surgery
No need to “shrink” tumor in operable disease
Target of systemic Tx includes micrometastatic dz

5. Pancreatic Cancer - Scope of the Problem
56,440 cases expected 20181
5 year survival 7.7%
By 2030, pancreas Ca expected to surpass breast, prostate and CRC to become 2nd leading cause of cancer death2
Small minority (~15%) with operable dz (includes resectable and borderline resectable disease)
Older patient population with co-morbidities and disease associated complications
1CA Cancer J Clin. 2018;68(1): Can Res 2014:74;2913

6. CT Criteria for Resection
No extra pancreatic disease
No extension to celiac/SMA
Patent SMV/PV
Encasement / reconstructable SMV/PV
Contact on SMA / celiac (<=180o)
Resectable

7. Resectable adenocarcinoma of the pancreatic head
Kitts
Resectable tumor, RRHA

8. Borderline resectable adenocarcinoma of pancreatic head

9. Resectable Pancreas Cancer
Patterns of Treatment Failure
Early Spread to Regional Nodes
Subclinical Liver Metastasis in Majority
In Resected Pts Loco-regional Failure > 85% without Adjuvant Treatment
Liver Metastasis in > 75% Patients with Improved Local Control
Poor Prognostic Factors + LN, + margins (R1 - R2 resections)

10. Localized Pancreatic Cancer Multi-Modality Treatment
Surgical Treatment - Necessary but not sufficient for cure
Goal is R0 resection
Morbidity and difficult recovery following surgery
Radiation Therapy - Enhances local control in resected pts
As neoadjuvant tx, increases R0 resection rate
Underutilized (?)
Systemic Chemotherapy - Increases survival
Combinations enhance benefits
Majority of patients still suffer distant recurrence

11. Resectable Pancreatic CA – Adjuvant Treatment
Study
year n
Intervention
Median Survival (mos)
ESPAC 11
2004
289
Obs vs. 5FU
15.5 vs. 20.1
Conko 0012
2007
354
Obs vs. Gem
20.2 vs. 22.1
ESPAC 43
2017
732
Gem vs. Gem / Cape
25.0 vs. 28.5
Prodige4
2018
493
Gem vs. m-Folfirinox
35.0 vs. 54.4
Apact
2019
866
Gem vs. Gem+nab-Pacli
TBD
1NEJM 2004:350;1200 2JAMA 2007:297;267 3Lancet 2017:389;1011 4NEJM 2018:379;2395

12. Resectable Pancreatic CA Receipt and Timing of Multimodality Therapy1
NCDB ,441 pts stage I and II
22.8% received no treatment
18.5% chemotherapy only
23.0% surgery only
35.8% multimodality treatment
Age is a barrier to multimodality treatment
OR as compared to < 55 yo , – 0.60, >
Multimodality tx increased over time (31.3  37.9%)
1J Gastrointestinal Surg 2016;20:93

13. Resectable Pancreatic Cancer
Surgery  Adjuvant Therapy m-FOLFIRINOX Gemcitabine/Capecitabine /- RT / Capecitabine Single agent chemotherapy
Neoadjuvant Therapy  Surgery
Chemotherapy (same) as in adjuvant +/- RT Surgery if no progression, metastatic disease

14. Rationale for preop therapy
Provides early treatment of micrometastatic disease
Treating an intact patient
Delayed recovery may prevent the delivery of postoperative adjuvant therapy
Patients with rapidly progressive disease will not be subjected to surgery
A logical strategy for the high incidence of positive margins

15. Potential Barriers to Neoadjuvant Therapy
Need for biopsy
EUS – FNA
Biliary decompression and a continuing risk of cholangitis
Patient / Family
Concern for localized disease progression

16. Neoadjuvant Gemcitabine-based Therapy in Resectable Pancreas Cancer - MDAH Experience
1 Gem 400 mg/m2 wkly x Gy RT wk 1-2 or
2 Gem 750 mg/m2 + Cis 30 mg/m2 qow x 4
 Gem 400 mg/m2 wkly x Gy RT wk 1-2
followed by surgery in those that remain resectable
Note: only 1 of 176 pts had isolated local progression
1 J Clin Oncol 26:3496, J Clin Oncol 26:3487, 2008

17. Localized / Resectable Pancreatic Cancer
Adjuvant
100
Surgery
Neoadjuvant
100
Chemo +/- RT 20 20
80 Resected
80 Explored 20 20
60 Resected
60 Chemo +/- RT

18. Preop vs Postop No. Patients Benefit Morbidity Med S of of (Resected)
Chemo XRT Surg
Neoadj > 20 mo
Adj < 20 mo

19. Neoadjuvant Gemcitabine-based Therapy in Resectable Pancreas Cancer - MDAH Experience
Comp/ Med Surv Med Surv
n Resected Resected not Oper
Gem/RT % mos mos
Gem-Cis % mos mos
Gem/RT2
Most failures systemic
More difficult to complete longer preop course
1 J Clin Oncol 26:3496, J Clin Oncol 26:3487, 2008

20. Resectable/Resected Pancreatic CA Nationwide Trends and Results with Neoadjuvant TX1
NCDB ,243 resections
Post-op adjuvant tx (58% che, 39% RT)
7.5% received neoadj tx (>99% che, 82% RT)
Use increased over time (4.3%  17%)
Neoadjuvant treatment associated with
R0 resection 85.5% vs 77.8%
Negative lymph nodes 59.3% vs 42.9%
Lower 30 day mortality 2.0% vs. 4.6%
Lower 30 day readmission rate 7.4% vs 9.5%
Median survival 24.3 mos vs mos
1J Surg Oncol. 2017;116:127

21. Phase II Full Dose Gemcitabine with RT
Week 1
Week 2
Week 4
Week 5
Week 6
Week 7
Week 8 M T W T F S S M T W T F S S M T W T F S S M T W T F S S M T W T F S S M T W T F S S M T W T F S S
XRT
XRT
XRT G G G G G G G G
Gemcitabine: 1000 mg/m2 30 min IV infusion
XRT
36 Gy in 15 fractions

22. Phase II Full Dose Gemcitabine with RT
n= (19.5%) ≥ grade 3 non-heme toxicity1
20 pts entered as resectable2
20 explored, 17 resected
Clear margins in 16/17
Uninvolved LN in 11/17
One Path CR , 3 microscopic foci only
Average LOS 13.5 days No 30-day mortality
Median f/u 12 mos - 10/17 alive without recurrence
1J Clin Oncol 2008, 26(6): Ann Surg Oncol 2006, 13(2):150

23. Baseline Characteristics Immediate Surgery (n=127)
PREOPANC-1 Preoperative chemo/RT vs surgery for resectable/borderline resectable pancreatic cancer - Phase III trial
Surgery  6 mos Gemcitabine
Preop Gem/RT  Surgery  Adj Gem x 4 mos
CMT – RT 36 Gy in 15 fractions + Gem 1 g/m2 R
Baseline Characteristics
Immediate Surgery (n=127)
Preoperative
Chemo / RT (n=119)
Median age (range)
67 (37-81)
65 (33-80)
WHO PS 0-1
94%
92%
Location
Head 88%
Head 87%
Borderline Resectable
46%
53%
J Clin Oncol 36, 2018 (suppl; abstr LBA4002)

24. Immediate Surgery (n=127)
PREOPANC-1 Preoperative chemo/RT vs surgery for resectable/borderline resectable pancreatic cancer - Phase III trial
Accrual April 2013–July 2017
Results
Immediate Surgery (n=127)
Preoperative
Chemo / RT (n=119)
P Value
Resection Rate
72%
60%
p=0.065
R0 Resection Rate
31%
63%
p<0.001
Serious Adverse Events
39%
46%
p=0.28
Median OS
13.7 mos
17.1 mos
p=0.074
Median DFS
7.9 mos
9.9 mos
p=0.023
Resected Med OS
16.8 mos (n=91)
42.2 mos (n=72)
J Clin Oncol 36, 2018 (suppl; abstr LBA4002)

25. UMCC 6-25 Phase II Trial Neoadjuvant Gemcitabine, Oxaliplatin and RT
Treatment Schema
SURGERY ?
Week 1
Week 2
Week 3
Week 5
Week 6
Week 7 M T W T F S S M T W T F S S M T W T F S S M T W T F S S M T W T F S S M T W T F S S
XRT
XRT
XRT G G G G G G O O O O
XRT
30 Gy in 15 fractions G
Gemcitabine: 1 g/m2, 30 minutes
Oxaliplatin: 85 mg/m2 O

26. UMCC 6-25 Phase II Trial Neoadjuvant Gemcitabine, Oxaliplatin and RT
n=68 pts (4 institutions) 12 resectable, 49 borderline, 7 unresectable 61 (90%) completed neoadjuvant treatment 5 PR, 50 SD (including 19 with MR), 12 PD 5/9 with Primary PD had RO resection 43 (63%) resected; 36/43 RO (84%) (32 whipple, 11 distal, 40% with vascular R&R) Cancer 2013;119:2692

27. Median OS 18.2 months

28. Med OS Not Resected 10.9 mos Med OS Resected – 27.1 mos
Med OS R0 Resection – 34.6 mos

29. UMCC Conclusions
Radiologic response not necessary for RO resection CA19-9 response associated with RO resection Evidence for downstaging (+LN 49% vs. ~70% post-op) 55% of treated patients received adjuvant therapy Cancer 2013;119:2692

30. Total Neoadjuvant Therapy (TNT) in Borderline Resectable Pancreatic CA
UMCC n= mos m-FOLFIRINOX  5 weeks IMRT/Gem  1 mos Gem  Surgery
21 pts completed 3 mos chemo, 19 all protocol tx Per serial CTs - 44% PR, 44% SD
One early death, 4 liver metastasis, 2 pts inoperable explored, 13 resected (all R0), venous resect 9 pts
By ITT – med PFS 13.1 mos, med OS 24.4 mos Resected pts - PFS 21.6 mos, OS 37.0 mos Unresected pts – PFS 8.9 mos, OS 12.6 mos
submitted Int J Rad Onc Biol phys

31. TNT in Borderline Resectable Pancreatic CA
DFCI - Phase II Trial in Borderline Resectable Dz 4 months of m-FOLFIRINOX then Individualized RT (SBRT or long course IMRT) + Cape
n= % received 8 cycles of m-FOLFIRINOX % IMRT, 56% SBRT per serial CTs 44% PR, 30% SD
R0 Resection in 65%
By ITT med PFS 14.7 mos, med OS 37.7 mos Resected pts - PFS 48.6 mos, OS NR Unresected pts – PFS 8.9 mos, OS 12.6 mos
Jama Oncol. 2018;4(7);963

32. A021501 – Neoadjuvant FOLFIRINOX +/- SBRT in borderline resectable pancreas cancer
Pancreatic head adenocarcinoma
Borderline resectable per intergroup criteria
No prior treatment
ECOG 0-1
No neuropathy
No ca19-9 limit
FOLFIRINOX x 8
If no metastasis, surgical exploration and resection
Resected patients receive post-op FOLFOX x 4
Primary: 18 mos OS
Secondary: PFS, QOL
R0 resection rate, Safety
N=67 R
N=67
FOLFIRINOX x then SBRT
As of 3/21/19, accrual at 121 of planned 134
SBRT arm closed 8/13/18 when interim data analysis < 11/30 with R0 resection met the protocol specified futility boundary

33. Neoadjuvant Tx - Resectable Pancreas Cancer
S1505–FOLFIRINOX vs. Gemcitabine/nab-Paclitaxel
Primary Endpoint - 2 Year Overall Survival with a “pick the winner” design
Accrual completed April 2018 with 147 registrations
39 registered patients ineligible due to > resectable disease on baseline CT scan
Grade 3-4 toxicity ~ 2/3 of patients = with either regimen
________________________________________________
GI Intergroup/NCTN planning randomized trial in
Surgery adjuvant FOLFIRINOX vs.
Neoadjuvant FOLFIRINOX  Surgery

34. Neoadjuvant Therapy of Pancreatic Cancer Practical Considerations
Chemotherapy
m-FOLFIRINOX, gemcitabine/capecitabine standard adjuvant therapies gemcitabine/nab-paclitaxel (?), single agent therapy
Radiation
Surgeon and institutional preferences
Continuing arterial contact
SBRT, 3 weeks of 3D conformal, 5 (or more) weeks of IMRT Concurrent chemotherapy – capecitabine (or 5FU), gemcitabine
Duration of neoadjuvant treatment to 6 months - shorter for resectable disease, longer for borderline
Surgical treatment
response not required for operation prepare for vascular resection / reconstruction
Post-operative adjuvant treatment target 6 mos of systemic therapy Postoperative RT in R1 resections, LN + resections