Neoadjuvant

Chemoradiotherapy in
Resectable and Borderline
resectable PDAC
Dr. Akhil Thomas Jacob
Moderator: Dr. Chandramohan K
Roadmap

● Evolution
● Resectability Assesment
● Resectable Pancreatic Cancer
● Borderline resectable PDAC
● Evidence
Evolution
Adjuvant
Primary surgery alone NACT
chemotherapy

● High local / ● ESPAC 1: improved OS ● Based on

systemic with 5 FU based extrapolation
recurrence chemo from
● R+ resection ● CONKO 001: improved Adjuvant
● Inoperability DFS setting
● PRODIGE 24,ESPAC4: ● PREOPANC
intensification etc
Conditional resectability
● Introduced by MD Anderson group
○ Age >80 years
○ ECOG > 2
○ Comorbidities requiring evaluation and optimization
● Performance status is the strongest predictor of survival
irrespective of stage
Harbinger of systemic disease: MDACC study: ⅓ developed
mets during NAT
Biological Resectability

Suspicious for, but not diagnostic of, metastatic disease

● Imaging
● Biopsy proven regional nodes(IAP: or by PET)
● CA19-9 > 1000 without biliary obstruction (IAP: > 500)
○ CA19-9 values <1,000 units/mL : median OS of 2.3
years VS. 1 year with CA19-9 ≥1,000 units/mL
○ May protend unresectablity ( Heidelberg group)
CA 19-9 Median OS 5 YR OS

<100 27 months 19-27%

100-500 20 m 12%

>500 12 7%

>1000 0%
Anatomic Resectability
Resectable PDAC
Neoadjuvant Therapy : benefits
● All data based on anatomical resectability
● Neoadjuvant Therapy group: 83% completed multimodal
therapy : 58% with surgery first
● 1 year cancer specific mortality: 30% with surgery alone
● 77% recurrence within 1st year of surgery
● NAT help to select patients who would have progressed
even with surgery
Neoadjuvant Therapy : benefits

● Allow time for general condition of patients to improve

● Downstage the tumor: increase R0
● Reduce nodal recurrence
● Preop : oxygenated tissue
RCTs in resectable PDAC
● Phase II: 30 Gy /#
● 78% surgery post chemo RT
● 4% R1
PREOPANC trial
● Phase 3 RCT
● T1 : excluded
Inclusion criteria

● Histologically or cytologically confirmed adenocarcinoma of the

pancreas
● Primarily resectable tumours or Borderline resectable tumours
● WHO performance status ≤ 1
● Ability to undergo surgery and radiochemotherapy
● Leucocytes ≥ 3.5 X 109/l
● Platelets ≥ 100X 109 /l
● Haemoglobin ≥ 6 mmol/l
● renal function: E-GFR > 50 ml/min
Protocol
● Multicenter randomized parallel group superiority phase III
● Arms
○ Exp lap + whipple→ adjuvant chemo
○ NACTRT→ Sx→ adjuvant chemo
● 3 cycles of gemcitabine preop
● 36 Gy 15 # RT during C2
● Dose developed based on 2 phase 1 and 1 phase 2 trials
● Primary end point: OS by ITT
● 244 patients 176 events
gem-RT: gemcitabine 1000 mg/m2 day 1,8,15 + radiotherapy 36 Gy 2.4 Gy fractions, 3 weeks, one week rest

gem’: gemcitabine 1000 mg/ m2, day 1,8, one week rest (before and after gem-RT)

gem: gemcitabine 1000 mg/m2 day 1,8,15 one week rest (six cycles = standard adjuvant chemotherapy)
OS

● Overall group: 16 vs 14.3 months p=0.096

○ Per protocol OS: 35.2 m vs 19.8 m
○ Long term
■ 3Y OS: 27.7 VS 16.5%
■ 5Y OS: 20.5% VS 6.5% ( P=0.025)
● Resectable disease: 14.6 vs 15.6 p=0.83
● Borderline resectable: 17.6 vs 13.2 m (p=0.029)
○ DFS: 6.3 m vs 6.2 m p=0.013
●
Preliminary result

● Improved R0: 71% vs 40%

● N0: 33% vs 78%
● PNI: 39% vs 73%
● DFS: 8.1 months vs 7.7 months( p=0.032)
● LRF: NR vs 13.4 months
Upcoming trial

● PREOPANC-2
○ total neoadjuvant chemotherapy with FOLFIRINOX
(eight cycles) followed by pancreatectomy
○ gemcitabine-based chemoradiotherapy followed by
pancreatectomy and adjuvant gemcitabine
Borderline resectable
Alliance A021101

● Multi-institutional phase I feasibility study of patients with

borderline resectable PDAC
● 4 cycles mFOLFIRINOX → 50.4 Gy 28# EBRT +
Capecitabine → gemcitabine 2 cycles: 29 patients
● 93% R0
● 80% vascular resection
● 13% PCR. 33% <5% malignant cells
● 5 progressed on therapy : 4 distant 1 locoregional
Alliance A021501

● Phase II RCT
● Arm A: 8 cycles of neoadjuvant mFOLFIRINOX
● Arm B: 7 cycles FOLFIRINOX→ SBRT(33-40 Gy 5#) or
HIGRT 25 Gy 5# → Surgery → FOLFOX6
● No survival advantage with RT
ESPAC 5F

● Phase 2
● 4 arm
○ A: upfront Surgery
○ B: gemcitabine/capecitabine 2 cycles
○ C:FOLFIRINOX 4 cycles
○ D:50.4 gy 28#:+ Capecitabine
● Primary endpoint: recruitment rate& R0/R1 rates
Results

● No difference in resection rates

● Improved 1 year OS
JASPAC 05

● S1 + NACTRT
● CRT completed in 96%
● R0: 63%
● OS : 58% 30 m
● AE: 7.5%
Thank you!!
Upcoming trials

● PREOPANC-2
● PANDAS- PRODIGE 44
Rebuttal!!
PREOPANC
ChemoRT IN LAPC
CONKO 007

● IC( Gem or FOLFIRINOX) x 3 m→ NO PROGRESSION⇒

RANDOMIZED:
○ ARM A Continue chemo for 3 more months
○ Arm B : chmoRT 50.4 Gy+ gem→ Gem
● Primary outcome: OS → Later changed to R0 resection
Results

● R0 CRM & PCR : significantly more in CRT Arm

● OS also more
Methods

● Phase II/ III open labelled

● 45 Gy 25#+ 9 Gy 5#: 5 /wk x6 weeks
● Gemicitabine 400mg/m2 1hour before RT on day 1 of each
week
● Rest 4-6 weeks→ surgery→ adj chemo: gemcitabine 1,000
mg/ m2 day 1,8,15 → 1week rest x 4 cycles
● Primary endpoint : 2-year survival per protocol
Results

● Arm 1 26/27 completed chemoradiotherapy→ 9

progressed → 24 surgery→ 17 resected → 14 R0(51%)
● Arm 2: 18/23 resected→ 26.1% R0 → adjuvant
chemoradiation
● 2 YSR: 40.7% vs26.1%