Debate on role of chemotherapy versus chemoradiation in pancreatic cancers

1. Max Cancer Congress 2019 Debates
The Motion : Inoperable Pancreatic Cancer – Partial
Response to Chemo - Radiotherapy is essential
My Stand - FOR
Dr. Ashutosh Mukherji
Senior Consultant and Academic Coordinator,
Department of Radiation Oncology
Yashoda Hospital, Hyderabad, India

2. Survival and Failure Pattern
• Surgery offers the only cure, but only 10-20% are
candidates and the 5-year survival is only 20% and median
13-20 months
• Locally advanced the median survival is 8-14 months
• Up to 60% already have metastases and survival of 4 to 6
months
• After surgery local relapse rate of 50 – 86% and distant
recurrence rate of 40 – 90%

3. Study number median 2y 5y
GITSG
chemoradiation 21 20.0 mos 42% 15%
observation 22 10.9 mos 15% 5%
chemoradiation 30 18.0 mos 46% 17%
EORTC
chemoradiation 110 21.6 mos 51% 25%
observation 108 19.2 mos 41% 22%
ESPAC-1
chemotherapy 147 20.1 mos 40% 21%
no chemo 142 15.5 mos 30% 8%
chemoradiation 145 15.9 mos 29% 10%
no chemorad. 144 17.9 mos 41% 20%
RTOG-9704
gemzar – chemorad 187 20.5 mos 31%/3 22%
5-FU – chemorad 201 17.2 mos 22%/3y 18%
Prospective Trials of Adjuvant Therapy

4. Benefits from Adjuvant Radiation
GITSG
postOp 40Gy + 5FU versus observation
The radiation arm had better median survival (20 mos versus 11
mos) and 2 year survival 20% versus 10%
EORTC
postOp 5FU versus chemorad (40Gy in split course) and better 2Y
survival in radiation arm: 34% versus 26%
NCDB review
chemoradiation improved survival (HR .784) but no chemoRx (1.08)
Hopkins/ Mayo Clinic Review (Hsu, 2008) n = 1.045
Adjuvant 5FU/XRT improved survival from 16.3 months to 22.5
months

5. Adjuvant Radiotherapy and Chemotherapy for
Pancreatic Carcinoma: The Mayo Clinic
Experience (1975-2005)
review 472 consecutive patients who underwent
complete resection with negative margins (R0) for
invasive carcinoma (T1-3N0-1M0)
Surgery S + Chemoradiation
Overall survival 19.2 mos 25.2 mos
Survival 39%/2y 50%/2y
15%/5y 28%/5y
JCO July 20, 2008:3511-3516

6. Adjuvant Chemotherapy and Radiation Large,
Prospectively Collected Database at the Johns Hopkins
Hospital /The final cohort includes 616 patients.
JCO July 20, 2008:3503-3510
Surgery S + Chemoradiation
Median Survival 14.4 mos 21.2 mos
Survival 31.9%/2y 43.9%/2y
15.4%/5y 20.1%/5y

7. Neoadjuvant Therapy (chemo or radiation prior to
surgery)
SEER Data Base: 3,885 Resectable Pancreas Cancer
Treatment Number Median Survival
Neoadjuvant XRT 70 (2%) 23 months
PostOp XRT 1,478 (38%) 17 months
Surgery Only 2,337 (60%) 12 months
. Int J Radiat Oncol Biol Phys 2008;72(4):1128–1133.

8. Radiation for Unresectable Pancreas
Cancer
ECOG Trial, Loehrer 2011)
Therapy Median Survival
Gemzar 9.2 months
Gemzar + Radiation 11.1 months
Michigan Trial / IMRT 55Gy + Gemzar, Ben-Josef 2012
Therapy Survival
Historical 11.2 months 13%/2y
IMRT 14.8 months 30%/2y

9. Survival in ECOG Trial
JCO November 1, 2011 vol. 29 no. 31 4105-4112
Chemo + Radiation
Chemo

10. • Neoadj CRT shown to improve median OS but at cost of
increased toxicities from CRT long course and delay in surgery /
adjuvant therapy.
• MD Anderson Study: 160 patients treated with neoadjuvant RT
either 50.4Gy/28 Fr or 30Gy/10 fr. 66 patients ultimately went to
surgery with 94% achieving a negative margin; median OS of 40
months for operated patients and 13 months for non-operated.
• Alliance trial: 22 patients received modified FOLFIRINOX x 4
cycles then CRT 50.4 Gy/28 fr with concurrent capecitabine. 15
patients had surgical resection with 14 achieving negative
margins. Five patients had less than 5% residual tumor cells and
2 patients had a pathologic complete response (pCR). Median
OS was 21.7 months, but 64% of patients experienced grade 3 or
greater toxicity.
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11. • ESPAC-1 trial, survival shorter with CRT (15.9 months vs 17.9
months; p = 0.05): SPLIT COURSE RT USED.
• Meta-analysis by Stoken et al of 875 patients: benefit of CRT in
patients with R1 resection, despite heterogeneity between trials
with R1 resection patients from 18–83%.
• Retrospective study (6165 patients), US National Cancer Data
Base, with pT1-3N0-1M0 resected PC: improved OS provided by
CRT (HR, 0.851; 95% CI, 0.793–0.913; P< 0.001) compared to
adjuvant chemotherapy alone.
• Subset analyses: CRT had improved OS in pT3 or pN1 disease
and particularly with R1 resection.
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12. • Unicancer-GI-PRODIGE Group randomized 493 patients with
surgically resected pancreatic adenocarcinoma to 24 weeks of
adjuvant therapy with either modified FOLFIRINOX or
gemcitabine. This trial demonstrated improved DFS and OS in
the adjuvant modified FOLFIRINOX group.
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13. • LAPC  Induction Chemotherapy Before CRT (LAP-07 TRIAL):
recruited 449 patients, patients with no tumour progression after 4
months of chemo (n=267) underwent 2nd randomization to receive
either 2 more months of gemcitabine or CRT. There was no diff
between Gem or Gem + erlotinib in OS.
• OS not significantly different between the 2 arms (15.2 vs 16.4
months, p = 0.8). But CRT resulted in improved PFS (9.9 vs 8.4
months, p = 0.06), treatment-free interval (6.1 vs 3.7 months, p =
0.017) and loco-regional tumour progression (32% versus 46%, p =
0.035), confirming the efficacy of CRT for local control.
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14. ICMR RECOMMENDATIONS
• BRPC and Adjuvant Chemoradiotherapy (CRT): Consider
chemoradiotherapy for patients with pT3 or pN1 disease
who underwent R1 resection.
• BRPC and Neo-adjuvant therapy: About one-third of initially
unresectable cancers (BRPC/LAPC) were rendered resectable
after neoadjuvant therapy which can be both SBRT or
chemo.
• LAPC  CRT versus chemotherapy alone: Acceptable
treatment options include both CRT or chemotherapy alone.
• LAPC  Induction Chemotherapy Before CRT: Standard of
care remains 6 months of chemotherapy with gemcitabine
(from LAP-07 trial). CRT is an option (with better PFS and
local control) in stable or responding patients after 3-4
months of chemotherapy.
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15. 15

16. 16
3D-CRT vs IMRT
JC Landry, Emory Univ, Med Dos 27, 121, 2002
• 1999-2001
• 3D-CRT and IMRT were compared using Volume at Risk
Approach (VARA)

17. • RTOG 0848: actively enrolling phase III trial in the modern era with current
chemotherapy and advanced radiation techniques (Adj chemo vs CRT)
• New studies have used SBRT as neoadj t/t instead of CRT with or without
chemo.
• Median OS with SBRT comparable or better than CRT, less OAR toxicity with
SBRT, Single institution studies shown OS advantage with neoadj SBRT.
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18. THANK YOU