1. Resection offers the only chance of cure for pancreatic cancer, but adjuvant therapy after surgery may improve outcomes. Studies have shown benefits from chemoradiation over chemotherapy alone. 2. For borderline resectable or locally advanced unresectable disease, neoadjuvant therapy or chemoradiation may help make initially unresectable tumors operable or improve survival compared to chemotherapy alone. 3. Intensity modulated radiation therapy (IMRT) allows safer dose escalation and better sparing of nearby organs compared to 3D conformal radiation, potentially improving local control and survival. Proper motion management and image guidance are needed to fully realize the benefits of IMRT.

1. IMRT in Pancreatic Cancers;IMRT in Pancreatic Cancers;
Potential Benefits and RisksPotential Benefits and Risks
Dr. Ashutosh Mukherji
Additional Professor,
Department of Radiotherapy,
Regional Cancer Centre, JIPMER

2. Summary of Treatment
1.Resection is the only chance for a cure, and
resectable patients show undergo surgery
without delay followed by adjuvant therapy
2.Borderline resectable patients may benefit
from neoadjuvant therapy and then surgery
3.Unresectable patients may benefit from
chemotherapy or chemoradiation
4.Metastatic disease may benefit from
chemotherapy or other palliative treatments

3. Survival
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

4. Patterns of Failure after Surgery
After surgery local relapse rate of 50
– 86%
and distant recurrence rate of 40 –
90%

5. RTOG 9704
postOp FU then chemoradiation versus
Gemcitabine then chemoradiation
(50.4Gy)
Slight advantage to the Gemzar arm for
head of pancreas group: median survival
of 20.5 months versus 17.1 months and
long term 22%/5y versus 18%/5y

6. Is there a proven role for postOp
radiation?
• European studies (CONKO 001 Trial, EORTC
Trial, ESPAC-1 showed benefit from
chemotherapy but no benefit or in fact harm
from including radiation and so they favor
chemotherapy alone
• American Trials (GITSG) showed benefit and
favor including radiation

7. 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

8. GITSG trial(1985)
• First prospective RCT in Ca Pancreas
arms Median Survival
Sx  Obs (n=22) 10 months
Sx  CRT(n=21)
(5FU based Split course RT)
21 months (p=0.03)

9. GITSG trial(1985):Drawbacks
• Small sample size (n=43)
• Poor accrual
• Early termination based on findings of the CRT
arm

10. GITSG 1987
• Tried to confirm the results of the GITSG 1985
• further 30 patients were registered to the
treatment arm.
• The median survival was noted to be 18 months.
• Limitations:
1.that it did not have a control arm,
2.the patients were not randomized
3.performance status of the participants before
study enrolment was better than that of all
patients in the initial study

11. EORTC study(Klinkenbijl et al, 1999)
• prospective randomized phase III study
Arms MS (months) DFS (months) 5 yr Survival
(months)
Sx alone (n=108) 19 16 22
Sx CRT (n=110)
(5FU based split
course RT)
24.5 (p>0.05) 17.4 (p>0.05) 25 (p>0.05)

12. RTOG 9704 (Regine et al 2008)
• N=451
arms Median Survival 3 yr survival P value
Sx
5FU5FU+RT
5FU
16.9 months 22 %
0.09
Sx
Gem5FU+RT
Gem
20.5 months 31 %

13. Herman et al (John Hopkins)
• Adjuvant CRT improved survival among both
margin-negative (P=.014) and margin-positive
(P =.001)patients
Arms Median
Survival
2 yr survival 5 yr survival P value
SxCRT
(n=271)
21.2 months 43.9% 20.1%
P<0.001
Sxobs
(n=345)
14.4 months 31.9% 15.4%

14. Herman et al: Limitation
• This study does not address the controversy
as to whether adjuvant CRT is superior to
chemotherapy alone.

15. EORTC 40013/FFCD 9203/GERCOR
Phase II study
• N=90
• Randomised to adjuvant Gemcitabine (4
cycles) and adjuvant Gem + RT (2 cycles Gem
Gem+RT)
Arms Median DFS Median OS First local
recurrence
Adj. Gem 11 months 24 months 24%
Adj. Gem+RT 12 months 24 months 11%

17. 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

18. 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

19. 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

20. RTOG 0848 Adjuvant
Step 1: Adjuvant chemotherapy:
(Arm1 Gemcitabine X 5 or Arm 2
Gemcitabine + Erlotinib X 5))
Step2: In no progression then: (Arm 3
one more cycle of chemo or Arm 2 1
cycle then chemoradiation with either
capecitabine or 5-FU)
Radiation dose is 1.8Gy X 28 (50.4Gy)

21. RTOG 0848 Adjuvant

22. NCCN Adjuvant

23. Summary of Treatment
1.Resection is the only chance for a cure, and
resectable patients show undergo surgery
without delay followed by adjuvant therapy
2.Borderline resectable patients may benefit
from neoadjuvant therapy and then surgery
3.Unresectable patients may benefit from
chemotherapy or chemoradiation
4.Metastatic disease may benefit from
chemotherapy or other palliative treatments

24. Neoadjuvant Therapy (chemo or
radiation prior to surgery)
-About 1/3 of patients have a long delay after
surgery getting started on PostOp therapy
- 20-40% who get preOp will be found to
develop Mets and avoid surgery
-PreOp may increase the number of surgical
candidates
-No good randomized Trials
-Some trials the 5 year survival in those
undergoing a curative resection in the 32 – 36%
range

25. 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 Phys2008;72(4):1128–1133.

26. Summary of Treatment
1.Resection is the only chance for a cure, and
resectable patients show undergo surgery
without delay followed by adjuvant therapy
2.Borderline resectable patients may benefit
from neoadjuvant therapy and then surgery
3.Unresectable patients may benefit from
chemotherapy or chemoradiation
4.Metastatic disease may benefit from
chemotherapy or other palliative treatments

27. 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

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

29. Median Survival in Months Inoperable
Pancreas Cancer
Gemzar Alone 9.1 – 9.9
Gemzar + Radiation 11.3 – 11.9
JCO November 1, 2011vol. 29 no. 31 4105-4112

30. RTOG 1201 Unresectable
Three Arms ChemoRx Radiation
1 gemcitabine X 12w 63Gy (IMRT) + capecitabine
2 gemcitabine X 12w 50.4Gy (3D) + capecitabine
3 FOLFIRINOX X 12w 50.4Gy (3D) + capecitabine
IMRT Dose is 2.25Gy X 28 (63Gy) / 3D Dose is 1.8 Gy X 28 (50.4Gy)
95% of the PTV must get 95% of the prescribed dose and the Dmax to
0.03cc is no higher than 110% of the prescription dose

32. NCCN Inoperable

33. The CT Images Are Contoured and
Labelled to Identify The Structures

34. Typical Radiation Fields

35. Radiation Fields

36. Computer Reconstruction from the CT
Scan

37. Cancer
Pancreas
Liver
Kidney Kidney
Stomach
Computer Reconstruction from the CT
Scan

38. Computer Reconstruction from the CT
Scan
Lymph
Nodes

39. Computer Reconstruction from the CT
Scan
Radiation
Zone

40. Small
Bowel
Colo
n

41. Multiple structures (Liver, Stomach, Small Bowel, Colon, Spinal
Cord, Kidneys) can all be effected by the radiation field

42. PV – Portal Vein
PJ – Pancreaticojejnosotomy
SMA – Superior Mesenteric
Artery
CA – Celiac Artery

43. Normal Tissue Dose Limits

44. Normal Tissue Dose Limits

45. Benefits of IMRT in Pancreas
• Avoidance Bowels (small and large) as well as
other GI tract organs surrounding the
Pancreas.
• Dose escalation beyond 50.4 Gy (studies have
gone up to 55-61 Gy mean dose) and even 70
Gy plus in selected cases of localised disease
to neck of pancreas.
45

46. Which patients might do well?
• LOCATION(Neck, proximal Body)
• Low initial CA 19.9
• Response to chemo
• Good KPS
• Small tumour
• SMAD4?
• Dose of RT (can we escalate dose by taking into
account surrounding organ tolerance and intra- plus
inter-fraction motion)
46

47. 3D-CRT of pancreatic tumors:
first experience at IRCC (98-02)
• 21 patients with locally advanced /vessels
infiltration
• All biopsy proven; all CT; 5 PET scan
• Protocol:
• CT ( GEM 50-100 mg/m2 twice weekly + 3D-
CRT (45 –50.4 Gy) in 1.80 Gy/session
• Re-evaluation for surgery 45 days after
radiotherapy
47

48. Results: - PR: 3(15%) - SD: 14 (70%)
- DFS: (m) 2, 3+, 5, 16, 24+
- OS : (m) 7, 8+, 18, 23, 28+
- Ca 19.9 reduction: 12/20 (60%)
- Clinical benefit: 12/60 (60%)
5 patients underwent radical surgery (1 N+, all
with free margins)
48

49. 3D-CRT vs IMRT
• 1999-2001
• 10 randomly selected patients were planned
simultaneously
• 3D-CRT and IMRT were compared using Volume at
Risk Approach (VARA)
• For the evaluation of small bowel toxicity were
employed DVH and NTCP
JC Landry, Emory Univ., Med Dos 27, 121, 2002
49

50. 3D-CRT vs IMRT
• Aim of treatment:
61.2 Gy to GTV
45.0 Gy to CTV
• Maintaining critical normal
tissues to below specified
tolerances
IMRT constraints:
•PTV: (Priority 90%)
•Presc. D.: 50.4 Gy
•Min D: 45.0 Gy
•GTV: (priority 90%)
•Presc. D.: 61.2 Gy
•Min. D.: 59.4 Gy
•Small bowel: (priority 80%)
•Max. D.: 45 Gy
50
JC Landry, Emory Univ, Med Dos 27, 121, 2002

51. 51
3D-CRT vs IMRT
JC Landry, Emory Univ, Med Dos 27, 121, 2002

52. 52

53. 53

54. 54

55. Tumor
Cross-sectional View
of Patient’s Chest
Tumor
Some motion is mostly
Anterior / Posterior
Some motion is mostly
Superior / Inferior
All tumor motion is
Complex
Tumor Motion During Respiration
• All tumor motion is complex

56. Account for target motion: ITV, PTV
Planning Scan
 4DCT
CTV 50%
(Inhale)
CTV 0%
(Exhale) Fused CTV = (ITV)
PTV = Fused GTV + 5 mm
Setup Margin
=

57. Differences in COM coordinates between (a)
FBCT vs. CBCT; (b) AIP vs. CBCT, (c) FBCT/CBCT vs.
AIP/CBCT. Vertical error bars represent the standard deviations
57

58. Yovino s, Regine Wf et al, IJROBP, 79(1): 158-62, 2011.
IMRT decreases acute GI toxicity in patients
receiving CCRT for abdominal malignancies
58
Changes in the PTV
coverage and normal
structure sparing for a
single case resulted from
using the markers on the
FBCT (solid curves)
versus the markers
on the AIP (dashed
curves) for IGRT

59. Why IMRT?
IMRT / VMAT can be better than 2D or 3DCRT
if:
•Proper GTV delineation by CT / PET-CT
•Set-up uncertainties decreased
•Organ motion accounted for
•AIP used for DVH calculation
•Dose escalation can and must be planned
where possible
59

60. • Thus benefits of IMRT lies
in:
 ensuring protection of
normal tissues and…….
 achieving dose escalation
to tumor volume.
• Technology has given us
new tools to hit
targets……….
• But to use it correctly
depends on us.

61. Thank youThank you