IMRT in pancreas

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%

16. 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

17. 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

18. 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

19. 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)

20. RTOG 0848 Adjuvant

21. NCCN Adjuvant

23. 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

24. 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. 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

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

28. 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

29. 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

30. NCCN Inoperable

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

32. Typical Radiation Fields

33. Radiation Fields

34. Computer Reconstruction from the CT Scan

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

36. Computer Reconstruction from the CT Scan Lymph Nodes

37. Computer Reconstruction from the CT Scan Radiation Zone

38. Small Bowel Colo n

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

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

41. Normal Tissue Dose Limits

42. Normal Tissue Dose Limits

43. 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

44. 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

45. 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

46. 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

47. 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

48. 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

49. 51 3D-CRT vs IMRT JC Landry, Emory Univ, Med Dos 27, 121, 2002

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53. 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

54. 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 =

55. 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

56. 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

57. 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

58. • 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.

59. Thank youThank you