This study compared outcomes of 61 gastric cancer patients treated with postoperative chemoradiotherapy using either intensity-modulated radiotherapy (IMRT) or 3-dimensional conformal radiotherapy (3D CRT). The 2-year overall survival rates were 51% for 3D CRT and 65% for IMRT, with no significant difference. Locoregional failure occurred in 15% of 3D CRT patients and 13% of IMRT patients. Both the 2-year disease-free survival and local control rates were similar between the two groups. Overall, the study found no significant differences in outcomes between IMRT and 3D CRT for adjuvant therapy of gastric cancer.

1. Journal Club:Comparison Of IMRT and 3DCRT as Adjuvant Therapy for Gastric CancerYuriko Minn, Annie Hsu et al.Cancer, 15Aug.2010. 116:3943-3952 Radiation Oncology Dr BRAIRCH, AIIMS Moderator : Prof. BK Mohanti Presenter : Dr AkhileshMishra

5. Sites of Origin And Histologies Antrum and Distal Stomach: ~ 40% Body: ~ 25% Proximal Stomach and GE Jn. : ~ 35% Adenocarcinomas : 90-95% Lymphomas (Usually with UnfavourableHistologies) : 4-5% Leiomyosarcomas : ~2% Rest : Carcinoids, Adenocanthomas, SCCs.

6. General Anatomy

8. Japanese Surgical Staging for Ca. Stomach S0 No serosal invasion S1 Suspected serosal invasion S2 Definiteserosal invasion S3 Adjacent organ involvement N1 Perigastric lymph nodes N2 Lymph nodes around the left gastric artery, common hepatic artery, splenic artery, and celiac axis N3 Lymph nodes in the hepatoduodenal ligament, posterior aspect of pancreas, and root of mesentery N4 Periaortic and middle colic lymph nodes P0 No peritoneal metastases P1 Adjacent peritoneal involvement P2 A few scattered metastases to distant peritoneum P3 Many distant peritoneal metastases H0 No liver metastases H1 Metastases limited to one lobe H2 A few bilateral metastases H3 Numerous bilateral metastases STAGE GROUPING Stage I S0, N0, P0, H0 Stage II S1, N0-1, P0, H0 Stage III S2, N0-2, P0, H0 Stage IV S3, N3-4, P1-3, H1-3

9. Prognostic Factors Stage is the most important prognostic factor Regional nodal involvement adversely affects the prognosis. The number and locations of the affected lymph nodes are both significant. According to the Japanese Classification of gastric cancer, numbers of positive level II nodes have more influence on the prognosis. The prognosis of proximal cancers is less favorable. Diffuse type pathology cases are associated with worse treatment results compared with intestinal type No biologic markers routinely utilized.

10. Genetic Alterations Associated With Worse Prognosis Aneuploidy Presence of viral genome (H. pylori) Telomerase Reactivation P53 gene Inactivation Dysfunction of repair genes Hmsh3 & Hmlh1 Overexpression: Her2Neu, bcl2, c-met, k-sam Oestrogenic Receptor Expression CD44 Expression

12. Proximal stomach total gastrectomy

14. Margin positive

15. Gross residual disease

16. Transmural infiltration

17. Serosal involvement

19. ADJUVANT THERAPY Curative resection (R0) * IRCH modification: 1)C2-3 5FUFA- Inj FU-375mgm2 IV bolus 2)EBRT by 3D-CRT instead of conventional RT C1 5FUFA Inj LV-20 mg/m2 IV D1-D5 Inj FU-425 mg/m2 IV D1-D5 4 wks EBRT-45 Gy/25#/5 wks C2-C3 5FUFA with RT (D1-D4; D23-D25) Inj LV-20 mg/m2 IV bolus Inj FU-400 mg/m2 IV bolus* C4-C5 5FUFA q 4wk Inj LV-20 mg/m2 IV D1-D5 Inj FU-425 mg/m2 IV D1-D5 4 wks -Macdonald etal. NEJM 2001; 345: 725-30.

21. NACT 2-3 cycles (CDDP+ Capecitabine) f/b assessment for surgery

22. Palliative –

23. Radiotherapy30Gy/10#/2wks (rarely used)

24. Chemotherapy5FUFA / capecitabine+ CDDP

25. Surgeryfeeding procedure/ gastric bypass surgery

27. Level and Extent of Surgery Japan, which reported a hospital mortality rate of in D2 suegery:0.8% :JCOG 95-01;Sasako et al. 2006; Sano et al. 2004. Italian study similar results on postoperative mortality:Degiuli et al. 2004. Spleenectomy is not routinely recommended. Spleen and pancreas-preserving lymphadenectomies are becoming more popular (Fenoglio-Preiser et al. 1996).

28. Latest in Surgery Endoscopic mucosal dissection (EMR) has been increasingly used in selected patients with early stage gastric cancer. Indications for EMR include : Tumor size < 3 cm, Absence of ulceration, Well differentiated histology, Absence of lymph node metastasis, And no evidence of invasive findings (Ono et al. 2001; Hiki et al. 1995; Noda et al. 1997).

29. Areas Included In Radiation Field Based On the likely sites of Locoregional Failure , the following are included in Radiation Field: Gastric / Tumour Bed Anastomosis and Gastric Remnant Nodal Chains at lesser and greater curvatures Celiac Axis, PancreatoDuodenal, Splenic nodes SupraPancreatic, PortaHepatis GastroDuodenal & ParaAorticupto level of L3

30. Conventional Radiation Portal:IRCH Upper Border - The bottom of T8 or T9 to cover celiac axis ,GE Jnfundus and dome of Left hemidiaphragm. Lower Border - The Bottom of L3 vertebra for Gastro-Duodenal nodes. Left Border- 2/3 to 3/4 of Left Hemidiaphragm for Fundus with Supra-Pancreatic and Splenic nodes. Right Border – 3-4 cms lateral to vertebral bodies for Antrum with Porta-Hepatis & Gastro-Duodenal nodes. 3DCRT is the preferred modality currently.

31. 3DCRT in Ca. Stomach Radiation Oncology , IRCH

32. 3DCRT in Ca. Stomach Radiation Oncology , IRCH

33. Abstract The current study was performed to compare the clinical outcomes and toxicity in patients treated with post-operative chemo-radiotherapy for gastric cancer using intensity-modulated radiotherapy (IMRT) versus 3-dimensional conformal radiotherapy (3D CRT). From December 1998 to June 2008, 61 patients with non-metastatic gastric or gastroesophageal (GE) junction cancer were treated with postoperative radiotherapy at Stanford University. Two patients treated with IMRT and 2 patients treated with 3D CRT who did not complete their radiation course were excluded, leaving 57 patients for this analysis.

34. Methods Fifty-seven patients with gastric or gastroesophageal junction cancer were treated postoperatively: 26 with 3D CRT and 31 with IMRT. Earlier patients were treated with 3D CRT; however, there was a gradual shift of practice toward IMRT beginning in 2002. Concurrent chemotherapy was capecitabine (n = 31), 5-fluorouracil (5-FU) (n = 25), or none (n = 1). The median radiation dose was 45 Gy. Dose volume histogram parameters for kidney and liver were compared between treatment groups

35. Methods For the bowel, the intestinal loops outside the planning treatment volume (PTV) were contoured, not the whole abdominal space. To account for daily setup error and organ motion, the CTV to PTV expansion was typically 5 to 10 mm. Normal structures were also contoured, including kidneys, liver, spinal cord, and bowel. Patients were treated with either a 3 or 4-field technique to 43.2 to 50.4 Gy (median, 45 Gy), 5 days a week. The PTV received a median dose of 45Gy(range, 41.4-54 Gy) with a median fraction size of 1.8 Gy(range, 1.8-2.08 Gy).

36. Methods Although the median doses were similar between the treatment groups, more patients received >45 Gy in the IMRT group than in the 3DCRT group (10 vs 2, respectively). For the 12 patients who received>45 Gy, the additional 5 to 9 Gy were given a sequential conedown or simultaneous integrated boost. Six patients with positive margins and 2 patients with close margins received >45 Gy. Twenty-three patients treated with IMRT were treated with respiratory gating while all other patients were treated with free breathing. Beam energies used included 6MV, 10 MV, 15 MV, or a mix of 6 and 15 MV.

37. Methods Dose constraint guidelines used for IMRT planning included: 75% of the liver<15 Gy; mean liver dose<20Gy; 70% of each kidney<15 Gy or 2/3 of 1 kidney <18 Gy; 95% of the bowel <45Gy.Max dose to the bowel<54Gy. The bowel space was contoured. The spinal cord dose was limited to 45 Gy. The IMRT plans were normalized to 95% volume to get 100% of the dose.

38. Methods All patients underwent routine systemic workup and disease evaluation that included history and physical examination, routine laboratory studies,CT of the chest and abdomen, and esophagogastroduodenoscopy with biopsy. Fifty-three patients (93%) received chemotherapy that was FU-based (5-fluorouracil [5-FU] or capecitabine) with or without Carboplatin before the start of radiotherapy, the latter regimen being part of an institutional protocol.

39. Methods The majority of patients received 2 cycles before radiation. Patients received concurrent chemotherapy with capecitabine (n ¼ 31), 5-FU (n ¼ 25), or none (n ¼ 1). After the completion of radiotherapy, 45 patients (79%) received 1 to 2 cycles of the same chemotherapy that was given before radiation, as directed by their medical oncologists

40. RESULTS

41. RESULTS

42. RESULTS

43. RESULTS

44. Results The 2-year overall survival rates for 3D CRT versus IMRT were 51% and 65%, respectively (P = .5) Four locoregional failures occurred each in the 3D CRT (15%) and the IMRT (13%) patients Median OS & DFS from initiation of RT:5.4 & 4.7 Yrs respectively The 2 Yrs DFS for 3DCRT & IMRT: 60% & 54% respectively (P=0.8) The 2 Yrs Local Control Rates for 3DCRT & IMRT: 83% & 81%(P=0.9) respectively The median volume receiving 42.75 Gy (95% of 45Gy) for 3DCRT versus IMRT: 1606ml versus 1282.6ml respectively(P=0.048)

45. Results Grade ≥2 acute gastrointestinal toxicity was found to be similar between the 3D CRT and IMRT patients (61.5%vs61.2%, respectively) but more treatment breaks were needed (3 vs 0, respectively) Grade ≥2 acute haematological toxicity was found to be 35% in 3D CRT and 29% of IMRT patients respectively Grade 3 late toxicity in 3DCRT arm in 3 patients versus 1 in IMRT arm 49 Patients had > 6 months F/U. A total of 17 patients developed distant metastases,the median time to distant metastases:8.7 months(range 3.9-21.6 months)

46. Results The median serum creatinine from before radiotherapy to most recent creatinine was unchanged in the IMRT group (0.80 mg/dL) but increased in the 3D CRT group from 0.80 mg/dL to 1.0 mg/dL (P = .02) The median kidney mean dose was higher in the IMRT versus the 3D CRT group (13.9 Gyvs11.1 Gy; P = .05). The median kidney V20 was lower for the IMRT versus the 3D CRT group (17.5%vs22%; P = .17) The median liver mean dose for IMRT and 3D CRT was 13.6 Gy and 18.6Gy, respectively (P = .19). The median liver V30 was 16.1% and 28%, respectively (P < .001)

47. Discussion Although the data are not consistent in demonstrating an advantage of IMRT over 3D CRT, there may be some gains in acute toxicities with the use of IMRT because of generally decreased dose to normal organs such as bowel, kidney, and liver. In addition, IMRT may allow for dose escalation in the hopes to improve disease control, especially in cases such as close/positive margins, extranodal disease spread, or other situations believed to have a high risk of residual microscopic disease, without increasing the dose to critical structures.

48. Discussion Adjuvant chemoradiotherapy was well tolerated with either 3D CRT or IMRT, with similar acute and late toxicities reported. The incorporation of image guidance likely confers additional improvements. Further investigation is required to determine the true clinical benefit of IMRT for this disease, and we believe it is highly warranted given the generally poor outcomes of this disease and the high rate of treatment morbidity.

49. Discussion Despite higher doses used, IMRT provides sparing to the liver and possibly the kidneys Although the dosimetric advantage of IMRT for the kidneys was not consistent, renal function appears to be preserved better These results need to be validated with longer follow-up as well as in larger studies

50. Conclusion LRC is good with adjuvant chemoradiotherapy but overall outcomes for Ca. Stomach remains poor. Improvement in both systemic & local t/t is required Adjuvant chemoradiotherapy was well tolerated with either 3D CRT or IMRT, with similar acute and late toxicities reported

51. Conclusion The differences in clinical outcomes were not statistically significant in 3DCRT versus IMRT IMRT was found to provide sparing to the liver and possibly renal function. (Cancer 2010;116:3943–52. VC 2010 American Cancer Society)

52. REFERENCES AND LANDMARK TRIALS Moertel et al (1969) first time demonstrated the clinical benefit of combining 5FU to Radiation in locally advanced unresectable Ca. Stomach. INT0116/-SWOG 9008 (Macdonald et al. 2001, 2004, 2009) UK-MRC MAGIC Trial 2006 NEJM. Japanese S-1 Trial 2007 NEJM. Boige et al. 2007 ASCO

53. Other Major References ECOG-CALGB 80101 Trial,2002-2009 Ringash J, et al.2005. IJROBP Wieland P, et al.2004. IJROBP Smalley,Gunderson.2002.IJROBP Tepper & Gunderson.2002.SRO Boda-Heggemann, Hofheinz et al. 2009.IJROBP RTOG 9904 Trial

54. Other Major References Milano et al. 2006.BJR Chung et al. 2008.IJROBP Alani et al. 2009.IJROBP Leong T et al.RadiotherOncol 2005 van der Geld YG et al.IJROBP 2007 de la Torre et al. Med. Dosim. 2004 ICRU-62(supplement to ICRU Report 50)1999 ICRU-83,VOL-10,No.1,2010

55. THANKS