1. www.DebbiesDream.org Raising Awareness. Funding Research.
Supporting Patients. Achieving the DREAM!

2. Radiation Therapy for Gastric Cancer:
Los Angeles Stomach Cancer Education Symposium
Radiation Therapy for Gastric Cancer:
Optimizing Radiation Outcomes and
Minimizing Toxicities
Lecturer: Richard Tuli, MD, PhD
Associate Professor, Clinical Director
Depts. Of Radiation Oncology & Biomedical Sciences
Samuel Oschin Comprehensive Cancer Institute
Cedars-Sinai Medical Center

3. Disclosures
None

4. Introduction
Ionizing radiation is effective in killing cells, both malignant and normal (electromagnetic, particulate)
Disrupt atomic bonds and produce free radicals to damage macromolecules, most important are double-stranded DNA breaks
Unrepaired or misjoined DNA damage leads to chromosomal changes that are lethal in most cases
Tumor >>> Normal cells; fractionated treatments

5. Patterns of spread
Direct extension: pancreas, diaphragm, colon, small bowel, celiac axis, kidney; direct extension will lead to peritoneal spread.
Lymphatics:
N1: greater and lesser curvature (1-6)
N2: celiac axis and three branches (7-11)
N3: non para-aortic non celiac axis (12-14)
N4: para-aortic LNs (15-16)
Peritoneal
Hematogenous: primary route of
metastatic spread to the liver
(via the portal system)
Classification and anatomic location of lymph node groups. Involvement of nodes along the lesser or greater curvature (groups 1–6) constitutes N1 disease, and the celiac axis and its three branches are N2 (7–11), N3 (12–14), and N4 (15, 16). N1: 1, right paracardial; 2, left paracardial; 3, lesser curvature; 4, greater curvature; 5, suprapyloric; 6, infrapyloric. N2: 7, left gastric artery; 8, common hepatic artery; 9, celiac artery; 10, splenic hilus; 11, splenic artery. N3: 12, hepatic pedicle; 13, retropancreatic; 14, mesenteric root. N4: 15, middle colic artery; 16, para-aortic. 
Abeloff, 2008.

6. Gastric cancer: adjuvant chemotherapy?
UTD

7. Gastric cancer: adjuvant chemotherapy?
Reasons for negative results:
Underpowered
inferior surgical techniques
inability to tolerate adjuvant therapy after surgery
geographic variation
UTD, 2008

8. The Case for Adjuvant RT
Gunderson et al., IJROBP 1982
107 patients who underwent ‘curative’ operations for gastric cancer had systematic use of planned re-operations.
In 1948, Wangentsteen at the University of Minnesota instituted the systemic use of planned re-operations in patients with gastric carcinomas and other abdominal malignancies who were at high risk for having recurrent or metastatic disease in spite of initial curative operative procedures. Of the 107 patients who had planned re-operations, 39 re-operations (or 36% of them) were done because of local symptoms. The remaining 69 patients (or 64.4% of the cohort) were taken for re-operation in the absence of local symptoms. In total, 80.4% of patients were found to have local failure after curative surgery. 97% had failure when they were taken for re-exploration because of local symptoms. 56% of patients without local symptoms were found to have local failure on re-operations. Conclusion: Local control is rarely achieved in this cohort of patients with surgery alone.
Conclusions:
- Surgery alone yields inadequate local control in gastric cancer.
PMID:

12. Adjuvant Radiotherapy: What’s the Benefit
British Stomach Cancer Group
436 pts post surgery randomized to no further tx, RT or chemo
MMC, doxorubicin, 5 FU
No survival difference between any of the groups
Critique:
1/3 randomized to adjuvant tx didn’t receive it.
68% of XRT arm received >40.5 Gy
62% of FAM arm received 6 or more cycles
21% had gross residual disease; 18% had microscopic positive margins .
PMID:

13. Adjuvant Radiotherapy: What’s the Benefit
INT 0116 (SWOG 9008)
556 pts, days post-op, pts randomized to:
Stage IB (T1N1 or T2N0) -IV (M0) Gastric ca or GE jxt adenoca (30%)
S/p curative gastric resection, negative margins
Observation
5-FU (425mg/m2) + leucovorin (20mg/m2) X 1 cycle then concomitant chemo/RT (45Gy starting on day 21) then 2 cycles chemo

14. Adjuvant Radiotherapy: What’s the Benefit
INT 0116 (SWOG 9008)
Treatment
Observation
Med survival
36 months
27 months
DFS
49%
32% OS
50%
41%
10% improvement in OS

15. Adjuvant Radiotherapy: What’s the Benefit
INT 0116 – patterns of failure analysis
Failure pattern Observation Treatment
Local 19% 7%
Regional 46% 27%
Distant 12% 13%
*regional failure included peritoneal failure

16. Adjuvant Radiotherapy: What’s the Benefit
Critique:
LN status (Gastric resection with D2 resection recommended):
D2: 10%
D1: 36%
D0: 54%
Central review findings:
35% of treatment plans were found to contain major or minor deviations from protocol
6.5% of treatments plan had major deviations when reviewed after RT was complete
Is adjuvant RT compensating for inadequate surgery?
PMID:

17. Adjuvant RT after D2 resection Kim et al., IJROBP, 2005.
Retrospective
544 patients underwent curative D2 resection f/b post op CRT
446 patients underwent curative D2 resection without adjuvant tx.
All patients treated in Korea b/t
All staged II-IV (not M1)
Adjuvant CRT regimen like INT 0116 (5-FU/RT sandwiched with 5-FU)
Results:
Median Survival
Median Relapse Free Survival
Observation
62.6 months
52.7 months
ChemoRT
95.3 months (p=.02)
75.6 months (P=.016)
PMID:

18. Adjuvant RT after D2 resection Kim et al., IJROBP, 2005.
Benefit to post-op RT (after D2 resection) seen regardless of stage:
Patterns of Failure:
PMID:

19. Adjuvant Radiotherapy: What’s the Benefit
ARTIST Trial - PMID
458 pts with curatively resected gastric cancer with D2 LND
Randomized:
Arm 1: XP: 6 cycles of XP Q3wks
Arm 2: XP/XRT/XP (reduced dose Xeloda, 45 Gy)
Outcomes:
Addition of XRT did not significantly prolong DFS, except in pN+ pt subgroup
Conclusion:
Addition of XRT to XP chemotherapy did not significantly reduce recurrence after curative resection and D2 LND except in N+ pts
ARTIST-II planned (pN+ gastric cancer)

20. Adjuvant Radiotherapy: What’s the Benefit
Dutch CRITICS Trial:
Stage IB-IVa operable gastric cancer (no distant mets)
Randomized:
Arm 1: Neoadjuvant chemotx (3 cycles of ECC (epirubicin, cisplatin, capecitabine)  D1+ surgery  Adjuvant chemoRT (XP, 45 Gy)
Arm 2: Neoadjuvant chemotx (3 cycles of ECC)  D1+ Surgery  Adjuvant chemotx (3 cycles of ECC)
ASCO 2016 UPDATE
80+% had D1+ resection
47% and 52% completed postoperative CT and CRT therapy, respectively
No difference in DFS or OS between 2 groups
CRITICS 2 – preop CT, CRT, CT-CRT

21. Radiation Field Design - 2D Therapy

22. Radiation Field Design - 3D Therapy

23. Radiation Field Design - 3D Therapy

24. Radiation Field Design – Breathing
Motion Management
Respiratory
Gating

25. Radiation Field Design - Imaging
Dalah et al. IJROBP 2014
Yang, Tuli. IJROBP 2015
Yue, Tuli. Med Phys. 2015

26. Radiation Field Design - IMRT

27. Conclusions Surgery is the ‘Gold Standard’ but we need to do more
Radiation with chemotherapy has been shown to decrease the likelihood of tumor recurrence
Improvements in targeting allow higher doses to be delivered
Improvements in targeting allow reduced rates of toxicities
Higher focused doses of radiation are still being investigated in stomach cancers
Not all gastric cancers are the same - one size doesn’t fit all

28. Conclusions Surgery is the ‘Gold Standard’ but we need to do more
Radiation with chemotherapy has been shown to decrease the likelihood of tumor recurrence
Improvements in targeting allow higher doses to be delivered
Improvements in targeting allow reduced rates of toxicities
Higher focused doses of radiation are still being investigated in stomach cancers
Not all gastric cancers are the same - one size doesn’t fit all
LOTS OF WORK TO DO!

29. Thank You

30. Thank You!

31. www.DebbiesDream.org Raising Awareness. Funding Research.
Supporting Patients. Achieving the DREAM!