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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

Disclosures None

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

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.

Gastric cancer: adjuvant chemotherapy? UTD

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

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: 7061243

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: 7910321

Adjuvant Radiotherapy: What’s the Benefit INT 0116 (SWOG 9008) 556 pts, 20-48 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

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

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

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: 11547741

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 1995-2001 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: 16099596

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: 16099596

Adjuvant Radiotherapy: What’s the Benefit ARTIST Trial - PMID 22184384 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)

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

Radiation Field Design - 2D Therapy

Radiation Field Design - 3D Therapy

Radiation Field Design - 3D Therapy

Radiation Field Design – Breathing Motion Management Respiratory Gating

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

Radiation Field Design - IMRT

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

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!

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