LANDMARK CHEMOTHERAPY AND RADIATION TRIALS IN GASTRIC CANCER.pptx
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Landmark Chemotherapy and Radiation Trials in Cancer Stomach
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LANDMARK CHEMOTHERAPY AND RADIATION TRIALS IN GASTRIC CANCER.pptx
- 1. LANDMARK CHEMOTHERAPY AND RADIATION TRIALS IN GASTRIC CANCER Prof. S. Subbiah et al
- 2. NCCN 2022 Prof. S. Subbiah et al
- 3. JGC treatment guidelines 2021 Prof. S. Subbiah et al
- 4. The search begins… Prof. S. Subbiah et al
- 5. • Stage II to IV adenocarcinoma of stomach, GEJ and lower third esophagus • N= 253 • Radical resection of primary and nodes Surgery alone • N=250 • 3 cycles ECF before and after surgery Perioperative chemotherapy Prof. S. Subbiah et al
- 6. • Increasing the likelihood of curative resection by downstaging the tumor • eliminating micrometastases • rapidly improving tumor-related symptoms • determining whether the tumor is sensitive to the chemotherapy Prof. S. Subbiah et al
- 7. • 229 pts (91.6%) underwent surgery • 104 out of 250 (41%) completed peri operative chemotherapy Prof. S. Subbiah et al
- 8. Prof. S. Subbiah et al
- 9. • 50% patients in MAGIC trial didn’t complete post operative chemotherapy • T3- T4 • N=144 • NACT+ surgery (72) vs surgery (72) • 2 cycles of 48 days – Cisplatin 50mg/m2 IV on days 1, 15 & 29 – Leucovorin 500mg/m2 IV over 2 hours – 5 FU 2g/m2 continuous IVI days – 1,8,15,22,29 & 36 Prof. S. Subbiah et al
- 10. Prof. S. Subbiah et al
- 11. • Number of D2 gastrectomies were almost equal – 96% vs 92% • Inadequate statistical power to detect potential survival difference • Better surgical resection might have compensated for the benefits offered by neoadjuvant chemotherapy Prof. S. Subbiah et al
- 12. 2-3 pre operative chemo 4 weekly cisplatin 100 mg/m2 IV day 1 5 FU 800mg/m2 CIVI day 1-5 Prof. S. Subbiah et al
- 13. Periop chemo + surgery Surgery alone 5 year os 38% 24% 5 year DFS 34% 19% R0 resection 84% 73% Post op complications 27% 19% Prof. S. Subbiah et al
- 14. • Docetaxel had shown benefit in metastatic gastric and GEJ tumors • 28 German centres • N= 716 • FLOT 4 (356) vs ECF (360) FLOT 4 every 2 weeks ECF/ECX every 3 weeks Docetaxel 50 mg/m2 IV day 1 Epirubicin 50 mg/m2 IV day 1 Oxaliplatin 85mg/m2 IV day 1 Cisplatin 60 mg/m2 IV day 1 LV 200mg/m2 IV day 1 5 FU – 200 mg/m2 CIVI day 1 5 FU – 2600mg/m2 IV day 1 Capecitabine 1250 mg/m2 PO day 1 - 21 Prof. S. Subbiah et al
- 15. Prof. S. Subbiah et al
- 16. FLOT ECF/ECX P 3 year OS 57% 48% 0.012 Median DFS 30 months 18 months 0.0036 Serious adverse events 27% 27% NS R0 resection 85% 78% 0.012 Post op complications 51% 50% NS In locally advanced resectable gastric and GEJ adenocarcinoma, peri operative FLOT improved OS when compared to peri operative ECF/ECX Prof. S. Subbiah et al
- 17. PERIOPERATIVE CHEMOTHERAPY TRIALS • T2 N0 and above – peri operative chemotherapy is the standard of care ( MAGIC, EORTC 40954, ACCORD 07 ) • FLOT 4 is the standard regimen at present ( FLOT 4 ) • Poor PS or multiple co morbidities – FOLFOX or CAPOX Prof. S. Subbiah et al
- 18. •Peri operative chemotherapy has shown improved overall survival in patients with resectable gastric cancer •Can addition of radiation in peri operative setting improve outcomes? Prof. S. Subbiah et al
- 19. • Stage IB – IVA adenocarcinoma of stomach and GEJ ( siewert II – III) • N= 788 Curative surgery (310) 3 cycles post op chemo (180) ECX/EOX 3 cycles 21 days 3 cycles chemo – curative surgery(342) RT 45 gy + capecitabine 575mg/m2 BD on days of RT + weekly CDDP 20 mg/m2 (188) CTRT Prof. S. Subbiah et al
- 20. Periop chemo Periop CTRT P Median OS 43 months 37months 0.9 Median EFS 28 months 25 months 0.92 Prof. S. Subbiah et al
- 21. Prof. S. Subbiah et al
- 22. Preoperative chemoradiation is safe and feasible and does not adversely increase morbidity Prof. S. Subbiah et al
- 23. • Outcomes with the addition of post operative therapy – Adjuvant trials Prof. S. Subbiah et al
- 24. Prof. S. Subbiah et al
- 25. Prof. S. Subbiah et al
- 26. Prof. S. Subbiah et al
- 27. Prof. S. Subbiah et al
- 28. • To evaluate the effect of adjuvant chemotherapy with capecitabine and oxaliplatin after D2 gastrectomy • Curative gastrectomy with atleast 15 nodes N=1035 Surgery alone n= 515 Surgery f/b adjuvant chemotherapy n = 520 •3 weekly cycle of capecitabine 1000mg/m2 BD days 1 – 14 •Oxaliplatin 130 mg/m2 IV day 1 •6 months •67% pts completed the course •90% needed dose modification Prof. S. Subbiah et al
- 29. Adjuvant treatment with capecitabine and oxaliplatin should be considered after D2 gastrectomy Prof. S. Subbiah et al
- 30. Addition of docetaxel to S-1 is effective with few safety concerns in stage III gastric cancer Prof. S. Subbiah et al
- 31. • Addition of radiation to adjuvant chemotherapy after D2 gastrectomy Prof. S. Subbiah et al
- 32. • Stage Ib – IV adenocarcinoma with R0 resection of primary with D2 lymphadenectomy N=458 N=228 Capecitabine 1000mg/m2 BD day 1- 14 + cisplatin 60mg/m2 day 1 – 3 weekly 6 cycles N = 230 2 cycles XP + EBRT 45 Gy/25# with capecitabine 825mg/m2 BD all days + 2 more cycles XP 3 weekly Prof. S. Subbiah et al
- 33. XP XP/XRT No benefit of post operative chemoradiation over adjuvant chemo after D2 dissection Prof. S. Subbiah et al
- 34. Prof. S. Subbiah et al
- 35. CALGB N=546 N=280 5 FU/LV x 1 5 FU CIVI + RT 5 FU/LV x 2 N= 266 ECF x 1 5 FU CIVI + RT ECF x 2 5 FU 425 mg/m2/day IV day 1-5 LV 20mg/m2/day IV day 1-5 RT – 45Gy/25# + 5 FU 200 mg/m2/day CIVI ECF – epirubicin 50 mg/m2 IV day1 Cisplatin 60 mg/m2 IV day 1 5 FU 200mg/m2/day D 1 - 21 Prof. S. Subbiah et al
- 36. Following a curative resection of GEJ and gastric adenocarcinoma, post op CTRT with ECF doesn’t improve survival when compared to bolus 5 FU/LV Prof. S. Subbiah et al
- 37. ADJUVANT TRIALS • After a potentially curative surgery without any neo adjuvant therapy, adjuvant chemotherapy is recommended - >T2 , N+ ( CLASSIC ) • After D2 dissection, there is no benefit of adjuvant radiation ( ARTIST 1 & 2, CALGB 80101) • Less than D2 dissection or < 16 nodes dissected – adjuvant chemoradiation is preferred ( INT 0116) • S 1 is the standard of care in Japan • CAPOX is the preferred regimen – 8 cycles 3 weekly – Capecitabine 1000mg/m2 PO BD days 1 to 14 – Oxaliplatin 130mg/m2 IV day 1 Prof. S. Subbiah et al
- 38. • Targeted therapies Prof. S. Subbiah et al
- 39. ToGA Post hoc – better OS with IHC 2+ and FISH + or IHC 3+ Median follow up was 19 and 17 months HER 2 overexpression positive, locally advanced, recurrent, metastatic GC or EGJ N= 594 Trastuzumab + cisplatin & 5FU/ capecitabine OS -13.8 months Chemotherapy alone OS -11 months Prof. S. Subbiah et al
- 40. • HERXO – Trastuzumab + oxaliplatin + 5FU/ capecitabine • DESTINY gastric 01 – Fam trastuzumab deruxtecan nxki + chemo as second line chemotherapy after failure of prior two lines even with trastuzumab Prof. S. Subbiah et al
- 41. • Ramucirumab – VEGFR 2 antibody for progressive disease – REGARD – median OS improved by 1.4 months – RAINBOW – paclitaxel + ramucirumab. Median OS 9.6 vs 7.3 months. Better PFS – RAINFALL – does not reduce disease progression in treatment naïve patients Ramucirumab + paclitaxel as second line therapy in progressive disease Prof. S. Subbiah et al
- 42. • Nivolumab – monoclonal PD 1 antibody – CHECKMATE – 649 : HER 2 negative, unresectable nivolumab + chemotherapy ( CAPOX or FOLFOX) Better OS and PFS Nivolumab + 5 FU/ capecitabine + oxaliplatin as first line treatment option in HER 2 negative tumours with PD L1 expression levels by CPS >5 Prof. S. Subbiah et al
- 43. • Pembrolizumab – PD 1 antibody – KEYNOTE 158 – tumors identified with TMB – H had an ORR of 29% and complete response rate in 4% Pembrolizumab in second line or subsequent treatment of MSI- H/dMMR or TMB- H tumors Prof. S. Subbiah et al
- 44. • Dostarlimab – gxly – anti PD 1 antibody – GARNET – dMMR solid tumors ( endometrial / GI) ORR 42% and complete response 5% median duration of response 35 months Progressive tumors who have not received PD 1, PD L 1 or CTLA 4 inhibitors as second line therapy Prof. S. Subbiah et al
- 45. • Entrectinib and Larotrectinib – NTRK fusion gene inhibitors – LOXO – TRK – 14001, SCOUT, NAVIGATE – ORR across 3 trials – 75% and complete response rate 22% – STARTRK – 2 : ORR 57%, CR 7% Second line or subsequent treatment options in NTRK gene fusion positive gastric tumors Prof. S. Subbiah et al
- 46. Conversion gastrectomy surgical treatment aiming at R0 resection for tumors that were deemed unresectable before chemotherapy. operitoneal cancer index (PCI)> 6 obilobar hepatic metastases onodal involvement outside D1-3 stations otechnically unresectable metastases Prof. S. Subbiah et al
- 47. R0 conversion surgery was associated with a significantly longer PFS than R1 resections More than one type of metastasis significantly affect prognosis Prof. S. Subbiah et al
- 48. HIPEC + CRS Prof. S. Subbiah et al
- 49. overall CRS+HIPEC CRS alone Prof. S. Subbiah et al
- 50. Significantly improved OS and RFS in limited peritoneal metastasis after complete cytoreduction Prof. S. Subbiah et al