Landmark Chemotherapy and Radiation Trials in Cancer Stomach

1. LANDMARK CHEMOTHERAPY AND
RADIATION TRIALS IN GASTRIC
CANCER
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2. NCCN 2022
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3. JGC treatment guidelines 2021
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4. The search begins…
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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
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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

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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
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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
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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?
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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
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20. Periop chemo Periop CTRT P
Median OS 43 months 37months 0.9
Median EFS 28 months 25 months 0.92
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22. Preoperative chemoradiation
is safe and feasible and does
not adversely increase
morbidity
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23. • Outcomes with the addition of post operative
therapy – Adjuvant trials
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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
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29. Adjuvant treatment with capecitabine and oxaliplatin should be
considered after D2 gastrectomy
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30. Addition of docetaxel to S-1 is effective with few
safety concerns in stage III gastric cancer
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31. • Addition of radiation to adjuvant
chemotherapy after D2 gastrectomy
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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
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33. XP XP/XRT
No benefit of post operative
chemoradiation over adjuvant chemo
after D2 dissection
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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
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38. • Targeted therapies
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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
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47. R0 conversion surgery was associated with a significantly longer PFS than R1 resections
More than one type of metastasis significantly affect prognosis
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48. HIPEC + CRS
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49. overall CRS+HIPEC CRS alone
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50. Significantly improved OS and RFS in limited peritoneal metastasis after
complete cytoreduction
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