perioperative adjuvant chemotherapy gastric cancer

1. Chemotherapy and chemoradiotherapy in
resectable gastric cancer
Dr Sujan Shrestha
MCh, GI surgery

2. Disclosure
• Available data will be focused on Gastric cancer
(Lower esophageal and GEJ tumors will not be focused of this presentation)
• Focusing on cases who are resectable
• Important clinicopathological findings, primary secondary outcomes and
limitations will only be discussed
• Only relevant details of respective guidelines will be discussed

3. What is the current management protocol ?
NCCN 2020
ESMO
JAPANESE

4. What is the current management protocol ?
NCCN 2020

5. What is the current management protocol ?
ESMO

6. What is the current management protocol ?
JAPANESE

7. WHAT ARE THE OPTIMAL APPROCH?
• T2-T4, ANY
• N(LOCOREGIONAL)
• MO
WHAT ARE THE POSSIBLE OPTIONS?
• SURGERY ONLY
• SURGERY THAN ADJUVANT CHEMO
• SURGERY THAN ADJUVANT CHEMORADIO
• PERIOPERATIVE CHEMO(CHEMO-SURGERY-CHEMO)
• PERIOPERATIVE CHEMORAD(CHEMORAD-SURGERY-CHEM0RAD)
• CHEMO-SURGERY-CHEMORAD
SO MANY OPTIONS
???????????

8. • T2-T4, ANY
• N(LOCOREGIONAL)
• MO
WHAT ARE THE OPTIMAL APPROCH?
TREATMENT DEPENDS UPON GEOGRAPHY
TREATMENT DEPENDS UPON WHERE ARE YOU
LIMITED SURGERY
+ ADJUVANT THERAPY
• INT 0116 TRIAL
• CALGB 80101 TRIAL
PERIOPERATIVE
CHEMOTHERAPY
• MAGIC TRIAL
• FNCCLC
• FLOT 4
RADICAL SURGERY +
CHEMOTHERAPY
• ACTS GC
• CLASICC
• JACCRO

9. • T2-T4, ANY
• N(LOCOREGIONAL)
• MO UPFRONT SURGERY
ADVANTAGES
• Better staging (pathological)
• Better risk assessment
• Everyone gets surgery
• Improves survival
• Phase three trial for both adjuvant CT and CRT

10. UPFRONT SURGERY
3 IMPORTANT QUESTIONS
WHICH WHEN WHAT
• DO ALL PATIENT AFTER UPFRONT SURGERY REQUIRES ADJUVANT
• WHEN SHOULD WE PROVIDE ADJUVANT THERAPY POST SURGERY
• WHAT ADJUVANT THERAPY SHOULD BE GIVEN CHEMORT OR CHEMO

11. UPFRONT SURGERY
WHICH
DO ALL PATIENT AFTER UPFRONT SURGERY REQUIRES ADJUVANT
• T2 or more with any
N
• N plus with any T

12. WHEN UPFRONT SURGERY
WHEN SHOULD WE PROVIDE ADJUVANT THERAPY POST SURGERY
• Duration post surgery for initiation of adjuvant therapy not clear
• Recommended (as done in major RCTS) = 6 TO 8 WKS
• REAL scenario patient are often delayed for adjuvant therapy ( around 12 wks)
Greenleaf et al. Ann Surg Oncol 2016
Timing of Adjuvant Chemotherapy and Impact on Survival for Resected
Gastric Cancer
Patients treated with gastrectomy for stages 1-3 gastric
cancer.
Treatment groups were stratified by time to initiation of
AC:
• Initiation of chemotherapy within 8 weeks
postoperatively,
• Between 8 and 12 weeks postoperatively,
• After 12 weeks postoperatively, and
7942 patients undergoing gastrectomy, 29 % received AC
Conclusions: Time to initiation
of AC does not impact
survival. With improved survival
over patients who did not
receive AC, even delayed
initiation of chemotherapy
should be offered, when

13. UPFRONT SURGERY
WHAT
Options for adjuvant treatment
• Adjuvant chemotherapy
• Adjuvant chemoradiotherapy
Both have level 1 evidence but in different scenario(type of surgery)

14. ADJUVANT CHEMORADIOTHERAPY
N Engl J Med
September 6, 2001
MACDONALD TRIAL

15. 556 patients

17. Conclusions Postoperative chemoradiotherapy should be considered for all patients
at high risk for recurrence of adenocarcinoma of the stomach or gastroesophageal
junction who have undergone curative resection.
BUT THE SURGERY WAS SUBOPTIMAL
• 10 percent of the patients underwent a D2
dissection
• 36 per- cent had a D1 dissection, and
• 54 percent had a D0 lymphadenectomy
PROVIDED MOST PATIENT IF UNDERGONE D2 DISSECTION THE RESULT MIGHT NOT BE SAME
MACDONALD REGIMEN
• 45% (GI TOXICITY)
• 33%(HEMATOLOGICAL TOXICITY)
MACDONALD TRIAL

18. CAN WE REPRODUCE THE SAME RESULTS AS MACDONALD WITH LESS TOXIC REGIMEN
THUS, THEY REPLACED FULV WITH MAGIC REGIMEN(ECF)

19. LESS TOXIC EQUAL OR NONINFERIOR OUTCOMES

20. CONCLUSION FOR ADJUVANT CHEMORT
• LESS THAN STANDARD SURGERY ( <D2, MARGIN POSITIVE)
• MACDONALD OR MODIFIED REGIMEN HAS SIMILAR EFFICACY
(BOLUS 5FU WAS GIVEN)
IN MODIFIED
• Good performance status - capecitabine
• For poor performance status - Infusional 5FU

21. CONCLUSION FOR ADJUVANT CHEMORT

22. ADJUVANT CHEMOTHERAPY
WHAT ARE AVAILABLE OPTIONS?
• S1
• S1 PLUS DOCETAXEL
• CAPOX

23. Japanese S1 trial
The New England Journal of Medicine, 2007
Stage II or III gastric cancer who underwent
gastrectomy with extended (D2) lymph-node
dissection
Adjuvant therapy with S-1
(529)
Surgery alone
(530)

24. 3-year overall
survival
80.1% vs
70.1%
RFS
72 % VS 59

25. Lancet 2012
CAPOX TRIAL
Stage II or III gastric cancer who underwent
gastrectomy with extended (D2) lymph-node
dissection
CAPOX
(520)
SURGERY ALONE
(515)

26. 3 year disease-free
survival
74% VS 59%

27. 2018 , JAPAN
S1+ DOCETAXEL TRIAL
ADDITION OF T WAS VERY TOXIC

28. UPFRONT SURGERY
WHICH
DO ALL PATIENT AFTER UPFRONT SURGERY REQUIRES ADJUVANT
• T2 or more with any
N
• N plus with any T

29. SURGERY IS THE CORE FOR BETTER RESULT

30. WHY SUCH A GOOD RESULT IN JAPANESE STUDIES?

31. TILL NOW WE HAVE 2 OPTIONS FOR UPFRONT SURGERY
ADJUVANT CHEMOTHERAPY
ADJUVANT CHEMORADIOTHERAPY
SUPPORTED BY SUPPORTED BY
• INT 0116 TRIAL
• CALGB 80101
TRIAL
• ACTS GC
• CLASICC
• JACCRO
CT OR CRT
ARTIST TRIAL

32. CT OR CRT
J Clin Oncol, 2012
RESECTED GASTRIC CANCER WITH D2
XP
(CT)
228
XP/XRT/XP
(CRT)
230

33. 3-year DFS
78.2% in the XP/XRT/XP arm
and 74.2% in the XP arm

35. Conclusion
The addition of XRT to XP chemotherapy did not significantly
reduce recurrence after curative resection and D2 lymph node dissection in gastric
cancer. A subsequent trial (ARTIST-II) in patients with lymph node–positive gastric
cancer is planned.

36. CT OR CRT IN NODE POSITIVE PATIENTS
Annals of Oncology , 2020
D2-resected, stage II or III, node-positive gastric cancer.
S1
182
SOX
181
SOXRT
183

37. Conclusion: In patients with curatively D2-resected, stage II/III, node-positive GC,
adjuvant SOX, or SOX/RT was effective in prolonging DFS, when compared to S-1
monotherapy. The addition of radiotherapy to SOX did not significantly reduce
the rate of recurrence after D2-gastrectomy.

38. TILL NOW WE HAVE 2 OPTIONS FOR UPFRONT SURGERY
ADJUVANT CHEMOTHERAPY ADJUVANT CHEMORADIOTHERAPY
SUPPORTED BY SUPPORTED BY
• INT 0116 TRIAL
• CALGB 80101
TRIAL
• ACTS GC
• CLASICC
• JACCRO
CT OR CRT
ARTIST TRIAL 1 AND 2
SO , NO EVIDENCE FOR ADDITION OF ADJUVANT CRT IN D2 RADICAL GASTRECTOMY
EVIDENT ROLE IN LESS THAN D2 SURGERY (AS PER MACDONALD TRIAL)

39. SECOND STRATEGY
Perioperative chemotherapy
Chemo Surgery Chemo
Standard treatment for resectable ca stomach

40. What is the current management protocol ?
NCCN 2020

41. ESMO GUIDELINES
ADVANTAGES
• DOWNSTAGING OF T AND N
• DELIVERY EASIER AND BETTER TOLERATD
• BETTER COMPLIANCE
• OS BENEFIT (LEVEL 1 EVIDENCE)

42. WHOM TO GIVE ?
MEDICALLY FIT AND POTENTIALLY RESECTABLE
NCCN 2020 ESMO 2017

43. WHAT TO GIVE?
MAGIC : ECF/ECX
FNCLCC : PF
FLOT 4 : FLOT
PS : 0.1 PS : 2
FOLFOX OR CAPOX : (BASE FROM CLASSIC)

44. MAGIC TRIAL
The New England Journal of Medicine, 2006
Resectable adenocarcinoma
ECF– SURGERY – ECF
250
SURGERY
253

47. Conclusions
In patients with operable gastric or lower esophageal adenocarcinomas, a
perioperative regimen of ECF decreased tumor size and stage and significantly im-
proved progression-free and overall survival.
LIMITATIONS

48. FNLCC TRIAL
J Clin Oncol , 2011
Perioperative Chemotherapy Compared With Surgery Alone for
Resectable Gastroesophageal Adenocarcinoma: An FNCLCC and
FFCD Multicenter Phase III Trial
Resectable adenocarcinoma
PF + SURGERY

49. MEDIAN NO OF NODES WERE 19 (D2)

50. FLOT4 TRIAL
Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and
docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for
locally advanced, resectable gastric or gastro-oesophageal junction
adenocarcinoma (FLOT4)
HEAD TO HEAD COMPARISON WITH THE STANDARD ECF OF MAGIC TRIAL
Resectable adenocarcinoma
FLOT – SURGERY - FLOT ECF – SURGERY- ECF
THE LANCET, 2019

53. 5 YRS OS :36% VS 45%

54. Interpretation In locally advanced, resectable gastric or gastro-
oesophageal junction adenocarcinoma, perioperative FLOT improved overall
survival compared with perioperative ECF/ECX.
MAGIC SAID
THERE IS SURVIVAL BENEFIT OF PERIOPERATIVE ECF
FNLCC SAID
THERE IS EQUAL SURVIVAL BENEFIT OF PERIOPERATIVE CF WITH AVOIDANCE OF TOXIC E
FLOT 4 SAID
THERE IS ADDED SURVIVAL BENEFIT OF FLOT OVER ECF WITH SIMILAR TOXICITY PROFILE
36%
38%
45%
OS

55. OTHER QUESTIONS NOT EXPLAINED BY ABOVE PERIOPERATIVE TRIAL
DO ADDITION OF POSTOPERATIVE RADIOTHERAPY IN PATIENT TREATED WITH
PREOP CHEMOTHERAPY WILL BENEFIT?
SCENARIO IS
CHEMO SURGERY CHEMORT
WILL THIS HAS BENEFIT OVER STANDARD PERIOPERATIVE THERAPY

56. CRITICS TRIAL
Chemotherapy versus chemoradiotherapy after surgery
and preoperative chemotherapy for resectable gastric
cancer (CRITICS):
Lancet Oncol 2018
DUTCH GROUP

57. At a median follow-up of 61·4 months (IQR 43·3–
82·8)
median overall
survival 43 months
chemotherapy group 37
months chemoradiotherapy
group
NO ADDED SURVIVAL BENEFIT

58. OTHER QUESTIONS NOT EXPLAINED BY ABOVE PERIOPERATIVE TRIAL
PERIOPERATIVE THERAPY
IF NO ROLE OF POST SURGERY RT
WHAT ABOUT PREOPERATIVE RT?
CRITICS 1
TOPGEAR CRITICS 2
WE ARE WAITING FOR RESULTS

59. 1000 DOLLOR QUESTION
IS PERIOPERATIVE CHEMO BETTER THAN ADJUVANT CHEMO?

60. MIND MAP FOR CHEMOTHERAPY AND CHEMORADIOTHERAPY GASTRIC CANCER
RESOLVE
PRODIGY
CRITICS 1 AND 2
TOPGEAR
CRT

61. THANK YOU