role of chemotherapy in carcinoma stomach
TRANSCRIPT
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ROLE OF CHEMOTHERAPY IN CARCINOMA STOMACH
DR SAILENDRASENIOR RESIDENT
DEPT OF RADIOTHERAPYMAULANA AZAD MEDICAL COLLEGE
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STAGING
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CURRENT RECOMMENDATION
• SURGERY ALONET1N0 and
selective T2N0
• SURGERY FOLLOWED BY CTRT • PRE OP CT SX POST OP CT
T2-T4/ N+,RESECTABLE
• CTRT• CHEMOTHERAPY ALONE• BEST SUPPORTIVE CARE
UNRESECTABLE
• CHEMOTHERAPY ALONE• BEST SUPPORTIVE CARE• PALLIATIVE RTM1
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CHEMOTHERAPY
NEOADJUVANT OR
PERIOPERATIVE
CONCURRENT
ADJUVANT
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NEOADJUVANT/PERIOPERATIVE
3 TRIALSMAGIC trial
French FNLCC/FFCD trial
EORTC trial 40954
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MAGIC TRIAL
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ELIGIBILITY CRITERIA
ANY AGESTAGE T2 OR HIGHERPS - 0 OR 1ADENOCARCINOMA OF STOMACH OR DISTAL
ESOPHAGUSNO EVIDENCE OF DISTANCE METASTASIS
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250 patients
Perioperative chemotherapy&
surgery
TOTAL 503 PATIENTS
JULY 1994 TO APRIL 2002
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CHEMOTHERAPY USED
Epirubicine Cisplatin Infusional
5FU
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PFS OS5 yr survival 36% Vs 23%
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SUMMARY
• PFS and OS are significantly better in perioperative chemotherapy arm
• Estimated improvement in the five-year survival rate was 13%.
• Local failure rate was 14% Vs 21%
• Distance metastasis rate was 24% Vs 37%
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Limitations
• Nonstandardized surgery• Inaccurate preoperative staging• Higher proportion of patients in chemotherapy
arm undergo potentially curative surgery(79% VS 70%)
• T1/2 (52 Vs 37%)and N0/1(84 Vs 71%)patients are more in chemotherapy arm
• Only 104 (42%) patients were able to complete protocol treatment.
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FRENCH FNCLCC TRIAL
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THIS TRIAL WAS CLOSED EARLY DUE TO LACK OF ACCRUAL
CHEMOTHERAPY USED WAS CISPLATIN AND 5FU
Between November, 1995, and December, 2003
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AFTER MEDIAN FOLLOW UP OF 5.7 YEARS
5YR DFS34% VS 19%
5YR OS 38% VS 24%
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SUMMARY
• Significant improvement in DFS and OS with perioperative chemotherapy
• Most common toxicity were neutropenia and nausea and vomiting.
• All the patients under go D2 resection which is the standard surgical procedure in gastric carcinoma.
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LIMITATIONS
• Pretreatment staging was not reported.• The planned sample size of the trial was not
reached.
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META ANALYSIS
• Concluded that neoadjuvant chemotherapy was associated with a statistically significant benefit in terms of both overall survival and PFS.
• Neoadjuvant chemotherapy was associated with a significantly higher complete (R0) tumor resection rate and did not significantly worsen rates of operative complications, perioperative mortality, or grade 3 or 4 adverse effects.
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ADJUVANT CHEMORADIATION
3 RANDOMIZED TRIALS
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patients with primaries T3 or higher and/or node-positive gastric cancer after R0 resection were randomised
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RADIOCHEMOTHERAPY CONSISTED OF BOLUS FLUOROURACIL AND LEUCOVORIN BEFORE, DURING, AND AFTER RADIOTHERAPY.
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STUDY DESIGN
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FIVE-YEAR OVERALL SURVIVAL 43% VERSUS 28% IN FAVOUR OF CTRT
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3 YEAR DISEASE FREE SURVIVAL 48% VS 31% IN FAVOUR OF CTRT
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• DISTANT RELAPSE WAS 16% VS 18%• REGIONAL RELAPSE WAS 22% VS 39%
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SUMMARY
• Even after 10years of follow up the survival advantage WITH CTRT is better than surgery alone.
• 3yr OS was 50% Vs 41%• 3yr RFS was 48% Vs 31%• Toxicity was more with CTRT• CTRT significantly decreases the locoregional
failure• Standard of care in USA
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LIMITATIONS
• D2 dissection was only performed in 10% of cases.
• Only 64% of cases completed the treatment and 17% discontinued treatment due to toxicity
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CALGB 80101: Study Schema
RANDOMIZE
5-FU/LV: 5-FU 425 mg/m2 d1-5, LV 20 mg/m2 d1-5
RT: 45 Gy (1.8 Gy X 25 fractions) with 5-FU 200 mg/m2/d CI
ECF (pre-RT): Epirubicin 50 mg/m2 d1, Cisplatin 60 mg/m2 d1, & 5-FU 200 mg/m2/d CI d1-21
ECF (post-RT): Epirubicin 40 mg/m2 d1, Cisplatin 50 mg/m2 d1, & 5-FU 200 mg/m2/d CI d1-21
5-FU/LVX1
5-FU/LVX2
5-FU IVCIRT
ECFX1
ECFX2
5-FU IVCIRT
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NO DIFFERENCE IN DFSP=0.99
0 1 2 3 4 5 6 7
Years from Study Entry
0.0
0.2
0.4
0.6
0.8
1.0
Prop
ortio
n Su
rviv
ing
Dis
ease
-Fre
e
ECF5-FU
Disease_Free Survival by Arm
0 1 2 3 4 5 6 7
Years from Study Entry
0.0
0.2
0.4
0.6
0.8
1.0
Prop
ortio
n Su
rviv
ing
ECF5-FU
Overall Survival by Arm
NO DIFFRENCE IN OSP=0.80
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ARTIST TRIAL
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CAPECITABINE AND CISPLATIN 2 CYCLES
XPRT 45Gy IN 25#
CAPECITABINE AND CISPLATIN 6 CYCLESRANDOMIZED
458 patients
SURGERY WITH D2 LN DISSECTION
CAPECITABINE AND CISPLATIN 2 CYCLES
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THERE WAS NO DIFFERENCE IN DFS AND OS
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SUMMARY
• No difference in DFS and OS• Subset analysis indicate a significantly better
DFS with chemoradiotherapy in those with node-positive disease (three-year DFS 76 versus 72 percent, p = 0.004).
• ARTIST –II TRIAL is going on that will further address the advantage with adjuvant CTRT over adjuvant chemotherapy.
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META- ANALYSIS
A meta-analysis compared 6 trials of adjuvant CTRT with chemotherapy and it conclude that
There is significantly improved 5 yr DFS and Local control with CTRT
There is a trend towards improved overall survival but that is not statistically significant
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ADJUVANT CHEMOTHERAPY
2 TRIALS
JAPANESE S-1 TRIAL CLASSIC trial
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JAPANESE S-1 TRIAL(ACTS GC)
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• Stage II or III gastric cancer• All had undergone potentially curative
surgery with D2 lymphadenectomy
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Dose of S-1 was (80 to 120 mg daily for four weeks, repeated every six weeks for one year)
S-1 is an oral fluoropyrimidine that includes three different agents: A. TegafurB. Gimeracil (5-chloro-2,4 dihydropyridine, a potent
inhibitor of DPD [dihydropyrimidine dehydrogenase])
C. Oteracil (potassium oxonate, which inhibits phosphorylation of intestinal FU, thought responsible for treatment-related diarrhea)
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RESULTSIGNIFICANT BENEFIT IN 5YR DFS
AND OS IN S-1 ARM
P =0.003
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• S-1 is approved in Japan for adjuvant therapy of gastric cancer and in Europe for treatment of advanced gastric cancer.
• It is not available in the United States.• Except for anorexia (incidence, 6%), grade 3 or
4 adverse events occurred in less than 5% of the patients in the S-1 group.
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CLASSIC TRIAL
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CLASSIC TRIAL DESIGN
CAPECITABINE AND OXALIPLATIN 8 CYCLESRANDOMIZED
1035 patients
SURGERY WITH D2 LN DISSECTION
NO ADJUVANT THERAPY
ATLEAST 15LN EXTRACTED
520 PATIENTS
515 PATIENTS
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3 YEAR DFS 74% VS 59%
P < 0.0001
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3 YEAR OS 83% VS 78%
P = 0.0493
5 YEAR OVERALL SURVIVAL IS 78% VS 69%
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SUMMARY
• CAPECTABINE 1000mg/m2 DAY 1 -14,OXALIPLATIN 130mg/m2 ON D1
• 9 TIMES MORE GRADE 3 & 4 TOXICITIES IN CHEMOTHERAPY ARM
• ONLY 67% OF PATIENTS RECEIVED ALL 8 CYCLES OF CHEMOTHERAPY
• 90% OF PATIENTS REQUIRE CHEMOTHERAPY DOSE MODIFICATION
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ACCORDING TO NCCN
Chemotherapy prefered in • PERIOPERATIVE REGIMEN IS – Cisplatin and 5FU(cat-1) and ECF(cat-2)
• POST OPERATIVE REGIMEN– CAPOX(IF RT CAN NOT BE GIVEN)
• CT BEFORE AND AFTER RT– CAPECITABINE D-1 TO 14 OR LVFU
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