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ROLE OF CHEMOTHERAPY IN CARCINOMA STOMACH
DR SAILENDRASENIOR RESIDENT
DEPT OF RADIOTHERAPYMAULANA AZAD MEDICAL COLLEGE
STAGING
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
CHEMOTHERAPY
NEOADJUVANT OR
PERIOPERATIVE
CONCURRENT
ADJUVANT
NEOADJUVANT/PERIOPERATIVE
3 TRIALSMAGIC trial
French FNLCC/FFCD trial
EORTC trial 40954
MAGIC TRIAL
ELIGIBILITY CRITERIA
ANY AGESTAGE T2 OR HIGHERPS - 0 OR 1ADENOCARCINOMA OF STOMACH OR DISTAL
ESOPHAGUSNO EVIDENCE OF DISTANCE METASTASIS
250 patients
Perioperative chemotherapy&
surgery
TOTAL 503 PATIENTS
JULY 1994 TO APRIL 2002
CHEMOTHERAPY USED
Epirubicine Cisplatin Infusional
5FU
PFS OS5 yr survival 36% Vs 23%
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%
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.
FRENCH FNCLCC TRIAL
THIS TRIAL WAS CLOSED EARLY DUE TO LACK OF ACCRUAL
CHEMOTHERAPY USED WAS CISPLATIN AND 5FU
Between November, 1995, and December, 2003
AFTER MEDIAN FOLLOW UP OF 5.7 YEARS
5YR DFS34% VS 19%
5YR OS 38% VS 24%
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.
LIMITATIONS
• Pretreatment staging was not reported.• The planned sample size of the trial was not
reached.
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.
ADJUVANT CHEMORADIATION
3 RANDOMIZED TRIALS
patients with primaries T3 or higher and/or node-positive gastric cancer after R0 resection were randomised
RADIOCHEMOTHERAPY CONSISTED OF BOLUS FLUOROURACIL AND LEUCOVORIN BEFORE, DURING, AND AFTER RADIOTHERAPY.
STUDY DESIGN
FIVE-YEAR OVERALL SURVIVAL 43% VERSUS 28% IN FAVOUR OF CTRT
3 YEAR DISEASE FREE SURVIVAL 48% VS 31% IN FAVOUR OF CTRT
• DISTANT RELAPSE WAS 16% VS 18%• REGIONAL RELAPSE WAS 22% VS 39%
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
LIMITATIONS
• D2 dissection was only performed in 10% of cases.
• Only 64% of cases completed the treatment and 17% discontinued treatment due to toxicity
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
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
ARTIST TRIAL
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
THERE WAS NO DIFFERENCE IN DFS AND OS
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.
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
ADJUVANT CHEMOTHERAPY
2 TRIALS
JAPANESE S-1 TRIAL CLASSIC trial
JAPANESE S-1 TRIAL(ACTS GC)
• Stage II or III gastric cancer• All had undergone potentially curative
surgery with D2 lymphadenectomy
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)
RESULTSIGNIFICANT BENEFIT IN 5YR DFS
AND OS IN S-1 ARM
P =0.003
• 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.
CLASSIC TRIAL
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
3 YEAR DFS 74% VS 59%
P < 0.0001
3 YEAR OS 83% VS 78%
P = 0.0493
5 YEAR OVERALL SURVIVAL IS 78% VS 69%
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
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