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