popescu razvan gastric cancer locally advanced
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Treatment of operable gastric cancer
Razvan Popescu MD, MRCP(UK)
ESO Balkan Masterclass in Clinical Oncology 11.5.2011-‐ 15.5.2011 Dubrovnik, CroaKa
Gastric Cancer Incidence in Males GLOBOCAN 2008, Interna3onal Agency for Research on Cancer
0 3.2 6.9 11.6 21.9 63 Age-‐standardised incidence rates per 100,000
Cancer Incidence in Central and Eastern Europe GLOBOCAN 2008, Interna3onal Agency for Research on Cancer
• Physical examinaKon, blood count and differenKal, liver and renal funcKon tests
• Endoscopy / EUS • CT scan of the thorax, abdomen and pelvis
• Laparoscopy (+ peritoneal washings) – +ve washings not independent prognosKc factor, conversion to –ve
washings up to 1/3 with preop chemotherapy (S. Lorenzen ASCO GI 2010)
• PET scans – can be negaKve, especially in paKents with mucinous tumours (up to 30%)
– If posiKve can be used for early response assessment
Work-‐up of Gastric Cancer
Years after surgery
Gastric Cancer Survival
CADO,1985
0
50
100%
5 10 years
Stage III
Stage II
Stage I
Stage 0
21.9
47.6
79.2
91.6 82.0
66.9
36.4
14.7
Distal esophagus
Proximal stomach
Distal stomach
GE junction
EGJ Cancers and Gastric cancers are different enKKes !!
OGJ Cancers and Gastric cancers are different !!
• Surgical resecKon is the only modality that is
potenKally curaKve, and is recommended for all non-‐
metastaKc cancers
• The extent of opKmal regional lymphadenectomy is
sKll debated.
• A minimum of 15 lymph-‐nodes should be recovered
(even if a formal D2 lymphadenectomy is not
performed)
Treatment of M0 Gastric Cancer
Dutch D1D2 surgical trial
• 996 eligible paKents randomized beteween 1989 and 1993 to D1 or D2 lymphadenectomy
• 771 paKents underwent assigned treatment, data reanalysed aaer 15 years
Outcome D1 D2 P
15-‐y survival 21% 29% 0.34
Gastric cancer death 48% 37% 0.01
Local recurrence 22% 12% -‐
OperaKve mortality 4% 10% 0.004
ComplicaKons 25% 43% 0.001
Strategies that increase cure rate in potenKally operable gastric cancer
• Adjuvant chemotherapy • Adjuvant Chemo-‐Radiotherapy
• Peri-‐operaKve Chemotherapy
• Pre-‐operaKve Chemotherapy, postoperaKve chemoradiotherapy
0.60 0.40 0.80 0.90 1.00 1.10 1.20 1.30 1.40 0.70 0.50 Surgery
alone better Any
chemotherapy better Hazard ratio
Overall effort HR: 0.82 (95% CI 0.76-0.91) P<0.0001
17 RCT 3838 pts
5 year survival: 55.3% vs. 49.6%
Benefit of adjuvant chemotherapy for resectable gastric cancer: a meta-analysis
JAMA. 2010 May 5;303(17):1729-3
• Efficacy of treatment is unknown for the individual paKent
• Results of individual trials discouraging – Some clearly underpowered to detect a significant survival difference. Other trials uKlized inferior surgical techniques.
• Commencement of post-‐operaKve treatment may be delayed by slow recovery from surgery or peri-‐operaKve morbidity, problems with nutriKonal status
• Treatment appears to be less well tolerated aaer major surgery
Challenges of adjuvant chemotherapy
POST-OP
PRE-OP
POST-OP
PRE-OP
Adjuvant chemotherapy: Percentage of Patients achieving adequate dose intensity
POST
PRE PRE
POST
SAKK TCF preop vs. postop Trial
• 4 cycles TCF planned either pre-‐ or postoperaKvely
• Trial closed due to slow accrual (70 pats in 6 Y) • PreoperaKve TCF given as planned in 74% of paKents, but only 34% postoperaKvely
• SAE were more common in postoperaKve arm (23% vs. 11%)
Strategies that increase cure rate in potenKally operable gastric cancer
• Adjuvant chemotherapy • Adjuvant Chemo-‐Radiotherapy
• Peri-‐operaKve Chemotherapy
• Pre-‐operaKve Chemotherapy, postoperaKve chemoradiotherapy
SURGERY NO TREATMENT
RANDOMIZED N= 556 5-‐FU/FA x 1 (Mayo) STRATIFIED infusional 5-‐FU / 45 Gy
T 1-‐4 5-‐FU/FA x 1 (Mayo) NODES 0, 1-‐3, >3
McDonald JS et al. N Engl J Med 2001 Sep 6;345(10):725-‐30
Postoperative Chemoradiotherapy For Localised Gastric Cancer : INT-‐0116
• Clear benefit in disease free and overall survival with median follow-‐up of 6 years. Risk reducKon of death by 24%.
• Surgery: D2 resecKon less than 10%, 54 % of paKents fewer than 15 nodes (less than D1)
• Planning of RadiaKon to be modified aaer central review in 35% of cases due to protocol deviaKons
Postoperative Chemoradiotherapy For Localised Gastric Cancer : INT-‐0116
McDonald JS et al. N Engl J Med 2001 Sep 6;345(10):725-‐30
• Complex RT schedule with significant toxicity
• SubopKmal chemotherapy schedule, role of the 2 flanking Mayo 5-‐FU/FA cycles unclear
Not an approach that has taken root in Europe
In the context of subopKmal surgery or if preoperaKve MDT is lacking an acceptable approach if good RT available
Postoperative Chemoradiotherapy For Localised Gastric Cancer : INT-‐0116
McDonald JS et al. N Engl J Med 2001 Sep 6;345(10):725-‐30
Impact of Extent of Surgery and PostoperaKve CRT on Recurrence Pamern
• Leyden retrospecKve analysis of 2 Dutch trials : 91 paKents receiving postop CRT vs. Cohort from Dutch Gastric Cancer Trial (694) split by D1 vs. D2 resecKon
• PaKents with D2 resecKon had as good an outcome as paKents receiving postop. CRT
• Clear benefit for D1 resected paKents, R1 resecKons and high Maruyama Index of unresected disease (computed from data base of cases giving likelihood of involvement of unresected LN staKons)
JL Dikken, JCO May 10, 2010
Strategies that increase cure rate in potenKally operable gastric cancer
• Adjuvant chemotherapy • Adjuvant Chemo-‐Radiotherapy
• Peri-‐operaKve Chemotherapy
• Pre-‐operaKve Chemotherapy, postoperaKve chemoradiotherapy
Eligible patients: • Adenocarcinoma of the stomach or lower third of the oesophagus (from 1999), suitable for curative resection • Non-metastatic disease • Stage II or greater
Chemotherapy (ECF): Epirubicin 50mg/m2, IV day 1 Cisplatin 60mg/m2, IV day 1 5-FU 200mg/m2/day, continuous infusion, days 1-21 (cycles repeated every 3 weeks)
Primary Overall survival
Secondary Progression-free survival Surgical resectability Quality of Life
Recruitment: July 1994-April 2002
MAGIC Trial Study entry and randomization
Pre-operative chemotherapy: ECFx3
Post-operative chemotherapy: ECFx3
Surgery
Surgery
S arm N=253
CSC arm N=250
3-6 weeks
6-12 weeks
Cunningham et al NEJM 2006
MAGIC Trial
CSC N=250
Commenced pre-operative chemotherapy N=237 (95%)
Completed pre-operative chemotherapy N=215 (86%)
Proceeded to surgery N=219 (88%)
Proceeded to surgery N=240(95%)
S N=253
Cunningham et al NEJM 2006
MAGIC Trial Postoperative Morbidity/ Mortality
CSC S
Postoperative deaths 6% (14/219)
6% (15/24 0)
Postoperative complications 46% 46%
Median duration of post - operative hospital stay
13 days 13 days
Cunningham et al NEJM 2006
MAGIC Trial Pathology Findings
• Median maximum diameter of the resected tumor was smaller in the perioperaKve-‐chemotherapy group than in the surgery group (3 cm vs. 5 cm, P<0.001)
• a greater proporKon of stage T1 and T2 tumors in the perioperaKve-‐chemotherapy group than in the surgery group (51.7 % vs. 36.8 %, P=0.002).
• less advanced nodal disease (i.e., N0 or N1) in the perioperaKve-‐chemotherapy group than in the surgery group (84.4 % vs. 70.5 %, P=0.01)
MAGIC Trial Survival
Logrank p-value = 0.0001 Hazard Ratio = 0.66
(95% CI 0.53 - 0.81)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Months from randomisation 0 12 24 36 48 60 72
163 250 190 253
Events Total CSC S P
rogr
essi
on-fr
ee S
urvi
val r
ate Logrank p-value = 0.009
Hazard Ratio = 0.75 (95% CI 0.60 - 0.93)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Months from randomisation 0 12 24 36 48 60 72
149 250 170 253
Events Total
Sur
viva
l rat
e
CSC S
2 year survival
5 year survival
Median survival
CSC 50% 36% 24 mo
S 41% 23% 20 mo Benefit to CSC arm
9% 13% 4 mo
*Included relapse, PD and death from any cause.
PFS* Overall
On multivariate analysis, treatment effect unchanged after adjustment for age, performance status, site of primary and gender
Hazard ratio for death Adjusted: 0.74 (95%CI:
0.59-0.93) Unadjusted: 0.75
Cunningham et al NEJM 2006
Cunningham D et al. N Engl J Med 2006;355:11-20
Tests for Heterogeneity of Treatment Effect According to the Baseline Characteristics of the Patients
FNLCC 94012-FFCD 9703 Trial
BOIGE et al ASCO 2007 *5-Fluorouracil 800 mg/m2 d1-5* + Cisplatin 100 mg/m2 day 1
FP (*) x 2/3 every 28 days
Resection
Within 4 weeks
4 - 6 weeks
Resection
4 – 6 weeks
FP x 3/4 or no treatment
Follow-up
Randomization N=224
CT + S S
Trial accrual 1995-2003
Median FU 5.7 yrs
2 year survival
5 year survival
Median survival
Periop CT 58% 38% 29 mo
Surgery 47% 24% 20 mo Benefit to CSC arm
10% 14% 9 mo
PFS* Overall
Median follow up: 5.7 years
___ S ___ CT + S
Logrank p value = 0.021 Hazard Ratio = 0.69 (95% CI 0.50-0.95)
On multivariate analysis, treatment effect unchanged after adjustment for age, performance status, site of primary and gender
Prognostic variables in Cox multivariate analysis: Preoperative CT Gastric location
FNLCC 94012-FFCD 9703 Trial
RFS OS
Pre-‐operaKve CT: the EORTC 40954 trial
144 paSents
resectable adenoca. of the stomach R
Surgery
PLF x 1 cycle
Surgery
PLF x 1 cycle
144 paSents randomized /360 in 4 years
Study prematurely closed because of poor accrual
Surgery
Restaging If NO PD/tox/WHO 2
N= 72
N= 72
Neoadjuvant Arm
Surgery arm
p
R0 resecSon 59 (81.9%) 48 (66.7%) 0.036
N0 node 27 (38.6%) 13 (19.1%) 0.018
Pre-‐operaKve CT: the EORTC 40954 trial
DFS OS
Pre-‐operaKve CT: the EORTC 40954 trial
ResecKon Rates
MAGIC (n=503)
FFCD (n=224)
EORTC (n = 114)
S Chemo+S S Chemo+S S Chemo+S
96% 92% 99% 96% 94% 96%
Survival Hazard RaKos
MAGIC (n=503)
FFCD (n=224)
EORTC (n = 114)
S Chemo+S S Chemo+S S Chemo+S
0.75 0.69 0.84
Summary pre-‐ /perioperaKve Chemotherapy
• All trials suggest a down sizing and down staging of gastric cancers, no relevant risk of progression whilst on chemotherapy, no increased complicaKons perioperaKvely and improved PFS and OS
• No standard chemotherapy regimen – choose best advanced chemotherapy available
Strategies that increase cure rate in potenKally operable gastric cancer
• Adjuvant chemotherapy • Adjuvant Chemo-‐Radiotherapy
• Peri-‐operaKve Chemotherapy
• Pre-‐operaKve Chemotherapy, postoperaKve chemoradiotherapy
Pre-‐ / peri-‐operaKve Chemotherapy, postoperaKve chemoradiotherapy
• RaKonale: sKll high rates of local failure, may be improved by postoperaKve RT, now combined to modern preoperaKve chemotherapy (mostly ECF or modificaKons thereof)
• Trials ongoing • Not standard, may be appropriate in paKents with expected poor surgical results (e.g. insufficient LN dissecKon, high number /raKo of involved / resected LN)
How to improve benefit of systemic treatment
• Improve regimens
• Tailor treatment
Role of PET in idenKfying paKents who may benefit from neo-‐adjuvant chemotherapy
PET -‐Responders
PET –NON Responders
PET -‐Responders
PET –NON Responders
How to improve benefit of systemic treatment
• Improve regimens
• Tailor treatment
• Establish working mulKdisciplinary teams that meet regularly and mandate that oncological treatment should be first discussed in an MDT
Summary
• Systemic treatment improves outcome of operable gastric cancer in all seqngs
• PreoperaKve approaches are preferred – Bemer delivery of treatment – Monitoring of response – Downstaging and downsizing of tumor
• Ongoing research regarding opKmal regimen and tailoring of treatment
• MDT essenKal in improving management