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Esophageal and Gastric Cancer: How do we sort out the treatment options?
David H. Ilson, MD, PhDGastrointestinal Oncology ServiceMemorial Sloan-Kettering Cancer Center
Esophageal and Gastric CarcinomaUS Incidence in 2008
37,970 new cases
– Gastric: 21,500 (57%)
– Esophagus: 16,470 (43%)
Decline in Gastric Cancer , Esophageal Squamous Cancer Incidence
Increase in Adenocarcinoma of the esophagus, GE JX, cardia
Esophageal cancer more virulent:
– 87% fatality rate
– Gastric: 52%
Jemal et al, CA 58: 71-96; 2008
Oral Presentations: Esophageal and Gastric Cancer, Phase III
Adjuvant Therapy
Igaki (Abs 4510): Esophageal Cancer
– Pre versus Post op chemo in squamous cancer
Kang (Abs LBA 4511): Gastric Cancer
– Adding IP and IV cisplatin to MMC / oral doxifluridine after resection
Advanced Disease
Ridwelski (Abs 4512): Gastric Cancer
– Docetaxel + cisplatin versus 5-FU + cisplatin
Esophageal CancerTrials of Adjuvant Therapy
Preoperative surgery
Preop Chemo Surgery
Preop Concurrent RT + Chemo + / - Surgery
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A randomized trial of postoperative adjuvant chemotherapy with cisplatin and 5-fluorouracil versus neoadjuvant chemotherapy for clinical Stage II/III squamous cell carcinoma of the thoracic esophagus (JCOG 9907)
H. Igaki, N. Ando, H. Kato, M. Shinoda, H. Shimizu, T. Nakamura,
S. Ozawa, H. Yabusaki, N. Aoyama, A. Kurita, H. Fukuda
Japan Esophageal Oncology Group (JEOG) of
Japan Clinical Oncology Group (JCOG), Japan
Prior JCOG Trials in Esophageal Squamous Cancer Similar stage patients, similar sample size and design
JCOG 8806: Surgery vs post op vindesine + cisplatin, 205 pts
– Negative Trial
– OS 5 year 45% for surgery, 48% for post op chemo (NS)
JCOG 9204: Surgery vs post op 5-FU + cisplatin, 242 pts
– Primary: DFS 5 year
– Negative Trial
– DFS 45% for surgery, 55% for chemo (NS)
– OS in node + patients: 38% 52% post op chemo (P = 0.041)
Unplanned subset analysis
Ando J Card Thor S 114: 205; 1997 Ando J Clin Oncol 24: 4592;2003
8
SchemeRandomization
Balanced with minimization byinstitution, cN0 / cN1
Post-op CTx(standard arm A)
Pre-op CTx(test arm B)
Surgery
2 x FP
FP: cisplatin + 5FU5-FU 800mg/m2 d1-5 ci cisplatin 80mg/m2 d1 div
Surgery
2 x FP
Surgery-Transthoracic esophagectomy with lymphadenectomy (>D2)
In pN0,no CTx
Igaki et al, Abstract 4510
Primary Endpoint: increase PFS by 10-13% for preoperative arm
Adequately powered trial
– Protocol excluded pathologic N0 pts on post op arm (38 pts) from chemo
– Based on analysis of prior post op trial: no benefit in N0
Arms balanced by preclinical stage
Therapy tolerable and feasible
Primary endpoint not reached
Median PFS: 2 year (post op) versus 3 year (pre op, NS)
OS 5 year 38% post op 60% pre op (HR 0.64, p = 0.014)
10
2nd Interim Analysis• To decide early publication or not @ Mar. 2007, all 330 pts
Years after randomization
Unadjusted one-sided stratified
logrank P = 0.0444 > 0.0254 (alpha)
Hazard ratio = 0.76 (94.91%CI: 0.56–1.04)
Years after randomization
Unadjusted two-sided logrank P = 0.013Hazard ratio by Cox model
= 0.64 (95%CI: 0.45–0.91, p=0.014)
DSMC recommended the early publication
Progression-free survival (PFS) Overall survival (OS)
PostMedian PFS=2.0y
PreMedian PFS=3.0y
Post5yOS=38.4%
Pre5yOS=60.1%
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Igaki et al, Abstract 4510
A large number of post op pts did not receive chemo
– Preop: 17 pts (10%) did not receive chemo
– Post op: 85 pts (51%) did not receive chemo Includes 38 path N0 pts excluded per protocol (23%) Another 28% failed to receive post op chemo
Trial did not reproduce results from post op arm of prior study
– 61% OS prior post op trial
– 38% OS current post op trial Different populations, pathologic staging on the prior trial
compared to clinical staging on the current trial Adequacy of clinical staging: EUS and PET scan were not
performed
– ? Treatment arms truly balanced by stage
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Subgroup Analyses: updated OSClinical
Stage
Years after randomization Years after randomization
Hazard ratio by Cox model
= 0.94 (95%CI: 0.61–1.46)
Two-sided P = 0.79
Pre-op chemotherapy may be more beneficial in Stage II
Stage II Stage III (non-T4)
Post(n=78)
5yOS=49.3%
Pre(n=80)
5yOS=69.7% Pre(n=84)
5yOS=52.1%
Post(n=88)
5yOS=36.5%
Hazard ratio by Cox model
= 0.48 (95%CI: 0.28–0.83)
Two-sided P = 0.0088
Data in Nov 2007
Igaki et al, Abstract 4510
Current Preop Trial: only Stage II patients benefit
Prior post op trial benefit limited to path N + pts
Dose this trial prove that pre op chemo is superior to post op chemo in esophageal squamous cancer?
No
Unplanned subset analyses generate hypotheses and not conclusions
Large number of pts did not receive chemotherapy
Adequacy and accuracy of pre treatment clinical staging
Esophageal Cancer: Preop Chemotherapy
Negative Trials
U.S. INT 113
– 440 pts
– Adeno 54%, Squamous 46%
– 3 pre, 3 post op cycles of 5-FU + Cisplatin
– No improvement in disease free or overall survival
0
20
40
60
80
100
0.5 1 1.5 2 2.5 3 3.5 4 4.5 5
Kelsen et al, NEJM 339: 1979; 1998
Esophageal Cancer: Preop Chemotherapy
Positive trials
U.K. MRC OEO-2
– 802 pts
– Adeno 66%, Squamous 31%
– 2 preop cycles of 5-FU + Cisplatin
9% increase in 2 year OS
Decreased to 6% increase in 5 years OS (17%23%)
10% operative mortality
MRC Lancet 359: 1727; 2002 Cunningham NEJM 355: 11; 2006
Meta Analysis Preop Chemo in Esophageal Cancer: Thirion (ASCO 2007)
Squamous and adeno
– 9 trials OS: 2102 pts
Overall survival improvement for preop chemo (HR 0.87, p = 0.0033)
– 4% improvement in OS at 5 yrs
– Squamous 4%
– Adeno 7%
Preop Chemo in Esophageal Squamous Cancer
Marginal benefit from larger trials and meta analysis
Operative mortality risk = survival benefit
Data do no support this approach as the optimal standard of care in squamous cancer
Preop Chemo in Esophageal Squamous Cancer
Primary chemo + radiotherapy: U.S. standard of care for locally advanced disease
– Curative potential without surgery (RTOG)
– Responding patients (FFCD)
Absence of a clear survival benefit for addition of surgery
– Surgery for biopsy positive / non responding patients after therapy
– Surgery for younger, fitter patients
Early stage disease:
– Surgery alone or Chemoradiotherapy alone
Gastric Cancer:Adjuvant Therapy Standards of Care
Post op Chemo oral S-1 (Japan)– 10% improved 5 yr OS
– 1000 pts, D2 resection
Post op Chemo 5-FU / LV + radiotherapy (U.S.)– 10% improvement in 5 yr OS
– Pts with less than a D1-D2 resection
Pre and post op Chemo ECF (U.K.)– 13% improvement in 5 yr OS
– without radiotherapy
Sakuramoto NEJM 357: 1810;2007 Macdonald NEJM 345: 725; 2001 Cunningham NEJM 355: 11; 2006
Rationale: Intraperitoneal Chemotherapy
Peritoneal recurrence in up to 40-50% of patients after gastric resection
IP chemo increases exposure to chemo agents by 10-100 + fold
No confirmed phase III trials of IP therapy
Postoperative adjuvant chemotherapy for grossly serosa-positive advanced gastric cancer:
A randomized phase III trial of intraperitoneal cisplatin and early mitomycin-C plus long-term
doxifluridine plus cisplatin (iceMFP) versus mitomycin-C plus short-term doxifluridine (Mf)
(AMC 0101) (NCT00296322)
Postoperative adjuvant chemotherapy for grossly serosa-positive advanced gastric cancer:
A randomized phase III trial of intraperitoneal cisplatin and early mitomycin-C plus long-term
doxifluridine plus cisplatin (iceMFP) versus mitomycin-C plus short-term doxifluridine (Mf)
(AMC 0101) (NCT00296322)
Yoon-Koo Kang, Heung-Moon Chang, Dae Young Zang, Jae-Lyun Lee, Tae Won Kim, Dae Hyun Yang, Se Jin Jang,
Jeong Hwan Yook, Sung Tae Oh, Byung Sik Kim
Asan Medical Center, Seoul, Hallym University Hospital, Anyang, Korea
ASCO 2008 Abs 4531: Adjuvant MMC + FU + / - IV Cisplatin after D2 resection (AMC 0201)
MMC x 1, Doxifluridine orally x 3 mos
– vs
MD + IV Cisplatin x 6, Doxifluridine x 12 mos MD: 67% 3 yr relapse free survival
MDP: 65% 3 yr relapse free survival
No improvement with addition of IV cisplatin or extended therapy
Current Trial (AMC 0101) MMC + FU + IV cisplatin + extended doxifluridine
– + IP cisplatin x 1 intra op
– Mitomycin administered earlier on
– Serosa positive gastric cancer
Grossly Serosa(+), Non-Metastatic Gastric Cancer
RANDOMIZATION
Intraperitoneal CDDP
MMC
CDDP DFUR
MMC
CDDPCDDP
CDDPCDDP
CDDP
Stage I, IV(M1)
Protocol off
DFURDFUR
DFURDFUR
DFURDFUR
DFURDFUR
DFURDFUR
DFURDFUR
DFURDFUR
DFUR
Mf armMf armiceMFP armiceMFP arm
Stratified by center, stage
Treatment SchemaTreatment Schema
At surgery
DFUR 460 – 600 mg/m2 po daily Cisplatin 60 mg/m2 iv D1 every 4 weeks
100 mg for 2h before closure
15 mg/m2 iv D1
4 weeks later
3 - 6 weeks after surgery
20 mg/m2 iv
Recurrence Free SurvivalRecurrence Free Survival
0 12 24 36 48 60 720
0.25
0.50
0.75
1.00
months after randomization
Rec
urr
ence
fre
e p
rop
orti
on
N Event 3yRFSR 5yRFSR
iceMFPiceMFP 263263 103103 60.2%60.2% 50.5%50.5%
MfMf 258258 126126 50.0%50.0% 43.8%43.8%
HR 0.695 [ 95% C.I.: 0.536 - 0.902 ]P = 0.006 by log-rank test
Overall SurvivalOverall Survival
0 12 24 36 48 60 720
0.25
0.50
0.75
1.00
months after randomization
Su
rviv
ing
pro
por
tion
N Event 3yOSR 5yOSR
iceMFPiceMFP 263263 8282 71.2%71.2% 56.2%56.2%
MfMf 258258 103103 59.6%59.6% 47.0%47.0%
HR 0.710 [ 95% C.I.: 0.531-0.950 ]P = 0.02 by log-rank test
Intraperitoneal Cisplatin, Gastric Cancer
Well designed and conducted phase III trial
Adequately powered
Ineligible patients common
– Randomization was intraoperative prior to final pathology reading
– Appropriate exclusion of metastatic disease, positive margins
Arms balanced, therapy tolerable, no increased operative complications
Intraperitoneal Cisplatin, Gastric Cancer
Achieved primary endpoint of improved relapse free survival:
– 3 yr RFS 50% 60%
Reduced peritoneal and distant recurrence
Suggests a potential benefit for IP cisplatin, early start of mitomycin
Intraperitoneal Cisplatin, Gastric Cancer
Four variables confound conclusion that IP chemo is superior in serosa + gastric cancer
– Trial also included early MMC, extending doxifluridine, adding IV cisplatin
Companion AMC 0201 trial
– No benefit for extended chemo or addition of cisplatin
Confirmatory trial in which only variable is IP chemotherapy
Esophago-Gastric Cancer: Metastatic Disease
• CIV 5-FU + cisplatin
• 4-5 day infusion
• RR 20-30%
• Med S 8-9 months• Adding a third drug:
• Epirubicin (ECF), protracted 5-FU CIV: RR 40-45%, Med S 9 mos
• 25-40% have locally advanced, non metastatic disease
• Docetaxel (DCF): RR 36%, Med S 9 mos
• 10% increment in response rate
• 1-2 month increment in survival• Capecitabine = 5-FU, Oxaliplatin = Cisplatin
DCF vs CF: Toxicity
Grade 3/4 Toxicity DCF CF
Stomatitis 21% 27%
Diarrhea 19% 8%
Nausea/vomiting 14% 17%
Neutropenia 82% 57%
Neutropenic fever 29% 12%
Taken off toxicity of AE
49% 37%
Toxic deaths 3.6% 5.4%
Van Cutsem J Clin Oncol 2006
Docetaxel–cisplatin (DC) versus 5-fluorouracil–leucovorin–cisplatin (FLC) as
first-line treatment for locally advanced or metastatic gastric cancer: Preliminary
results of a Phase III study
4512
K Ridwelski, J Fahlke, C Schmidt, E Kettner, U Keilholz, D Quietzsch, M Assmann, M Stauch, K Zierau, H Lippert
Objectives
Primary objectiveTime to tumor progression (TTP) increase from 40% to 60% in patients without progression at 6 months
Secondary objectivesToxicityOverall response rate (ORR)Overall survival (OS)
DCDocetaxel 75 mg/m2 iv over 1 h, day 1Cisplatin 75 mg/m2 iv over 1 h, day 1 Repeated q3w for up to 6 cycles
FLC5-FU 2000 mg/m2 iv over 24 hLeucovorin 500 mg/m2 iv over 2 h Both on days 1, 8, 15, 22, 29, 36
+Cisplatin 50 mg/m2 iv over 1 h, days 1, 15, 29 Repeated q7w for up to 4 cycles
(cisplatin omitted in Cycle 4)
Chemotherapy-naïve patients with metastatic or locally advanced (stage III-IV) gastric cancer
RANDOMIZATION
Study design
273 patients randomized between October 2001 and September 2006 from 21 centers in Germany Data available for 270 patients
Results
DC
n=133
FLC
n=137Median TTP, months 5.8 6.6
Median OS, months 8.2 9.6
1-year survival data 28 % 34 %
TTP
OS
P=0.468
P=0.616
DC, docetaxel–cisplatin; FLC, 5-FU–leucovorin–cisplatin; OS, overall survival; TTP, time to progression
Median follow up: 8.2 months 9.5 months
Response to treatment
Response, nDC
n=133
FLC
n=137Complete response (CR) 0 4
Partial response (PR) 32 29
Stable disease 59 59
Progressive disease 26 25
Not evaluable 16 20
ORR (CR + PR), % (95% CI)p-value
24.1 (0.17-0.32) 24.1 (0.17-0.32)
DC, docetaxel–cisplatin; FLC, 5-FU–leucovorin–cisplatin; ORR, overall response rate
p = 0.244
Confirmed response per RECIST
Safety
Grade 3/4 adverse event (NCI-CTC)patients
DC n=127
FLC n=134
Hematologic ( % )LeukopeniaNeutropenia
Febrile NeutropeniaAnemia
45.2
46.2 5.5
15.1
8.2
12.20.0
10.4Non-hematologic ( % )
Gastrointestinal Nausea VomitingPain
Infection
18.517.3 8.713.4 5.6
29.222.215.512.6 5.2
DC, docetaxel–cisplatin; FLC, 5-FU–leucovorin–cisplatin
DC vs CF
DC is not superior to CF, DC = CF
– Contrasts the V325 study: D + CF superior to CF
CF well tolerated on this dose and schedule
Use colorectal cancer like schedule for cisplatin or oxaliplatin + FU
– Weekly or two weekly infusional FU
– Single digit toxicities
Colorectal Scheduling: Gastric Cancer, Weekly infusional 5-FU + every 2 week Oxaliplatin or Cisplatin
Grade 3/4 Toxicity
FLO FLP
Stomatitis 3% 3%
Diarrhea 3% 6%
Nausea/vomiting 5% 9%
Neutropenia 5% 9%
Neuropathy 14% 2%
Off therapy due to toxicity or AE
17% 23%
Al Batran J Clin Oncol 26: 1435; 2008
DC vs CF
DC = CF, failed to achieve primary endpoint of superiority
Contrast to V325 study, three drug DCF superior to CF
– Toxicity of DCF limits its general use
If DCF is used:
– Lower starting doses
– Consider colorectal like scheduling of drugs
Marginal differences in outcome for three drugs: Doublets better platform for future study
– Adding targeted agents
– Perioperative therapy or added to radiotherapy