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May 28, 2009
Yong Hee Kim, MD, PhD
Dept. of Thoracic & Cardiovascular Surgery
ASAN Medical Center, University of Ulsan College of Medicine
2009 년 제 25 차 대한흉부외과학회 춘계학술대회
Induction Therapy for Locally Advanced Esophageal Cancer
Asan Medical CenterUniversity of Ulsan College of Medicine
Overall Survival after Esophagectomy
Rice, Dis Eso 2009;22
Years
Su
rviv
al (
%)
Locally advanced esophageal cancer by surgery alone : 5-YSR : < 20 ~ 30%
Asan Medical CenterUniversity of Ulsan College of Medicine
Treatment of Esophageal Cancer
• Surgery Alone• Radiation Alone• Chemotherapy Alone• Nonsurgical: Definitive Chemoradiation • Preoperative Radiation • Postoperative Radiation• Preoperative Chemotherapy• Preoperative Cheomoradiotherapy • Postoperative Chemotherapy• Palliation
Asan Medical CenterUniversity of Ulsan College of Medicine
Rationale of Multimodality Therapy
• Poor survival with surgery alone
• Distant dissemination of disease occurs early
• Downsize tumors
- improve resection rate, and local control
- improve control of micrometastatic disease
Asan Medical CenterUniversity of Ulsan College of Medicine
Preoperative ChemoRadiation Therapy (CRT) in Locally Advanced Esophageal Cancer
• RTOG* trial 8501 (1992) - RT 6,400 cGy vs 5,000 cGy + FU / Cisplatin
- 5-YSR : 32% vs 12%
• GI Intergroup 0113 (1997) - Preop / postop CTx with FU / Cisplatin vs Surgery
- no survival benefit
• Medical Research Council Study (2002) - induction CTx
- median survival benefit : 3.5 months*, Radiation Therapy Oncology Group
Asan Medical CenterUniversity of Ulsan College of Medicine
Survival Benefit, Yes ? : CALBG 9781
Tepper, J Clin Oncol 2008;26
p = 0.002
Asan Medical CenterUniversity of Ulsan College of Medicine
Survival Benefit, No ? : USA Intergroup 113
Kelsen, J Clin Oncol 2007;25 (Update RTOG trial 8911)
p = NS
Asan Medical CenterUniversity of Ulsan College of Medicine
Methodological Concerns in CRT
• Optimal radiation dose
• Adequate radiation field
• Chemotherapeutic agents
• Administration schedule
• Control side effect
Asan Medical CenterUniversity of Ulsan College of Medicine
Patients Selection for CRT ASAN Medical Center
• Indications for CRT - pathologically confirmed esophageal cancer
- surgically resectable clinical stage of II/III by CT
- age : 18 ~ 75, ECOG performance 0 ~ 2
- adequate bone marrow function, LFT, renal function
• Exclusion Criteria for CRT - stage I by EUS
- invasion to recurrent laryngeal n., trachea, aorta
- evidence of esophageal fistula, malignant pleural effusion
- metastatic LN at celiac or paraaortic LN
- inadequate cardiac/pulmonary function
Asan Medical CenterUniversity of Ulsan College of Medicine
Protocol of CRT in Esophageal Ca.
Author Year Regimen Radiation
RTOG85-01 1999 Cisplatin / 5-FU 5,000 cGy
RTOG94-05 2002 Cisplatin / 5-FU 6,400 cGy
Nabeya 2005 Cisplatin / 5-FU 4,600 cGy
Kesler 2005 Cisplain / 5-FU 4,907 cGy
AMC 2008 Cisplatin / Capecitabine 4,600 cGy
Rizk 2007 Cisplatin / Paclitaxel or 5-FU 5,040 cGy
Asan Medical CenterUniversity of Ulsan College of Medicine
Prospective Clinical Trials in Asan Medical Center
1993 - 1997 1999 - 2002 2003 - 2005
Asan Medical CenterUniversity of Ulsan College of Medicine
Diagnostic work up (GFS,CT, EUS, PET)
Stage II,III resectable esophageal SCC
CAP 1000mg/m2 bid (D1-14)CDDP 60mg/m2 (D1)
CAP 800mg/m2 bid 5 days/wk)CDDP 30mg/m2 (D1, 8,15, 22)RT 46Gy, 2Gy/Fx, 23 Fx
Surgery
3 wks later
4-6 wks later
Treatment Scheme of Induction Chemotherapy (Capecitibine, CDDP) followed by Concurrent Chemoradiation
Phase II study in AMC
Asan Medical CenterUniversity of Ulsan College of Medicine
Randomized phase II study of preoperative concurrent chemoradiotherapy with or without induction chemotherapy with
S-1/oxaliplatin in patients with resectable esophageal cancer
Resectable advanced esophageal cancerStage II - IVa
No induction Group
Induction chemotherapy1) S-1 40 mg/m2 BID, D1-142) Oxaliplatin 130 mg/m2, IV, D1 Every 3 weeks, 2 cycles
Concurrent chemoradiotherapy• XRT 4600 cGy, 200cGY x 23 times (5 times/week)• S-1 30 mg/m2 bid, 5 days/week, during XRT• Oxaliplatin 130 mg/m2 IV D1, D22 of XRT
Operation
± Induction chemotherapy :every 3 weeks, 2 cycles
Concurrent chemoradiotherapy
Operation
evaluation 3- 4 weeks after chemoradiation
Patients selection
Randomization
evaluation after cycle 2 of induction chemotherapy in induction group
Study offSalvage treatment
Disease progression
< Schema >
Induction Group
2008 - 2010
Asan Medical CenterUniversity of Ulsan College of Medicine
Review of Phase II trials of CRT
Author Pt ChemoRT(Gy)
Resection Rate(%)
pCR(%)
Med S(Mo)
Franklin(1983)
305FUMMC
30 79 26 18
SWOG(1987)
113 FP 30 49 25 12
RTOG(1988)
41 FP 30 71 30 13
Carter(1989)
31 EP 44 53 42 13
Forastiere(1990)
43FPVelban
37.545
84 24 29
AMC*
(2003)52 FP 48 95 43 36
Kim et al(2005)
54 XP 46 97 49 NR
Asan Medical CenterUniversity of Ulsan College of Medicine
Review of Randomized Phase III studies
AuthorPt No
HistResect
RatepCR
Op
Mot(%)
3YS
(%)P
Le Prise
1994
CRTS 41 scc 85 10 8 190.6
S 45 scc 84 7 14
Apinop
1994
CRTS 35 scc 74 20 12 260.4
S 34 scc 100 15 20
Walsh
1996
CRTS 58 Ad 90 22 10 320.01
S 55 Ad 100 4 6
Walsh
1999
CRTS 46 scc 36(5ys)0.017
S 52 scc 11(5ys)
Urba
2001
CRTS 50 scc
/Ad
28 320.15
S 50 15
AMC
2003
CRTS 51 scc 100 43 3 28(MS)0.69
S 50 scc 88 2 27(MS)
Asan Medical CenterUniversity of Ulsan College of Medicine
Phase III trials of Impact of CRT
Author Protocol Histology No. of Pts R0 Mortality Med
Survival p
U.S. intergroup Surgery SCC/AC 227 59% 6% 16.1 m ns
1998CDDP/5-FU
213 62% 7% 14.9 m
MRCOCWP Surgery SCC/AC 400 54% 10% 13.3 m 0.004
2002CDDP/5-FU
402 60% 10% 16.8 m
MRCOCWP, Medical Research Council Oesophageal Cancer Working Party
Asan Medical CenterUniversity of Ulsan College of Medicine
Prognostic Factors for CRT + S
• Good performance status
• Major response to chemoradiation
• Presence of micrometastases
• Number of pathologic metastases
• Early metabolic response with FDG PET - Siewert, Ann Surg 2007;246
- Port, Ann Thorac Surg 2007;84
=> > 50% reduction in maxSUV
median survival 35.5 vs 17.9 mo
Asan Medical CenterUniversity of Ulsan College of Medicine
Predictor of Prognosis for CRT + S
• Favorable prognosis - female with clinical response to CRT
- esophagectomy
- good performance
- initial stage II
• Poor prognosis - poor performance status
- severe dysphagia
- poor clinical response to CRT
Asan Medical CenterUniversity of Ulsan College of Medicine
Effect of Esophagectomy on Survival
All patients (n=180, p < 0.001) cCR or PR (p = 0.001)
AMC, I J Radiat Oncol 2008;71
Asan Medical CenterUniversity of Ulsan College of Medicine
Overall Survival by Type of Resection
USA Intergroup 113 (Update RTOG trial 8911)Kelsen, J Clin Oncol 2007;25
Asan Medical CenterUniversity of Ulsan College of Medicine
Spread of Esophageal Cancer
• Intraesophageal spread
- "skip" or "satellite" lesion ; submucosal spread
• Direct extension to adjacent structure
• Lymphatic spread
- extensive submucosal longitudinal lymphatics
Asan Medical CenterUniversity of Ulsan College of Medicine
Lymphatics of Esophageal Wall
““skip or satellite nodule formation”skip or satellite nodule formation”
Asan Medical CenterUniversity of Ulsan College of Medicine
Extent of Esophageal Resection
• Microscopic spread by length of margin
- resection margin : 3 cm 64%
- resection margin : 6 cm 22%
- resection margin : 9 cm 11%
- resection margin : 10.5 cm 3%
• Miller Miller (Br J Surg 1962:49)(Br J Surg 1962:49) : > : > 10 cm
• DiMusto (Ann Thorac Surg 2007;83) : > 5 ~ 6 cm
Asan Medical CenterUniversity of Ulsan College of Medicine
Survival based on No. of Positive LNs
Kesler, Ann Thorac Surg 2005;79
Asan Medical CenterUniversity of Ulsan College of Medicine
Survival based on Response to CRT
Kesler, Ann Thorac Surg 2005;79
Asan Medical CenterUniversity of Ulsan College of Medicine
Response to CRT
Rizk, J Clin Oncol 2007;25
3-YSR 70.4%
3-YSR 41.8%
Asan Medical CenterUniversity of Ulsan College of Medicine
Months
0 10 20 30 40 50 60 70 80 90 100
Surv
ival
Pro
babi
lity
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Pathologic CR (n=17)
Pathologic non-CR (n=21)
P=0.006
Median FU = 77.4 mo
Survival by Response to CRT in AMC
pCR
Non-pCR
p = 0.006
Asan Medical CenterUniversity of Ulsan College of Medicine
Survival Curves by Response to CRT
USA Intergroup 113 (Update RTOG trial 8911)Kelsen, J Clin Oncol 2007;25
Asan Medical CenterUniversity of Ulsan College of Medicine
Definition of Response : CALBG 9781
• Complete response - no gross or microscopic tumor in surgical specimen
using light microscope
• Partial response - shrinkage in tumor size c/w the original GFS
- macroscopic or microscopic residual tumor
• Progession - increase in ≥ 25% of perpendicular diameters
• StableTepper, J Clin Oncol 2008;26
Asan Medical CenterUniversity of Ulsan College of Medicine
Tumor-Regression Grade to CRT
TRG 1
TRG 2
TRG 3
TRG 4
TRG 5
Fareed, Gut 2009;58
Asan Medical CenterUniversity of Ulsan College of Medicine
Response Evaluation after CRT
Methods Sensitivity SpecificityPositive predictive value
Negative predictive value
Accuracy
GFS 60% 34% 49% 44% 47%
Rebiopsy 36% 100% 100% 24% 47%
EUS 7% 79% 18% 57% 50%
Schneider, Ann Surg 2008;248
The diagnostic accuracy is inadequate for
objective response evaluation after induction CRT
Asan Medical CenterUniversity of Ulsan College of Medicine
MUNICON trial Metabolic response evalUation for Individualisation of neoadjuvant Chemotherapy in
oesOphageal and oesophagogastric adeNocarcinoma
• Metabolic response by FDG-PET :
- decrease of 35% or more in tumor SUV at induction
CRT 2weeks
- continue induction CRT followed by surgery
- longer survival in response group
• Predictive role of response
- major histological response : 58%
- metabolic response may correlate with tumor response
Lordick, Lancet Oncol 2007;87
Asan Medical CenterUniversity of Ulsan College of Medicine
Heterogenicity in Response to CRT
• Age, sex, ethnicity, drug-drug interaction,
genetic variation in pharmacokinetics,
pharmacodynamic, drug action pathways
• Genetic variation in AKT1, AKT2, FRAP1
- FRAP1SNPs; increase risk of death
- AKT2, FRAP1; poor response to treatment
- AKT1:rs3803304; better response to treatment
Asan Medical CenterUniversity of Ulsan College of Medicine
Pathways Involved in Repair of CRT Injury
Fareed, Gut 2009;58
AP, apurinic /
apyrimidinic;
ERCC, excision repair
cross-complementing
group;
FEN-1, flap structure
specific endonuclease 1;
PCNA, proliferating cell
nuclear antigen;
RPA, replication protein
A;
RFC, replication factor C;
XPA and XPC,
xeroderma pigmentosum
complementation groups
A and C;
XRCC1, x ray cross-
complementation group 1
Asan Medical CenterUniversity of Ulsan College of Medicine
OS according to Tx (CRT-S versus S) for patients with ERCC1-negative and ERCC1-positive tumors
AMC, Clin Cancer Research 2008;14
Median OS in ERCC1 ( - ) = 51.2 mo Median OS in ERCC1 ( + ) = 43.2 mop = ns
Asan Medical CenterUniversity of Ulsan College of Medicine
Surgical Considerations of CRT - I
• Poorer nutritional status
• Depressed respiratory activity
• Depressed mental condition
• Diminished immunologic reserves
• Lower WBC or Hb level
Asan Medical CenterUniversity of Ulsan College of Medicine
Surgical Considerations of CRT-II
• Increase postoperative morbidity
• Increase operative mortality - 2~5% vs > 10%
- Jones (1997), Hennequin (2001), Nakadi (2002)
• Fail to receive surgery d/t progression
• Late complication - Murthy (J Clin Oncol 2009;4)
- pleural effusion : 2 times
- pericardial effusion : 5 times
Asan Medical CenterUniversity of Ulsan College of Medicine
Comparison of Postoperative Result
CRT group Control P-value
Pulmonary complication 7 (36.8%) 6 (9.4%) 0.008
Anastomotic leakage 4 (21.1%) 5 (7.8%) 0.199
Palsy of recurrent nerve 4 (21.1%) 3 (4.7%) 0.045
Liver dysfunction 3 (15.8%) 7 (10.9%) 0.411
Chylothorax 2 (10.5%) 1 (1.6%) 0.130
Morbidity 14 (73.7%) 25 (39.1%) 0.010
Mortality 0 0
Hospital stay Longer Shorter
Nabeya, Dis Eso 2005;18
Asan Medical CenterUniversity of Ulsan College of Medicine
Review of Recent Meta-analysis
Author YearNo. of
SutdiesNo. of
Pts Conclusions
Urschel 2003 9 1,116Improved 3-year survival
Reduce loco-regional recurrence
Increase operative mortality (ns*)
Fiorica 2004 6 764Improve 3-year survival & downstaging
Increase operative mortality
Graham 2007 14 2,751Increase quality-adjusted life expectancyIncrease toxicityReduce quality of life
Gebski 2007 10 1,209Small significant survival benefit
Increase operative mortality
*ns, not significant
Asan Medical CenterUniversity of Ulsan College of Medicine
Summaries
• If surgery is performed in patients with locally advanced esophageal cancer, there may be small survival advantage if combined with induction chemoradiation therapy.
• Preoperative chemo/chemoradiotherapy is probably useful for subgroup of patients, but not clear for whom.
• Further efforts should be made in optimization of multimodality therapy in locally advanced esophageal cancer.
Asan Medical CenterUniversity of Ulsan College of Medicine
Future Improvements
• Incorporation of targeted agents that add minimally to
existing toxicity
• Use of molecular predictors of response to individualize
selection of the chemotherapeutic regimen
• Early identification of responders such that therapy might
be altered dynamically
• How to restage patients after completion of their treatment
- accurate restaging provides prognostic information
- accurate restaging can help direct subsequent treatment decisions
Asan Medical CenterUniversity of Ulsan College of Medicine
Thanks for Your Attention !