may 28, 2009 yong hee kim, md, phd dept. of thoracic & cardiovascular surgery asan medical...

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%


Treatment of Esophageal Cancer

• Surgery Alone• Radiation Alone• Chemotherapy Alone• Nonsurgical: Definitive Chemoradiation • Preoperative Radiation • Postoperative Radiation• Preoperative Chemotherapy• Preoperative Cheomoradiotherapy • Postoperative Chemotherapy• Palliation


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


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


Survival Benefit, Yes ? : CALBG 9781

Tepper, J Clin Oncol 2008;26

p = 0.002


Survival Benefit, No ? : USA Intergroup 113

Kelsen, J Clin Oncol 2007;25 (Update RTOG trial 8911)

p = NS


Methodological Concerns in CRT

• Optimal radiation dose

• Adequate radiation field

• Chemotherapeutic agents

• Administration schedule

• Control side effect


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


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


Prospective Clinical Trials in Asan Medical Center

1993 - 1997 1999 - 2002 2003 - 2005


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


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


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


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)


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


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


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


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


Overall Survival by Type of Resection

USA Intergroup 113 (Update RTOG trial 8911)Kelsen, J Clin Oncol 2007;25


Spread of Esophageal Cancer

• Intraesophageal spread

- "skip" or "satellite" lesion ; submucosal spread

• Direct extension to adjacent structure

• Lymphatic spread

- extensive submucosal longitudinal lymphatics


Lymphatics of Esophageal Wall

““skip or satellite nodule formation”skip or satellite nodule formation”


Extent of Esophageal Resection

• Microscopic spread by length of margin

- resection margin : 3 cm 64%



- 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


Survival based on No. of Positive LNs

Kesler, Ann Thorac Surg 2005;79


Survival based on Response to CRT

Kesler, Ann Thorac Surg 2005;79


Response to CRT

Rizk, J Clin Oncol 2007;25

3-YSR 70.4%

3-YSR 41.8%


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


Survival Curves by Response to CRT

USA Intergroup 113 (Update RTOG trial 8911)Kelsen, J Clin Oncol 2007;25


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


Tumor-Regression Grade to CRT

TRG 1

TRG 2

TRG 3

TRG 4

TRG 5

Fareed, Gut 2009;58


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


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


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


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


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


Surgical Considerations of CRT - I

• Poorer nutritional status

• Depressed respiratory activity

• Depressed mental condition

• Diminished immunologic reserves

• Lower WBC or Hb level


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


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


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


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.


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


Thanks for Your Attention !

may 28, 2009 yong hee kim, md, phd dept. of thoracic & cardiovascular surgery asan medical...

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