Elshami Elamin, MD Medical Oncologist

Central Care Cancer Centerwww.cccancer.comNewton, KS - USA

ESOPHAGEAL CANCER

Risk factors Alcohol / Tobacco Head / neck cancer High fat, low protein & calories Barrett’s Tylosis Plummer Vinson syndrome

(Paterson-Brown-kelly Synd) Achalasia

Symptoms & Signs Dysphagia Wt. Loss Cough Pain Hoarseness Malig pleural effusion, Ascites Hypercalcemia

Work-UpWork-Up

H&PH&PEGDEGDCBC, CMPCBC, CMPCT chest/abdCT chest/abd

No Mets:No Mets: BronchoscopyBronchoscopy *Tumor at or above Carina*Tumor at or above Carina

EUSEUS Laparoscopy Laparoscopy (GEJ)(GEJ)

PET/CTPET/CT

Locoregional I-III/IVA

IVB

INTRODUCTION

Surgery has been the raditional management of patients with localised esophageal cancer

Survival is poor, and many pts develop mets or locoregional recurrence soon after surgery

Treatment modalities

Esophagectomy: Resectable esophageal cancer:

>5 cm from cricopharyngeus Cervical and cervicothoracic cancer i.e

<5 cm from cricopharyngeus should be treated with definitive chemoradiation.

R.T. Chemotherapy BSC

Locoregional I-III/IVA

IVB

SalvageTherapy

•Medically Fit•Resectable(>5cm from cricopharyngeus)

•Inresectable: T4•Medically unfit

•Multidisiplinary Multidisiplinary EvalEval

•NutritionalNutritionalAssessmentAssessment

(NGT, J-Tube, PEG (NGT, J-Tube, PEG not recommended)not recommended)

GEJ: Celiac nodal involvement may not exclude combined modality therapy

Resectable stage IVA: Distal esophageal cancer with resectable

celiac node No involvement of aorta or other organ No involvement of celiac artery

ReseInvctable T4: Involvement of

Pericardium Pleura Diaphragm

•Medically Fit•Resectable disease

•Esophagectomy (preferred for noncervical)

•Tis, T

1a

Tis, T

1a

•Medically Fit•Resectable

•T1b,N0-1T1b,N0-1

•T1b, N1•T2-4, N0-1,Nx•M1a (IVA)

•Endoscopic mucosal resection OR•Esophagectomy

•T1b, N1•T2-4, N0-1,Nx•M1a (IVA)

Preop Chemo for adeno Preop Chemo for adeno

of distal Esoph or GEJof distal Esoph or GEJ

(ECF)(ECF)

PreopPreop ChemoRTChemoRT

RT 50-50.4 GyRT 50-50.4 Gy

Definitive Definitive ChemoRTChemoRT

Preop Chemo for Preop Chemo for adeno adeno

of distal Esoph or of distal Esoph or GEJGEJ

PreopPreop ChemoRTChemoRT

RT 50-50.4 GyRT 50-50.4 Gy

Definitive Definitive ChemoRTChemoRT

PET-CT/CTPET-CT/CT

*EGD*EGD

Salvage Salvage esophagectomesophagectom

y for local y for local residual residual diseasedisease

EsophagectomyEsophagectomy

PET-CT/CTPET-CT/CT

*EGD*EGD

See See SurgicSurgic

al al outcooutco

meme

•*EGD *EGD >> 5 wks with biopsy or brushings 5 wks with biopsy or brushings

PreopPreop ChemoRTChemoRT

RT 50-50.4 GyRT 50-50.4 GyPersistent Persistent

local dislocal dis

NEDNED

unresectableunresectable

MetsMets

See See SurgicSurgic

al al outcooutco

meme

•PET-CT/CTPET-CT/CT•*EGD*EGD

•Esophagectomy (preferred)Esophagectomy (preferred)•ObserveObserve

•Esophagectomy Esophagectomy

(preferred)(preferred)•paliative/ (chemo)paliative/ (chemo)

•*EGD *EGD >> 5 wks with biopsy or brushings 5 wks with biopsy or brushings

RR00

Surgical outcomesSurgical outcomes

RR11RR22

•N -N -

•N+N+

•adenoadeno

•Tis, T1, N0: observeTis, T1, N0: observe

•T2,N0: observe or chemoRT T2,N0: observe or chemoRT *ECF if given *ECF if given preop (categ 1)preop (categ 1)

•T3,N0: chemoRT *T3,N0: chemoRT *ECF if given ECF if given preop (categ 1)preop (categ 1)

•Observe or Observe or chemoRTchemoRT

•SquamousSquamous •ObserveObserve

•Adeno prox or midAdeno prox or mid

•Adeno distal or GEJAdeno distal or GEJ •chemoRT *chemoRT *ECF if given preop ECF if given preop (categ 1)(categ 1)

•chemoRT chemoRT

•chemoRT or palliativechemoRT or palliative

•Medically Unfit•Unresectable dis.

•ChemoRT•Chemo•RT•BSC

•Tis, T

1a

Tis, T

1a

•Medically unfit•unresectable

•Medically unfit•Chemo is tolerable•Unresectable: T4/IVA

•Endoscopic mucosal resection OR•ChemoRT

•Medically unfit•Chemo is not tolerable •Palliative Palliative RTRT•BSCBSC

ANY SCEINTIFIC EVIDENCE TO ANY SCEINTIFIC EVIDENCE TO SUPPORT THE USE OF SUPPORT THE USE OF CHEMOTHERAPY/R.T. IN CHEMOTHERAPY/R.T. IN

LOCALLY ADVANCED OPERABLE LOCALLY ADVANCED OPERABLE ESOPHAGEAL/GASTRIC CANCERESOPHAGEAL/GASTRIC CANCER

??

LITRETULITRETURE RE

REVIEWREVIEW

ADJUVANT THERAPY

Adj RT, chemo, or chemoRT Mixed results and disappointing

Because trials were small and lacked statistical power

Adj treatment based on 2 or 3-year survival rates

chemoRT and chemo have similar benefits

NEOADJUVANT THERAPY

Due to sig postop complication rate, focus has turned to neoadj treatment.

Currently, there is no evidence to support the use of neoadj RT alone

Any role for Chemo/RT

<30% of locally advanced Gastric/GEJ adeno could be cure with surgery alone

Previous adj chemo failed to show clinical benefit

INT-0116 (SWOG 9008)

Randomized lll Trial: Resectable adeno of stomach GEJ (lB-IVA)

5-FU/LVx5d--> RT+5-FU/LV during first 4d and last 3d of RT --> 2cycles of 5-FU/LVx5d

postop CT/RT improve DFS&OS in R0 (resected locally advanced) [standard of care]

•Adj Option

•Macdonald et al; N Engl J Med. 2001 Sep 6;345(10):725-30.

The MAGIC TrialThe MAGIC TrialThe Medical Research Council The Medical Research Council Adjuvant Gastric Infusional Adjuvant Gastric Infusional

Chemotherapy Chemotherapy Operable adeno of the stomach, the lower third of the esophagus, and the GEJ ( 74% of pts had tumors in the stomach)

ECFx3->surg->ECFx3 (250 pts) vs Surgery alone (253 pts): 5Y survival: 36% vs 23% Chemo sig. improves resectability,PFS and OS

•Periop. option•D. Cunningham, et al ; N Engl J Med. 2006 Jul 6;355(1):11-20.

Preoperative Chemotherapy vs Surgery

Alone FNLCC ACCORD 07-FFCD 9703,

multicenter, randomized trial indicated benefit of preoperative chemotherapy vs surgery alone for resectable adenocarcinoma of stomach and lower esophagus[1]

Higher rate of R0 resection (87% vs 74%; P = .04)

Higher 5-yr OS (38% vs 24%; P = .021) No increase in postoperative morbidity or

mortalityBoige V, et al. ASCO 2007; Abstract 4510.

Preoperative Chemotherapy vs Surgery

Alone

Meta-analysis also demonstrated benefit for preoperative chemotherapy in resectable esophageal cancer[2]

5-yr OS benefit of 4.3% (P = .003) 5-yr DFS benefit of 4.4% (P = .0001)

Thirion P, et al. ASCO 2007. Abstract 4512.

CALGB 9781

Only 56 pt with stage I-III Preop-chemo/RT vs

surgery alone MS 4.5y vs 1.8y

Trimodality imroves survival

Lancet Oncol 2007; 8: 226–34

Survival benefits from neoadjuvant chemoradiotherapy or

chemotherapy in oesophageal carcinoma

(meta-analysis)

Val Gebski, Bryan Burmeister, B Mark Smithers, Kerwyn Foo, John Zalcberg, John Simes, for the Australasian Gastro-

Intestinal Trials Group

Meta-analysis

MEDLINE, Cancerlit, and EMBASE databases from major scientific meetings (1980-2006)

Pts with local operable esophageal ca

10 randomised trials of neoadjuvant chemoRT vs surgery (n=1209)

SCC = 6, adeno =1, both = 3

8 of neoradjuvant chemo vs surgery (n=1724) with comparisons

SCC = 7, both = 2

Meta-analysisFindings

The hazard ratio for all-cause mortality with neoadj chemoRT vr surgery

0·81 (95% CI 0·70–0·93; p=0·002) corresponding to a 13% absolute difference in

survival at 2 years 0·84 (0·71–0·99; p=0·04) for SCC 0·75 (0·59–0·95; p=0·02) for adeno

The hazard ratio for neoadj chemo was 0·90 (0·81–1·00;p=0·05)

2-year absolute survival benefit of 7% No sig effect on all-cause mortality of chemo for

SCC (hazard ratio 0·88 [0·75–1·03]; p=0·12) Sig benefit for adeno (0·78 [0·64–0·95]; p=0·014)

NEOADJ CHEMO

For SCC, neoadj chemo did not have a survival benefit

hazard ratio for mortality 0・ 88 [0・ 75–1・ 03]

p = 0・ 12

For adeno, neoadj chemo showed sig survival benefit (UK Medical Research Council MRC trial)

hazard ratio for mortality 0・ 78 [0・ 64–0・ 95] P = 0・ 014

Long term results of the MRC OEO2 randomized trial of surgery with or without preoperative chemotherapy in

resectable esophageal cancer

Conclusions: Long term follow-up confirms that preoperative chemotherapy improves survival in operable esophageal cancer and should be considered as a standard of care.

2002 (Lancet 2002; 359: 1727-33)

NEOADJUVANT CHEMO/RT

Neoadj chemoRT vs surgery sign benefit over surgery for both

histological types 0・ 84 (0・ 71–0・ 99); p = 0・ 04 for SCC

0・ 75 (0・ 59–0・ 95); p = 0・ 02 for adeno

Sequential vs Concurrent chemoRT

No survival benefit of sequential chemoRT in SCC

hazard ratio for mortality 0・ 90 [0・ 72–1・ 03]; p=0・ 18) similar to SCC treated with neoadj chemo

Concurrent chemoRT had sig benefit for both histological types

hazard ratios 0・ 76 and 0・ 75 for SCC and adeno, respectively

Meta-analysisInterpretation

A signifi cant survival benefi t was evident for preoperative chemoradiotherapy and, to a lesser extent, for chemotherapy in patients with adenocarcinoma of the oesophagus.

MDACC study: Salvage Resection for Esophageal

Carcinoma: OS No difference in OS between salvage and planned resection

5-year survival 46% for salvage vs 42% for planned resection

Hofstetter WL, et al. GI Cancers Symposium 2009. Abstract 7.

OS

Cu

mu

lati

ve S

urv

ival

Pro

bab

ilit

y

Months

P = .125

Median follow-up: 24 months

Salvage

Planned surgery

0.0

0.2

0.4

0.6

0.8

1.0

0 10 20 30 40 50 60

THANKS