Carcinoma of esophagus

Shankar Zanwar

Epidemiology World

Ca esophagus is 6th most common cause of cancer death in males

Highest prevalence in Asia and S-E Africa

Of the common varieties SqCC and EAC – SqCC is commoner more prevalent in developing countries

Jemal CA cancer J clin 2011

India Sq. CC 3rd leading cancer in males and 4th in females

Highest incidence in J & K and north-east

Majority present in 5-6th decade, bidi, paan & alcohol MC risk factorsChitra A, Jayanti V, I J Gastro 2004

Risk factors – Squamous cell Ca.

Developed countries Tobacco - ↑ risk – 3-7X Alcohol - ↑ risk – 3-5X Highest with smoked

tobacco, alcohol >140g/wk.

Developing countries Low socioeconomic strata Nutritional deficiencies Diet low in vit A, C, E,

selenium, folate and zinc Achalasia – 5%

Lye stricture Plumer- vinson

syndrome Tylosis – TOC gene, chr –

17 – life time risk 40-90% - Howel Evan syndr.

Pickels ?Oral bisphosphonates -

alendronate ?HPV 16/18 Hot tea/other beverages Protective role of aspirinFanconi’s - chr 15 mutn

Blooms synd – chr 16 mutn a/w AML/ALL/wilms tumour

Risk factors – adenocarcinoma Male : Female – 8:1

Obesity – ↑ risk by 2-3X

Tobacco - ↑ risk by 2X

GERD - ↑ risk by 4-8X,

Barrett’s esophagus - No dysplasia – 0.1-0.3% per year Low grade dysplasia – 0.45% pa High grade – 6% pcpa

High calorie diet NSAID H pylori infection risk reduction at 50% Fruits and vegetables

Genetic factors Self sufficiency of growth factors

HER2/neu – growth factor receptor - ↑ expression - ↓ survival Cyclin D – expression – cell cycle regulator – a/w ↓survival

Insensitivity to antigrowth signals p53 – tumor suppressor – low p53 a/w - ↑ mortality Similarly with p21 and p16 expression

Antiapoptosis avoidance – ↓ expression of Bax, Bcl-2 and Bcl-X gene – poor prognosis Survivin – Antiapototic factor –↓ response neo adj chemo

…Genetic factors

Uncontrolled replicative potential - ↑ telomerase expresn

Sustained angiogenesis - ↑ expression of VEGF, b-FGF, COX-2

Invasion and mets – cadherins, glycoprt., cadherins, MMPs

Clinical features C/f same for ESCC and adenocarcinoma

Early stages – asymptomatic Dysphagia – solids liquids, for solids diam. <13mm Weight loss Odynophagia – if growth is ulcerated Chest pain – radiating to back – paraesophageal

invasion Anemia, cervical lymphadenopathy TOF – recurrent pneumonia and pleural effusion GI bleed – exsanguinating – esophago-aortic fistula Hoarseness – recurrent laryngeal nv. Involvement.

Location of the disease

Diagnosis Labs – anemia – IDA/anemia of chr. disease

Hypoalbu., hypercalcemia – mets/paraneoplastic

X ray chest Aspiration pneumonia Pseudoachalasia – air fluid levels Mets, pleural effusion

Barium study Abnormal mucosal lining Plaque Polypoid lesion/ ulceration Masses/ stricture/ shouldering Particularly useful in TOF

▪ roadmap for stenting, ▪ specific care – avoid gastrograffin in this situation – ditrizoate – risk of severe

pulmonary edema and pneumonitis

Endoscopy Findings

Relatively normal appearing mucosa(s/mucosal infiltrative patterns)

Ulcer/nodules/overt masses

Techniques to ↑ diagnostic yield for targeted Bx Conventional chromoendoscopy Electronic chromoendoscopy Auto fluorescence Confocal laser endomicorscopy Optical coherence tomography Endocytoscopy High resolution microendoscopy

Further work up

CT chest and upper abdomen To find location of tumor and mets CT value in local regional spread limited Local tumour staging accuracy – 42%

Lowe V J Mol Imaging Biol 2005 EUS

Sensitivity T staging - 85-90%, N – 70-90% For stenotic lesions – miniprobes but

compromised depth of evaluation ~3cm Malignant LN on EUS – hpoechoechoic,

rounded, smooth, >1cm and near the tumor

Evaluation for distant mets

PET correctly upstaged 15- 20% of pt. from M0 to M1 in studies detecting distant mets by Flamen et al and Lowe et al

Staging – AJCC 2010

T4 T4a – Resectable tumour invading pleura/pericardium/diaphragm T4b – Unresectable tumour invading adjacent structures

Nodal N1 1-2 nodes N2 3-6 nodes N3 >7 nodes

Earlier unresectibility criteria(M1a) for involved celiac LN now reclassified as N1 for upper and mid ESCCS

HER2/neu - testing Human epidermal growth factor receptor(HER)2, is

implicated in development of adenocarcinoma

HER seen in SqCC-5-13%, EAC – 15-30%.

For patients with inoperable locally advanced/recurrent/mets adenoca – tarstuzumab - IHC/FISH for HER2 recommended

IHC criteria for scoring – 0 - < 10 % staining cells – negative 1+ - barely perceptible reactivity – negative 2+ - weak to moderate reactivity – equivocal – needs FISH 3+ - strong reactivity – positive

Bang Y-J Lancet ToGA trial 2010

Treatment Multidisciplinary approach

Evaluation for medical co-morbidities, current performance status, nutrition status and cardio-pulmonary status

Staging using EUS, CT chest and abdomen and PET/CT(if presumed resectable)

Nutritional assessment, if under nourished enteral nutrition best option, FJ preferred over PEG

General principle of treatment Surgery standard treatment for medically optimized pt. with

localized non superficial tumour

T1 and T2 lesions with no LN, surgery alone is sufficient

T1 to T4 resectable with LN – surgery with multimodal approach

Localized tumor non surgical candidate – chemoradiation with curative intent

Metastatic disease – palliationStahl, Annal of oncology 2010

Surgery Usually performed with curative intent

But may be done with palliative intent for fistula or dysphagia,

Palliative surgery avoided in clearly unresectable disease or those with severe cardio-pulmonary disease

For cervical esoph. lesions – definitive chemoradiation, esophagectomy reserved for resectable recurrence without mets.

Swisher, J th card vas sur, 2002

Surgical approach for Seiwert I and II is similar to ca esophagus, type III management is as ca stomach

Criteria for resectibility T1-T3 with regional lymphnodes, bulky multistation LN

involvement is relative C/I, pt to pt consideration T4a with pericardial/pleural/ diaphragmatic involvement

Unresectable EJG with supraclavicular LN Involvement of Distant mets, heart, Ao/PA, trachea, pancreas, lung, spleen

Surgical approaches Acceptable approaches

Transthoracic▪ Ivor Lewis – laparotomy + rt. Thoracotomy

▪ McKeown – Laparaotmy + rt. Thoracotomy + cervival anastomosis

▪ Minimally invasive Ivor-Lewis/McKeown – laparoscopy + thoracoscopy

▪ Transhiatal esophagogastrectomy (Laparotomy + cervical anastomosis)

▪ Robotic minimally invasive esophagogastrectomy

Transthoracic approach Better mediastinal view ↓adjacent organ injury Complete resection ↑ chances of post operative morbidity

Transhiatal approach Shorter post-op recovery Less morbidity Long term survival is not different in two approaches

Hulscher, NEJM, 2002

Overall post-op morbidity for both approaches – Morbidity – 40-50% Mortality - 3-13%

Chang AC, Ann Thora Surg 2003

Minimally invasive surgery A study with 222 patients, ▪ mortality – 1.4%, ▪ Hospital stay – 7 days▪ 7.2%(n=16) required conversion to open

But 62% patients here early stageLuketich, Ann Surg 2003

Another study - Neo adjuvant chemo increases mortality from 1.4-1.8%

Zingg, Ann Tho Surg 2009

Surgery Site of anastomosis choice

Cervical – more extensive resection – less reflux sympt., avoids thoracotomy

Thoracic – lower anastomotic leak, ↓ stricture and RLN injury

Conduits Gastric – majority prefer this – thus PEG avoided Colonic – those who have undergone gastric

surgeries earlier/ devascularised stomach Jejunum can also be used

Klink, Surgery, 2010

Lymphnode dissection The number of LN removed has direct correlation

with survival

In patients under going esophagectomy without preop chemo – at least 15 LN should be removed for adequate staging – NCCN 2015 (Sleisenger 6 LN)

Newer 3 field dissection abdomen, mediastinum and B/l neck is under evaluation.

Endoscopic therapy Basically can be divided as

Curative Palliative

Curative is reserved for T1a tumours where chances of lymphnodal spread are less than 10% Types – resection/ablation▪ Resection – EMR/ESD▪ Ablation – cryoablation/RFA/PDT

Palliative therapy is for inoperable pts. for maintaining patency and reliving dysphagia. Dilatation and stenting Laser, alcohol injection, intratumoral injection

Minimally invasive thoracolaproscopic surgery(n= 130) in prone position no conversion to open, periop mortality – 1.54%, low post pneumonia

Palanivelu C J, Am Coll Surgery 2006

This approach is still in developmental, no work on large bulky tumours available yet

Endoscopic curative resection EMR/ESD with complete resection

curative only of tumor limited to epithelium and lamina propria muscle layer – T1a

Those invading the musclaris mucosa and beyond have significant LN mets risk

EMR is preferable for lesion less than 2cm while ESD is for lesions >2cm.

Outcomes For Sq.CC rate of en-block resection 100%

with curative resection rate 68-79%

Non curative resection patient managed with esophagectomy

In curative resection group no recurrences or mets for 2 years follow up

Yamada GIE 2013

For Barrett’s German study 90% en-block resection R0 38% (any dysplasia precludes R0) Follow up for 17 month 96% neoplasia free

Gertier Surg Endo 2011

Five year disease free survival with 96.7% for T1a lesion 76% for T1b lesion

Zehetner, J CTVS, 2011

Complications Bleeding ~10%, perforation – EMR <3%, ESD 2-5%, Stricture 5-

17%

Ablative therapies usually are to be combined with resection, alone they have recurrence rates of 18%

Esophageal stenting Indications

Unresectable obstruction Actual or impending fistula Malignant GE anastomotic leak Tumour recurrence after surgery or chemo C/I to chemo

Contraindications Tumour or stricture with in 2 cm of UES Uncorrectable coagulopathy Potential for significant air way compression Recent high dose chemo-radio therapy(3-6wk) Terminal ill pt with limited life expentancy

Outcomes Metal stents have made plastic stents a

thing of past

Dysphagia relief – 96%, improve score by 1-2, TOF sealing achieved in 86%.

No significant difference in metal stents among different companies

Reintervention rates 25-35% Baron, GIE, 2001

Median survival after stent placement is 4 monthsYakoub, W J surgery 2008

Delayed complication rates 53-65%(bleeding, peforationand aspiration), direct stent related deaths 0.5-2%

Other modalities alcohol, LASER and PDT are comparable to stents but have higher reintervention rates – making them undesirable.

Future of esophageal stenting is drug eluting stents preventing restenosis

Systemic therapy

Chemotherapy Preop chemotherapy alone -63% underwent R0 Increased 5 year survival, number needed to

treat 1 extra survivor is 11 Regimen▪ Paclitaxel and carboplatin▪ Cisplatin and 5FU▪ Oxaliplatin and 5 FU▪ ECF regimen– Epirubicin, CiSplatin and 5 FU

preferred▪ 3 cycles prior and 3 cycles post operative

Neoadjuvant chemo-radiotherapy Better outcome than chemo alone

Combined modality has survival 49.4 months vs 24.0 months irrespective of histologic type

van Hagen, NEJM 2012

Loco-regional recurrence rate reduced from 34% - 14%, and peritoneal carcinomatosis reduced to – 4 from 14%

Oppedikj J clin Onco 2014

Radiotherapy alone is not found successful as modality in isolation

Radiation therapy

Preop RT - A dose range of 41.4 to 50.4Gy fractions of 1.8-2Gy per day

For radiotherapy non surgical candidates 50-54 Gy

CT simulation, immobilization device and IMRT are newer modalities which give more focused RT avoiding peripheral damage

Brachytherapy alone is palliative measure, 5 month survival 25-35%, no significant difference with EBRT in RCTs

Post op chemoradiation SWOG trial – all post op patients with or without

LN involvement, N=281 Median overall survival – surgery only group 27

months vs CT/RT group was 36 months Significant decrease in local failure 19 vs 29%

Regimen Chemo 4 cycles leucovorin, 5FU and capecitabin Radiotherapy same dose as preop

Principles of metastatic disease Agents

Docetaxel,Cisplatin 5FU, Oxaliplatin Irinotecan,Mitomycin

Targeted therapies Trastuzumab – Her2/neu blocker positive patients, benefit limited

to pts. with IHC 3+/2+ or FISH positive pts., gives additional 2 months added to conventional CT

Ramucirumab – VEGF blocker - RAINBOW trial similar to earlier gives additional 2 months alone/in combination

If ECOG is >/= 3 then no chemo and only palliative therapy with TLC

Surveillance and screening Tylosis – recommended in family

members after 20 years of age

Familial Barrett’s esophagus – males older than 40 year age

Bloom syndrome – after age of 20 years

Interval not mentioned

Tis/ high grade Barrett’s After ER – every 6 month for 2 year then annually for 3 years – UGI

scopy

T1a ER/esophagectomy – OGD every 3 month – 1st and then 6 monthy

2nd year, then annually for 3 years

T1b any N Esophagectomy – PET/CT or CT 6-12monthly for 3 years, then SOS,

UGI scopy SOS when symptomatic, if residual disease every 3 month till 1 year, 6 mon 2nd tear and…

Chemoradiation – OGD every 6-12 monthly for 2 yrs, PET/CT every 6 months for 2 years and then annually for 5 year

T2-T4b any N endoscopy every 4 months for first 2 yrs, every 6 month 3rd year and then as required

Prognosis Fiver year survival▪ Tis – 95-100% after ablation▪ Local LN spread – 33%▪ Regional LN – 16.9%▪ Distant LN – 2.9%

Despite advances overall 5 year survival is 17%

Thank you