MANAGEMENT ISSUE

ADVANCED ESOPHAGEAL CANCER

Speaker: Vishal GargModerator: Dr. S. Sachdeva

Date: 27th Nov, 2009

Issues

Introduction Diagnosis and staging Definitive therapy Palliation of malignant dysphagia Management algorithm

IntroductionSQUAMOUS CELL CARCINOMA

70 % found in upper & middle 1/3rd of esophagus

Most common form of esophageal cancer worldwide

Risk factors Smoking Alcohol Food additives eg

nitrosamines (smoked food)

ADENOCARCINOMA

Distal 1/3rd and at the GE junction

Most common subtype in the US and Western world

Risk factors Barrett’s esophagus GERD Obesity

Diagnosis

Esophagram

Recommended for any patient presenting with dysphagia

Differentiate intramural vs intraluminal lesions

Differentiate intrinsic vs extrinsic compression

DiagnosisEndoscopy

Visualize the lesion Location Biopsy

Recommendation: at least 6 biopsies (standard biopsy forceps)

Lal N, Bhasin DK et al. Gut. 1992

PGI, Chandigarh

Staging2 Classification systems exist:

TNM system T – tumor depth N – Involvement of regional lymph nodes M – Disease to nonregional lymph nodes &

distant sites

WNM system (Ellis system) W –Wall penetration N – number of positive lymph nodes M – Distant disease

TNM staging

Current AJCC 2002 staging

Regional nodes Cervical Esophagus: Scalene,

Internal jugular, Upper and lower cervical, Peri-esophageal, Supraclavicular nodes

Intra-thoracic esophagus: Upper peri-esophageal, Sub carinal, Lower peri-esophageal, mediastinal nodes

Gastro-esophageal junction: Lower esophageal, diaphramatic, para-cardial, left gastric and celiac nodes

Comparison of TNM & WNM

staging systems

EUS CT FDG-PETPooled Sensitivity

Pooled specificity

Pooled Sensitivity

Pooled specificity

Pooled Sensitivity

Pooled specificity

Regional LN metastases

0.80 (0.75–0.84)

0.70 (0.65–0.75)

0.50 (0.41–0.60)

0.83(0.77–0.89)

0.57(0.43–0.70)

0.85 (0.76–0.95)

Celiac lymph node metastases

0.85 (0.72–0.99)

0.96 (0.92–1.00)

Abdominal lymph node metastases

0.42 (0.29–0.54)

0.93 (0.86–1.00)

Distant metastases

0.52 (0.33–0.71)

0.91 (0.86–0.96)

0.71 (0.62–0.79)

0.93 (0.89–0.97)

For detection of regional and celiac lymph node metastases: EUS is most sensitive, whereas CT and FDG-PET are more specific tests.

For distant metastases, FDG-PET may have a higher sensitivity than CT.

Difficult case Old male, chronic smoker, presents with

symptoms of dysphagia, weight loss and anorexia

Investigations reveal a stricture of esophagus

Repeated attempts at endoscopic biopsy negative

Strong suspicion of malignancy

Management????

Role of EUS in malignant stricture

Endoscopic ultrasound mini-probes: small, rotating ultrasound probes

Passed through the working channel of a standard endoscope

Only 2 mm to 3 mm in diameter Frequency between 12 Mhz and 20

Mhz

Role of EUS in malignant stricture

Celiac or retroperitoneal lymph nodes were identified in 18 of 42 (43%) patients with malignant strictures

FNA was attempted in 10 patients and confirmed metastatic disease in 7

Gastrointest Endosc 2000;51:

Role of PET/CT Limited role in evaluating the extent

of primary tumor. T1 and T2 do not show significant

FDG uptake Small regional nodes suspicious on CT

are no better visualized on PET/CT Current role is still not defined in the

management of esophageal cancer.

Diagnosis and staging of esophageal cancer

Staging of advanced esophageal cancer

CECT chest + upper abdomen

Consider chemotherapy

Endoscopic ultrasound

Consider chemo/radiation therapy

PET

Consider chemo/radiation therapy

Surgical resection

Evidence of Stage IV disease

No Evidence of Stage IV disease

Evidence of Stage III-IV diseaseNo Evidence of Stage III-IV

disease

Evidence of Stage III-IV disease

No Evidence of Stage

III-IV disease

Management of advanced esophageal cancer

Definitive therapy

Palliation of malignant dysphagia

Definitive therapy

Surgery remains the treatment of choice

Almost 50% patients are unresectable or inoperable at presentation

Types of esophagectomiesTranshiatal

Exposure is provided by an upper midline laparotomy and a left neck incision.

The thoracic esophagus is bluntly dissected, and a cervical anastomosis created; thoracotomy is not required.

Drawbacks: inability to perform a full thoracic lymphadenectomy, and lack of visualization of the midthoracic dissection.

Transthoracic The Ivor Lewis

esophagectomy combines a laparotomy with right thoracotomy, and produces an intrathoracic anastomosis.

This technique permits direct visualization of the thoracic esophagus, and allows the surgeon to perform a limited lymphadenectomy.

However formal dissection of lymph nodes is not performed

Types of esophagectomiesThree field lymphadenectomy: Widely practiced in Japan En bloc resection of esophagus, azygous vein,

thoracic duct, lateral pleural surfaces, part of pericardium

Dissection of cervical, mediastinal and upper abdominal nodes with RPLD performed

Two field lymphadenectomy: En Bloc resection of esophagus, azygous vein,

thoracic duct along with lateral pleural surfaces and part of pericardium and mediastinal nodes and dissection of upper abdominal nodes with RPLD performed

Neoadjuvant /adjuvant therapy

Neo-adjuvant Chemotherapy Neo-adjuvant Radiation Neo-adjuvant Chemo-Radiation Adjuvant Chemotherapy Adjuvant Radiation Adjuvant chemoradiation

Why Neoadjuvant/Adjuvant therapy In most cases esophageal cancer is a

systemic disease at diagnosis. Surgery alone is curative in a small group of

patients. Patterns of recurrence suggest both local

and systemic failure. Disadvantages: Only 50 % of patients

respond to treatment Delay in surgery Main aim of therapy is to downstage the

lesion so as to make it resectable.

Ann Thorac Surg 2007;83:1257– 64

Ann Thorac Surg 2007;83:1257– 64

Ann Thorac Surg 2007;83:1257– 64

Ann Thorac Surg 2007;83:1257– 64

Chemo-RT + surgery

Surgery alone

Ann Thorac Surg 2007;83:1257– 64

Treatment of choice for locally advanced disease

Chemo-radiotherapy followed by surgical resection (Neo-adjuvant chemo-radiotherapy)

Not candidates for surgery

Radiation alone Combination chemoradiation

Chemoradiation Vs Radiation Herskovic et al

Randomize

Radiation64GyN=62

Cis/5 FUx4Radiation

50GyN=61

Median follow up 5 yrs for all ptsMedian Survival 9.3m

5 yr 0%

Median Survival 14.1m5 yr survival 27% P <0.0001

8 yr 22%Locally advanced adeno or squamous esophageal carcinoma.Cisplatin, 75 mg/m2 intravenously, on the first day of weeks 1, 5, 8, and 11. The patients were given a continuous infusion of fluorouracil, 1 g/m2, for the first 4 days of weeks 1, 5, 8, and 11.Radiation was delivered at 30 Gy in 15 fractions over 3 weeks starting on day 1, followed by 20 Gy in 10 fractions over 2 weeks

N Engl J Med. 1992 Jun 11;326(24):1593-8.

Chemoradiation Vs Radiation The trial was stopped after the

results in 121 patients demonstrated a significant advantage for survival in patients who received combination therapy.

The patients who received combined treatment had fewer local (P less than 0.02) and fewer distant (P less than 0.01) recurrences.

No significant relation of histology to survival noted

Chemoradiation Vs Radiation

Currently accepted chemotherapeutic regimen

Targeted therapy for esophageal cancer

Target Drug

EGFR CetuximabGefitinibErlotinib

EGFR/HER LapatinibTrastuzumabPertuzumab

VEGFR SU6668

VEGF Bevacizumab

Targeted therapy for esophageal cancer

GENETIC POLYMORPHISMS AND PROGNOSIS

Palliation of Malignant Dysphagia

Palliative modalities for esophageal carcinoma

Injection therapy Intratumoral injection of absolute alcohol

results in tissue necrosis and sloughing. Cheap, widely available, and relatively

simple to perform. Case series: initial success rate of 80%–

100% in improving dysphagia. Palliative effect is short-term (<1 month)

Injection therapy Alcohol injection is probably best

reserved for short, protuberant, and nonfibrotic tumors that are not amenable to other endoscopic palliative therapies.

Intratumoral injection of cisplatin/epinephrine gel: experimental therapy till date.

Laser therapyNEODYMIUM YTTRIUM ALUMINUM GARNET (Nd:YAG) LASER

Offers an effective way of palliation

Can coagulate up to 6 mm in depth and can obliterate vessels up to 4 mm in diameter

Successful tumor recanalization can be achieved in more than 90% of appropriately selected patients (those with exophytic and not infiltrating tumors that are unassociated with tight strictures)

Laser therapyNEODYMIUM YTTRIUM ALUMINUM GARNET (Nd:YAG) LASER

Treatments are performed every other day and are usually completed in 3–4 sessions (1 week)

Nd:YAG laser therapy needs to be repeated every 4–6 weeks due to tumor regrowth

Symptomatic relief may result for 1 or more months.

Laser therapy

NEODYMIUM YTTRIUM ALUMINUM GARNET (Nd:YAG) LASERDrawbacks

Equipment cost and availability Technical expertise required by the

operator Difficulty in management of long or

tortuous segments

Role of PDT

PDT has role in ablation of barrett’s mucosa

High prohibitive costs and short life expectancy: limit its role in palliation of malignant dysphagia

ARGON PLASMA COAGULATION

Ablative endoscopic technique

Form of monopolar electrocautery

Only one study till date

Need for repeated sessions

No comparison to ND:YAG laser

Stents

SEMS

SEPS

SEMS

SEMS Wallstent

Gianturco-Rösch Z stent

Ultraflex stent

Stents

Two new stent designs:

Polyflex® stent (Boston Scientific)

Niti-S double stent (Taewoong Medical, Seoul, Korea)

SEMS

Dua stent (Z-stent with a windsock-like antireflux valve)

Choice of SEMS Various trials have failed to demonstrate

superiority of one stent over another

Choice for a particular SEMS primarily depends on device availability, familiarity, and personal preference

Stents are ideal for obstructing midesophageal cancers

Esophageal SEMS are indicated for palliation of tracheo-esophageal fistulas.

Proximal esophageal cancer

Traditionally been regarded as too difficult to manage with stents.

Proximal esophageal cancer

Author Year Number of patients

Distance of the stricture from UES

Technical success

Major complications

Type of stent

Dumonceau JM et al.

1999 17(4) NS 100% NR UltraflexWallstent

Verschuur EM et al.

2007 104 4 cms 95% 18% Ultraflex(57%)

Proximal esophageal cancer

Ultraflex stent because of its relatively low radial force and flexible mesh may be the preferred stent

Strictures as near as 2-4 cms from UES have been successfully stented

TRACHEOESOPHAGEAL FISTULA

Dreaded complication 5% of all cases Can lead to aspiration and respiratory

failure Covered SEMS is the treatment of choice

Closure of the fistula can be achieved with a covered stent in 70%–100% of patients

Raijman I, et al. Gastrointest Endosc 1998;48:

SEMS related complications

Immediate technical complication (5%–17%)

Misplacement (0.3%–5%)

Failed expansion (4%–7%)

Failed deployment (1%–3%)

Migration (0.3%–2%).

Delayed technical complications (9%–18%)

Tumor ingrowth/overgrowth (6%–11%)

Stent migration (3%–7%).

SEMS related complications

Immediate patient complications (7%–15%)

Chest pain (6%– 12%) Bleeding (0.2%– 0.6%) Perforation (0.6%–1%) Death (0.5%–1.4%).

Delayed patient complications up to 27%

Reflux symptoms (4%–5%)

Recurrent dysphagia (8%-9%)

Tracheoesophageal fistulas (1%–3%)

Bleeding (0.5%–4%) Perforation (0.5%– 0.8%) Death as a result of

underlying malignancy occurring within 30 days (7%).

Esophageal SEPS

Advantages of SEPSare: easy removability,ease of repositioning, an equal expansive force as SEMS,and half the cost of SEMS in Europe.

Diseases of the Esophagus (2009)

Management of stent related complications

If dysphagia is recurrentafter stent placement

Tumor ingrowth

PDT

APC

ND YAG laser

If dysphagia is recurrentafter stent placement

Is there any role of radiation therapy after stent placement??

Studies done so far have shown conflicting results

Survival benefit has been shown in some studies

Major complications Creation of a tracheal-esophageal fistula Massive hematemesis from stent erosion

into the aorta.

Current role is not defined

Chemotherapy for palliation of malignant dysphagia

Radiotherapy Doses of 30–37.5 gy are used for

palliation A diagnostic bronchoscopy prior to

radiation therapy is recommended Patients with a suspected

tracheoesophageal fistula should not be treated with radiation therapy

Risk for post-radiotherapy esophageal strictures

Takes longer for symptom improvement to occur

Intraluminal brachytherapy

May be used as the sole therapy for palliation of malignant dysphagia

Limited availability Frequent occurrence of post-

treatment strictures.

Newer forms of radiotherapy

Minimises radiation to other organs

Patient specific planning target volume (PTV) using cone beam computed tomography (CBCT) imaging is acquired in the first week of radiotherapy

14 patients have been studied

Needs further evaluation

Chemoradiation

Stent v/s brachytherapy

GASTROINTESTINAL ENDOSCOPY 2005

GASTROINTESTINAL ENDOSCOPY 2005

To summarize…Management Options for the Palliation of

Dysphagia

Management algorithm

Is there e/o TOF

Is there e/o TOF

Is there e/o TOF

Is there e/o TOF

Future perspectives Need for tumor markers to predict

response to therapy and survival

Intratumoral injection of cisplatin/epinephrine gel

Targeted therapy needs further evaluation

Future perspectives

Cone Beam Computed Tomography-Derived Adaptive Radiotherapy

Role of biodegradable stents needs to be defined further

Summary

Advanced but localized cancers: surgical resection

Cancers with regional lymphadenopathy: neoadjuvant chemotherapy and radiation therapy

Summary

Advanced unresectable disease: primary therapy with radiation and chemotherapy

Palliation of dysphagiaStentBrachytherapy

Thank you