Carcinoma Esophagus

Presented By:Dr. Vandana

Dept. of Radiation Oncology

CSMMU, Lucknow

Clinical Anatomy Hollow muscular tube 25 cm in

length which spans from the cricopharyngeus at the cricoid cartilage to gastroesophageal junction (Extends from C7-T10).

Has 4 constrictions- At starting(cricophyrangeal

junction) crossed by aortic arch(9’inch) crossed by left bronchus(11’inch) Pierces the diaphragm(15’inch)

Histologically 4 layers: mucosa, submucosa, muscular & fibrous layer.

FIGURE Anatomy of the esophagus

Contd…

Four regions of the esophagus:

Cervical = cricoid cartilage to thoracic inlet (15–18 cm from the incisor).

Upper thoracic = thoracic inlet to tracheal bifurcation (18–24 cm).

Midthoracic = tracheal bifurcation to just above the GE junction (24–32 cm).

Lower thoracic = GE junction (32–40 cm).

Figure Anatomy of the esophagus with landmarks and recorded distance from the incisors used to divide the esophagus into topographic compartments. GE, gastroesophageal.

Lymphatic Drainage

Rich mucosal and submucosal lymphatic system.

The submucosal lymphatics may extend long distances (proximal and distal margins used for RTP have traditionally been a minimum of 5 cm).

The submucosal plexus drains into the regional lymph nodes in the cervical, mediastinal, paraesophageal, left gastric, and celiac axis regions

Figure Lymphatic drainage of the esophagus with anatomically defined lymph node basins

Epidemiology

Esophageal cancer is the 7th leading cause of cancer deaths.

accounts for 1% of all malignancy & 6% of all GI malignancy.

Most common in China, Iran, South Africa, India and the former Soviet Union.

The incidence rises steadily with age, reaching a peak in the 6th to 7th decade of life.

Male : Female = 3.5 : 1

African-American males : White males = 5:1

Contd…

Worldwide SCC responsible for most of the cases.

Adenocarcinoma now accounts for over 50% of esophageal cancer in the USA, due to association with GERD , Barretts’s esophagus & obesity.

SCC usually occurs in the middle 3rd of the esophagus (the ratio of upper : middle : lower is 15 : 50 : 35).

Adenocarcinoma is most common in the lower 3rd of the esophagus, accounting for over 65% of cases.

Risk Factors : Squamous Cell Carcinoma

Smoking and alcohol (80% - 90%) Dietary factors

N-nitroso compounds (animal carcinogens) Pickled vegetables and other food-products Toxin-producing fungi Betel nut chewing Ingestion of very hot foods and beverages (such as tea)

Underlying esophageal disease (such as achalasia and caustic strictures, Tylosis)

Genetic abnormalities: p53 mutation, loss of 3p and 9q alleli, amp. Cyclin D1 &

amp. EGFR

Risk Factors: Adenocarcinoma

Associated with Barretts’s esophagus, GERD & hiatal hernia.

Obesity (3 to 4 fold risk) Smoking (2 to 3 fold risk) Increased esophageal acid exposure such as

Zollinger-Ellison syndrome.

Fig. Barretts’s esophagus

Barrett’s esophagus is ametaplasia of the esophageal epithelial lining. The squamous epithelium is replaced by columnar epithelium,with 0.5% annual rate of neoplastic transformation.

Barrett’s esophagus is ametaplasia of the esophageal epithelial lining. The squamous epithelium is replaced by columnar epithelium,with 0.5% annual rate of neoplastic transformation.

Pattern of spread

No serosal covering, direct invasion of contiguous structures occurs early.

Commonly spread by lymphatics (70%)

Lymph node involvement increases with T stage. T1 – 14 to 21% T2 – 38 to 60%

25% - 30% hematogenous metastases at time of presentation.

Most common site of metastases are lung, liver, pleura, bone, kidney & adrenal gland

Median survival with distant metastases – 6 to 12 months

Site-wise nodal involvement

Pathological Classification

95%

Clinical Features

It is commonly associated with the symptoms of dysphagia, wt. loss, pain, anorexia, and vomiting

Symptoms often start 3 to 4 months before diagnosis

Dysphagia - in more than 90% pt. Odynophagia - in 50% of pt.

Wt. loss – more than 5 % of total body wt. in 40 – 70% pt. associated with worst prognosis.

Contd…

Complications: Cachexia, Malnutrition, dehydration, anaemia,. Aspiration pneumonia. Distant metastasis. Invasion of near by structures: e.g.

Recurrent laryngeal nerve → Hoarseness of voice Trachea → Stridor & TOF→ cough, choking &

cyanosis Perforation into the pleural cavity → Empyema back pain in celiac axis node involvement

AJCC TNM classification

a: Includes nodes previously labeled as “M1a”

b : “M1a” designation is no longer recognized in the 7th edn. of the AJCC system

Staging : Squamous cell carcinoma

Staging : Adenocarcinoma

Group T N M Grade

0 Tis (HGD)

N0

M0

1, X

IA T1 1-2, X

IB T1 3

T2 1-2, X

IIA T2 3

IIB T3

Any

T1-2 N1

IIIA T1-2 N2

T3 N1

T4a N0

IIIB T3 N2

IIIC T4a N1-2

T4b Any

Any N3

IV Any Any M1

Diagnostic Workup

Detailed history & Physical examination: Dysphagia, odynophagia, hoarseness, wt. loss, use of tobacco, nitrosamines, history of GERD. Examine for cervical or supraclavicular adenopathy.

Confirmation of diagnosis: EGD: allow direct visualization and biopsy, measure proximal & distal distance

of tumor from incisor, presence of Barrett’s esophagus.

Early, superficial cancer

Circumferential ulceration esophageal cancer

Malignant stricture of esophagus

Staging: CT chest and abdomen: Essential for staging because it can identify extension

beyond the esophageal wall, enlarged lymph nodes and visceral metastases.

Figure Esophageal cancer with tracheal invasion. CT scan shows circumferential wall thickening of the proximal esophagus (arrowheads), which shows irregular interface with the posterior wall of the trachea (arrows), indicating direct extension into the lumen

Figure Esophageal cancer with aortic invasion. An arc (bent arrow) of the contact between the esophageal cancer (arrows) and the aorta (arrowheads) is more than 90 degrees, indicating aortic invasion.

Endoscopic Ultrasonography

EUS: assess the depth of penetration and LN involvement. Limited by the

degree of obstruction. Compared with EUS, CT is not a reliable tool for evaluation of the

extent of tumor in the esophageal wall.

Fig. —55-year-old man with T2 esophageal tumor (m) shown on endoscopic sonogram. Note alternating hyperechoic and hypoechoic layers (arrowheads) of normal esophageal wall as seen on sonography. Innermost layer is hyperechoic and corresponds to superficial mucosa. Second layer is hypoechoic and corresponds to deep mucosa and muscularis mucosae. Third layer is again hyperechoic and corresponds to submucosa and its interface with muscularis propria. Fourth layer is hypoechoic and corresponds to muscularis propria, and outer fifth layer is hyperechoic and corresponds to adventitia.

PET Scan most recently, proven to be valuable staging tool can detect up to 15–20% of metastases not seen on CT and EUS low accuracy in detecting local nodal disease compared to CT /

EUS Value in evaluating response to Chemo Therapy & Radio Therapy addition of PET to CT can improve specificity and accuracy of

non-invasive staging

Figure Distant lymph node metastases of esophageal cancer detected by integrated CT PET. A, Integrated CT PET demonstrates para-aortic lymph node metastases showing increased FDG uptake (arrowheads). B, Corresponding CT image shows lymph nodes (arrowheads) measuring 5 to 8 mm in diameter. Based on size criteria, these lymph nodes may be considered benign on CT scan

Barium swallow: can delineate proximal and distal margins as well as TEF Helpful for correlation with simulation film.

Bronchoscopy: rule-out fistula in midesophageal lesions.

Routine Investigations: CBC, chemistries, LFTs.

Cancer lower 1/3 Cancer lower 1/3 Filling defect (ulcerative Filling defect (ulcerative type)type)

Rat tail appearanceApple core appearance

Treatment

Management depends upon:

Site of disease Extent of disease involvement Co-morbid conditions Patient preference.

Surgery

Prerequisite for surgery disease should be 5 cm beyond cricophyrangeus.

Surgery indications Lower 1/3 rd oesophageal ds involving GE junction. Tumor size <5 cm . palliative surgery

5-Year OS for surgery alone is 20–25% (no significant difference between surgical techniques according to results of 2 meta-analyses)

Local failure rate around 19–57% when used alone

surgical morbidity/mortality related to experience of the surgeons.

Types of Surgery

Transhiatal esophagectomy: for tumors anywhere in esophagus or gastric cardia. No thoracotomy. Blunt dissection of the thoracic esophagus. Left with cervical anastomosis. Limitations are lack of exposure of midesophagus and direct visualization and dissection of the subcarinal LN cannot be performed.

Right thoracotomy (Ivor-Lewis procedure): good for exposure of mid to upper esophageal lesions. Left with thoracic or cervical anastomosis.

Left thoracotomy: appropriate for lower third of esophagus and gastric cardia. Left with low-to-midthoracic anastomosis.

Radical (en block) resection: for tumor anywhere in esophagus or gastric cardia. Left with cervical or thoracic anastomosis. Benefit is more extensive lymphadenectomy and potentially better survival, but increased operative risk.

Chemotherapy

No data proving that chemotherapy alone provides improved survival or palliation. Partial response, not long-term remission, is the rule

Indication Used in combination with radiation for locally advanced cancers Used as single treatment modality in stage IV disease Combination chemotherapy has been used preoperatively in a

combined modality approach to esophageal Ca in hopes of controlling occult metastatic disease and improving the resectability rate.

Platinum doublet is preferred over single agents Cisplatin plus 5-FU or docetaxel are commonly used

combinations

Regimens: Paclitaxel and carboplatin Cisplatin and 5-FU or capecitabine Oxaliplatin and 5-FU or capecitabine Paclitaxel or docetaxel and cisplatin Carboplatin and 5-FU Irinotecan and cisplatin Oxaliplatin, docetaxel and capecitabine Epirubicin, cisplatin and 5-FU (Only for adenocarcinoma)

Radiotherapy

Curative Radical RT Pre-Op RT Post Op RT Concurrent chemo-radiation

PalliativeEBRTBrachytherapy

EBRT Techniques

Patient Positioning: CERVICAL ESOPHAGUS: Supine with arms by the side

MID AND LOWER THIRD: SUPINE With arms above their head if AP – PA portals are being

planned

PRONE if posterior obliques are being included.

• Esophagus is pulled anteriorly and spinal cord can be spared.

IMMOBILISATION : Perspex cast

Vertebral column should be as parallel to couch as possible.

Barium swallow contrast to delineate the esophageal lumen and stomach.

EBRT – Cervical Esophagus

Field Portals: AP – PA foll. by opposed oblique pair. 2 anterior obliques and 1 posterior field. 2 posterior obliques and 1 anterior field 4 field box with soft tissue compensators foll by obliques

( Univ of Florida tech )

SUPERIOR BORDER: At C 7 INFERIOR BORDER : At T 4 ( carina ) 2 cm lateral margins. SC nodes irradiated electively. SC nodes will be underdosed if oblique portals are used to

treat primary; can be boosted by a separate field if required.

EBRT – Mid & Lower1/3rd

AP – PA followed by 1 Ant and 2 Post oblique pair 4 FIELD : AP-PA & opposed laterals – for mid 1/3rd lesions

with patient in prone position. AP-PA upto 43 Gy foll by 2 Post obliques upto 50 Gy ( gross

disease boosted to 60 Gy )

SUPERIOR BORDER: 5 cm proximal to superior extent of disease.

INFERIOR BORDER: MID 1/3RD – AT GE jn. As visualised by Barium swallow LOWER 1/3RD - Coeliac plexus ( L 1 ) to be included.

Radiotherapy for CA

esophagus

EBRT - DOSES

Energy 6 – 10 MV linac or Co60

Chemoradiation: 50.4 Gy in 28 # at 1.8 Gy per # Boost to 60 – 66 Gy for residual disease

Radical RT: 45 Gy / 25 # / 1.8 Gy per # boost with 2 cm margin to total dose of

60Gy

Dose limitations Spinal cord Dmax:45 Gy at 1.8 Gy/fx Lung: Limit 70% of both lungs <20 Gy Heart: Limit 50% of ventricles <25 Gy

Brachytherapy (Intraluminal)

As a boost after EBRT or as a palliative measure Local control of 25% - 35 in palliative setting In curative setting, addition of brachytherapy does not

improve results compared to Chemoradiation. Limit dose to critical structure Dose escalation to primary Relief bleeding, pain and improves swallowing status in

palliative setting.

American Brachytherapy Society Guidelines

Patient selection: Primary tumor length ≤ 10 cm length Tumor confined to esophageal wall Thoracic esophagus location No nodal / systemic metastasis.

Contraindications: T E fistula Cervical esophagous location Stenosis which cannot be bypassed

Contd…

EBRT 45 – 50 Gy in 1.8-2.0Gy /#,5#/wk HDR – 5 Gy x two # one week apart , 2 – 3weeks after EBRT.

LDR – single 20 Gy # @ 0.4 – 1.0 Gy per hr, 2 -3 weeks after EBRT.

Never concurrently with chemotherapy

Ext diameter of applicator must be 6 – 10 mm.

Active length : visible tumor by UGI scopy plus 1 – 2 cm proximal & distal margin.

Dose is prescribed 1 cm from mid source or mid dwell position.

APPLICATORS

Trials – RT alone

No randomized trials of RT Vs Sx 5 yr survival with conventional RT : < 10% Tumors < 5 cm , 5 yr survival : 20% Stage wise 5 yr survival:

Stage I – 20% Stage II – 10% Stage III – 3 % Stage IV – 0%

Contd…

For cervical esophagus, cure rates were similar with Radical RT or Sx alone.

RT or Sx alone DOES NOT alter the natural history of the disease.

RTOG 8501: RT Vs Chemo RT Better LRC and improved OS with ChemoRT

RT alone should be used for palliation or in medically unfit patients.

Trials– PreOP RT

Principle:

resectability, likelihood of tumor dissemination during Sx , radioresponsiveness due to unaltered blood supply

5 randomised trials ,shows no apparent clinical benefit to use of preop rt alone except,

Only one trial ( Huang et al ) showed survival advantage of 46% Vs 25% with 40 Gy RT

Recent meta analysis Oesophageal Cancer Collaborative Group study showed no clear survival advantage.

No difference in resectability rates, LRC or survival with pre-op RT

Trials– PostOP RT

Advantages: Treat areas at risk for recurrences while

minimizing dose to OAR. Patients with node negative , completely

resected T1 / T2 tumors can be excluded.

Disadvantage: Tolerance of stomach or bowel used for

interpositioning.

Contd…

2 randomised trials: Peniere et al :-

221 pts, mid / low 1/3rd growth RT : 45- 55 Gy @ 1.8 Gy per # 3 yrs - local failure rate ( from 35% to 10%)

- no significant disease free survival. Fok et al :-

130 pts , RT – 49 Gy @ 3.5 Gy per # Local failure rate in patients who had palliative resection

( from 46% to 20% ) No difference for completely resected patients

Post op RT improves local control, but does not confer any survival advantage.

Trials– Chemoradiation

ChemoRT Vs RT Alone RTOG 8501 INTERGROUP TRIAL:

121 pts: 60 pts RT alone – 64 Gy @ 2 Gy per #

61 pts chemoRT – 50 Gy RT + 5 FU + CDDP – on 1 , 5 , 8 & 11 weeks

Median survival : 8.9 Vs 12.5 months 5 yr survival : 0% Vs 30 % Distant mets @ 5 yrs: 40% Vs 12 % Acute toxicity : 25% Vs 44 %

Median & overall survival, LRR and Acute toxicity in Chemo RT arm.

Chemoradiation is a standard Non-surgical Tx.

Contd…

RT dose escalation in Chemo RT

Intergroup 0123 TRIAL – 218 pts Chemoradiation - either 50.4 Gy or 64.8 Gy

No significant difference in median survival, 2 yr survival or loco-regional failure.

Intensification of RT dose beyond 50.4 Gy(in combination

with chemotherapy ) does not improve results.

Contd…

PRE OP CHEMO RT Vs Sx ALONE 44 Randomised trials 2 studies showed in local recurrence

Urba et al – 19 % Vs 42 % Bosset et al ( EORTC ) – 28% Vs 40%

One study showed significant survival benefit at 3 yrs (in pts who had a pathologic CR ) Urba et al – 64% Vs 19%

One study (Walsh et al) showed benefit in median (16 Vs 11 months ) and overall survival at 3 yrs ( 32 Vs 6%)

Results support TRIMODALITY approach.

Pre-operative Chemotherapy

The role of preoperative chemotherapy alone is controversial, according tomixed results from clinical trials.

The role of preoperative chemotherapy alone is controversial, according tomixed results from clinical trials.

Stage Recommended treatment

Stage I–III and IVAresectablemedically-fit

definitive chemo-RT (preferred for cervical esophagus)

Or, Pre-op chemo-RT → surgery. Surgery preferred for adenocarcinoma regardless of response to chemo-RT.

Or, surgery. (noncervical T1N0 and young T2N0 patients with primaries of lower esophagus or gastroesophageal junction. Indications for post-op chemo-RT include: unfavorable T2N0, T3/4, LN+, and/or close/+ margin.

Stage I–III inoperable

Definitive chemo-RT

Stage IV palliative Concurrent chemo-RT (5-FU + cisplatin, 50 Gy) or RT alone (e.g., 2.5 Gy × 14 fx) or chemo alone or best supportive care.

Pain: medications ± RT

Bleeding: endoscopic therapy, surgery, or RT

Current approach

EBRT using 3D-CRT to a total dose of 50.4 Gy (1.8 Gy per daily fraction) is standard.

IMRT is often utilized to minimize exposure to adjacent structures. Proton beam in combination with chemotherapy is being explored. Targeted biologic agents added to standard cytotoxic

chemotherapy is being explored

Conclusion

Esophageal cancer is the 7th leading cause of cancer deaths.

Adenocarcinoma now accounts for over 50% of esophageal cancer in the USA, due to association with GERD & obesity.

Dysphagia and weight loss are the two most common presentations in patients with esophageal cancer.

Endoscopic ultrasound (EUS) is necessary to accompany a complete workup for proper staging and diagnosis of esophageal cancer.

Surgery is the standard of care for early-stage esophageal cancer.

Preoperative chemotherapy and radiation is the standard option for locally advanced esophageal cancer in surgically eligible patients.

Thank YouThank You

ChemoRT followed Sx Vs.ChemoRT

Patient undergoing surgery have worse quality of life.

Surgery following combined CRT appears to improve local control, its impact on ultimate survival remains controversial.

Patient undergoing surgery have worse quality of life.

Surgery following combined CRT appears to improve local control, its impact on ultimate survival remains controversial.

Figure: A proposed treatment algorithm for esophageal cancer.