Esophagus

Management Of Carcinoma Esophagus

Management Of Carcinoma Esophagus

Dr. Jageshwar Sonkar , PG IIIrd Yr MD Radiation Oncology

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-

1-starting cricophyrangeal  junction 15cm from incisor .

2-crossed by aortic arch(22.5cm) 

3-crossed by left bronchus (37cm)

 4-Pierces the diaphragm( 40cm)

Histologically 3 layers:

mucosa, submucosa, muscularis propria . Absent serosal layer.

ESOPHAGEAL CONSTRICTIONS

Esophageal Constriction

THE ESOPHAGEAL WALL

The Esophageal Wall

Four regions of the esophagus:

Cervical = cricoid cartilage to  thoracic inlet (15–20 cm from  the incisor).

Upper thoracic = thoracic inlet  to tracheal bifurcation (20–25 cm).

Midthoracic = tracheal  bifurcation to just above the GE  junction (25–30cm).

Lower thoracic = GE junction  (30–40 cm).

Four regions of the esophagus

Lymphatic Drainage

Rich mucosal(lamina propria ) and submucosal  lymphatic system.

The submucosal lymphatics may  extend long distances and directly drains into thorasic duct up to 8 cm or more. Normal tissue can exist between gross tumor and micrometastesis “skip area “secondory to this extensive lymphatics network.

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

Lymphatic drainage of the esophagus  with anatomically defined lymph node basins

Epidemiology

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

accounts for  6% of all GI malignancy.

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

Male : Female = 3.5:1.

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.

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: 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.

Barrett’s esophagus is a  metaplasia 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.

lower esophageal & gastroesophageal junctional adenocarcinomas , approx 70% have nodal mets at presentation . T2 ,T3, T4 have mets 45%, 85%, 100% nodal mets respectively .

Most common site of metastases are

lung, liver, pleura, bone, kidney & adrenal gland

Median survival with distant metastases – 6 to 12 months.

Pathological Classification

Pathological Classification

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.

Functional Grades of Dysphagia

Advance lesion can produce sign and symptoms from tumor invasion into local structure : hematemesis,  hemoptysis, melana, dyspnea ,persistent cough secondary to tracheoeshphageal fistula may occur.

 Superior vena cava syndrome and Horners syndrome can also occur for very advanced lesion.

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 : Adenocarcinoma

GroupTNMGrade
0Tis (HGD)N0M01,X
IAT1N0M01-2 ,X
IBT1N0M03
T2N0M01-2 ,X
IIAT2N0M03
IIBT3N0M0Any
T1-2N1M0Any
IIIAT1-2N2M0Any
T3N1M0Any
T4aN0MOAny
IIIBT3N2M0Any
IIICT4aN1-2M0Any
T4bAnyM0Any
AnyN3M0Any
IVAnyAnyM1Any
Staging Adenocarcinoma

Staging : Squamous cell carcinoma

Staging : Squamous cell carcinoma

TNM Staging By CT

PROGNOSIS OF ESOPHAGEAL CANCER

STAGE5 YEAR OS {%}
I50-80%
IIA30-40%
IIB10-30%
III10-15%
IV0-5%

Management of CA oesphagus-

ROUTINE INVESTIGATIONS

DISEASE SPECIFIC INVESTIGATIONS

TREATMENT  OF CA ESOPHAGUS

HISTORY

Detailed  history  & Physical examination:

Dysphagia , Odynophagia,hoarseness,  wt.loss,  use of  tobacco, nitrosamines,  history of GERD. Examine for cervical or supraclavicular adenopathy.

ROUTINE INVESTIGATIONS

COMPLETE  BLOOD COUNTS – Hemoglobin, total luekocyte count, platelet count

LFT

RFT

S . electrolyte.

ECG

chest x ray

2D ECHO

Diagnostic Workup

UPPER GI ENDOSCOPY

Confirmation of diagnosis:

EGD: allow direct visualization and biopsy, measure proximal & distal distance of  tumor from incisor.

Early, superficial  cancer
Circumferential ulceration  esophageal cancer
Malignant stricture  of esophagus

CT chest and abdomen: Essential for staging because it can identify extension  beyond the esophageal wall, enlarged lymph nodes and visceral metastases.

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.

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 .

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.

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.

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.

Bronchoscopy: rule-out fistula in midesophageal lesions.

Rat tail appearance
Cancer lower 1/3
Filling defect (ulcerative type )
Apple core appearance
Apple core appearance

Management depends upon:

Site of disease

Extent of disease involvement  Co-morbid conditions

Treatment modalities for esophageal cancer

1.concurrent chemoradiotherapy

2. surgery

A  proposed  treatment  algorithm for esophageal cancer

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 .

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.

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:

1.Paclitaxel and carboplatin  : 50 mg/m2 IV + AUC 2 IV repeat weekly for 5 weeks {days 1,8,15,22,29                                                                             2.Cisplatin : DAYS{ 1 and 29} 75-100 mg /m2 IV.            

 5 -FU -DAYS 1-4 and 29-32 : 750-1000 mg/m2 continuous infusion over 24 hr .                                                                   3.Oxaliplatin(85 mg/m2 D1, 15 ,29) and 5-FU or capcitabine D1-5 (625 mg/m2     twice daily for 5 weeks.

4. capectiabine 800 mg/m2 D1-D5 twice daily repeat cycle weekly for 5 weeks and cisplatin(30 mg/m2) D1

Oxaliplatin, docetaxel and capecitabine

Epirubicin, cisplatin and 5-FU (Only for adenocarcinoma)

Radiotherapy

Curative

RadicalRT  ,Pre-Op RT  Post Op RT

Concurrent chemo-radiation

Palliative  EBRT

Brachytherapy

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

à AP – PA followed by 1 Ant and 2 Post oblique pair

à  4  FIELD  :  AP-PA  &  opposed  laterals  –  for  mid  1/3rd  lesions  with  patient in prone position.

à 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.

CROSS TRIAL

TRIAL comparing  effects of chemoradiotherapy followed by surgery vs surgery alnoe

 the neoadjuvant chemoradiotherapy in the treatment of esophageal cancer showed a significant survival benefit in pt receving pre op chemotherapy . majority of pt having advance adenocarcinoma.

 pt with resectable TINI OR T2-3 N0-1 DISEASE received preop chemoradiotherapy weekly paclitaxel and carboplatin

results:-

R0 resection rates were 92% vs 69%

complete respons war 29%

median survival was 49 months vs 24 months

3 yr survivls were 58% vs 44%

EBRT –  DOSES

Energy

6 – 10 MV linac or Co60

Chemoradiation:

39.6 to 41.4 Gy at 1.8 Gy per # for total 22/23 #

followed by total of  50.4 Gy in left / rt oppose oblique pair field.

Radical RT:

45 Gy / 25 # / 1.8 Gy per #

boost with 2 cm margin to total dose of 60Gy.

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.

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%.

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 è 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.

è 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.

2 randomised trials:

Peniere et al :-

221 pts, mid / low 1/3rd  growth  RT : 45- 55 Gy @ 1.8 Gy per #

3 yrs – Ô 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 Ô in patients who had palliative resection  ( from 46% to 20% )

No difference for completely resected patients è  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 %

á Median & overall survival, ÔLRR and áAcute toxicity in Chemo RT  arm.

= > Chemoradiation is a standard Non-surgical Tx.

RT  doseescalation  in ChemoRT

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.

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%)

è Results support TRIMODALITY approach.

Pre-operative Chemotherapy

The  role  of  preoperative  chemotherapy  alone  is  controversial, according to  mixed  results  from  clinical  trials.
StageRecommended treatment
Stage I–III and IVA  resectable  medically-fitdefinitive 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 inoperableDefinitive chemo-RT
Stage IV palliativeConcurrent 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.

Dose Constraints for Esophageal Cancer

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  ineligible patients.

follow up shedule and examination

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