Carcinoma EsophagusPresented By:Dr. VandanaDept. of Radiation OncologyCSMMU, 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(9inch)crossed by left bronchus(11inch)Pierces the diaphragm(15inch)

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

FIGURE Anatomy of the esophagus

ContdFour regions of the esophagus: Cervical = cricoid cartilage to thoracic inlet (1518 cm from the incisor). Upper thoracic = thoracic inlet to tracheal bifurcation (1824 cm). Midthoracic = tracheal bifurcation to just above the GE junction (2432 cm). Lower thoracic = GE junction (3240 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 DrainageRich 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 regionsFigure Lymphatic drainage of the esophagus with anatomically defined lymph node basins

EpidemiologyEsophageal 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 , Barrettss 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: AdenocarcinomaAssociated with Barrettss 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. Barrettss esophagusBarretts 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

Clinical FeaturesIt 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.

ContdComplications: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 Empyemaback pain in celiac axis node involvement

AJCC TNM classificationa: Includes nodes previously labeled as M1ab : M1a designation is no longer recognized in the 7th edn. of the AJCC system

Staging : Squamous cell carcinoma

Staging : Adenocarcinoma

GroupTNMGrade0Tis (HGD)N0M01, XIAT11-2, XIBT13T21-2, XIIAT23IIBT3AnyT1-2N1IIIAT1-2N2T3N1T4aN0IIIBT3N2IIICT4aN1-2T4bAnyAnyN3IVAnyAnyM1

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 Barretts 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 lumenFigure 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 Scanmost recently, proven to be valuable staging toolcan detect up to 1520% of metastases not seen on CT and EUSlow accuracy in detecting local nodal disease compared to CT / EUSValue in evaluating response to Chemo Therapy & Radio Therapyaddition of PET to CT can improve specificity and accuracy of non-invasive staging

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.

Treatment

Management depends upon: Site of disease Extent of disease involvement Co-morbid conditions Patient preference.

SurgeryPrerequisite for surgerydisease should be 5 cm beyond cricophyrangeus.

Surgery indications Lower 1/3 rd oesophageal ds involving GE junction. Tumor size

Types of SurgeryTranshiatal 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.

ChemotherapyNo data proving that chemotherapy alone provides improved survival or palliation. Partial response, not long-term remission, is the rule

IndicationUsed in combination with radiation for locally advanced cancersUsed as single treatment modality in stage IV diseaseCombination 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 agentsCisplatin plus 5-FU or docetaxel are commonly used combinations

Regimens:Paclitaxel and carboplatinCisplatin and 5-FU or capecitabineOxaliplatin and 5-FU or capecitabinePaclitaxel or docetaxel and cisplatinCarboplatin and 5-FUIrinotecan and cisplatinOxaliplatin, docetaxel and capecitabineEpirubicin, cisplatin and 5-FU (Only for adenocarcinoma)

RadiotherapyCurativeRadical RTPre-Op RTPost Op RTConcurrent chemo-radiationPalliativeEBRTBrachytherapy

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 EsophagusField Portals:AP PA foll. by opposed oblique pair.2 anterior obliques and 1 posterior field.2 posterior obliques and 1 anterior field4 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 swallowLOWER 1/3RD - Coeliac plexus ( L 1 ) to be included.

Radiotherapy for CA esophagus

EBRT - DOSESEnergy6 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 limitationsSpinal cord Dmax:45 Gy at 1.8 Gy/fxLung: Limit 70% of both lungs

Brachytherapy (Intraluminal)As a boost after EBRT or as a palliative measureLocal control of 25% - 35 in palliative settingIn curative setting, addition of brachytherapy does not improve results compared to Chemoradiation.Limit dose to critical structureDose escalation to primaryRelief bleeding, pain and improves swallowing status in palliative setting.

American Brachytherapy Society GuidelinesPatient 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 aloneNo randomized trials of RT Vs Sx5 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%

ContdFor 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 RTBetter LRC and improved OS with ChemoRT

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

Trials PreOP RTPrinciple:

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 RTAdvantages: 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 ChemoradiationChemoRT Vs RT AloneRTOG 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.

ContdRT dose escalation in Chemo RT Intergroup 0123 TRIAL 218 ptsChemoradiation - either 50.4 Gy or 64.8 GyNo 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.

ContdPRE OP CHEMO RT Vs Sx ALONE 44 Randomised trials 2 studies showed in local recurrenceUrba 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

Stage Recommended treatmentStage IIII 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 IIII inoperableDefinitive chemo-RTStage 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 RTBleeding: endoscopic therapy, surgery, or RT

Current approachEBRT 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

ConclusionEsophageal 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 You

ChemoRT followed Sx Vs.ChemoRTPatient 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.

***For cervical primaries, patients are placed supine. Various field designs are possible and their choice depends on the geometry of the primary tumor in relation to the spinal cord. The ideal design is a three-field technique (two anterior obliques and a posterior). However, since the primary tumor is rarely limited to the midline, the most common approach is anteroposterior (AP)/posteroanterior (PA) to 39.6 to 41.4Gy (Fig. 36-3) followed by a left or right opposed oblique pair with photons to 50.4Gy (Fig. 36-4A-C). Since this technique will exclude the ipsilateral supraclavicular fossa, a separate electron field is added (commonly to a depth of 2 to 3cm depending on the patient's anatomy) thereby bringing the total dose to 50.4Gy. For cervical primaries, patients are placed supine. Various field designs are possible and their choice depends on the geometry of the primary tumor in relation to the spinal cord. The ideal design is a three-field technique (two anterior obliques and a posterior). However, since the primary tumor is rarely limited to the midline, the most common approach is anteroposterior (AP)/posteroanterior (PA) to 39.6 to 41.4Gy (Fig. 36-3) followed by a left or right opposed oblique pair with photons to 50.4Gy (Fig. 36-4A-C). Since this technique will exclude the ipsilateral supraclavicular fossa, a separate electron field is added (commonly to a depth of 2 to 3cm depending on the patient's anatomy) thereby bringing the total dose to 50.4Gy.*