Esophageal Cancer

Epidemiology

Esophageal cancer is a world-leading cause of death -7th and 6th leading cause of cancer in industrialized countries. In Europe in 2006 apaurut around 32,000 cases and 28,200 cases died. Esophageal cancer is a disease of poor countries. Esophageal cancer is a disease of the elderly occurs more frequently after 50-70 years. Esophageal cancer is one of the most common cancers in men blacks aged over 55 years. In the world rate of occurrence is higher in men as in women, 5/2 ratio. In many Western European countries mortality rates have stabilized or begun to decline in last decade. The decline in incidence is mainly through squamous cancer while adenocarcinomas are increasing. The probability of survival in Europe in the period 1995-1999 was 36% at one year, and only 12% at 5 years. There is no difference in survival between the sexes. Survival decreased with increasing age at diagnosis of 34% (from 15-44 years) to 7% (> 75 years). Tumor stage is the strongest prognostic factor of survival.

In Romania, the incidence of esophageal cancer in 1996 was 3 per 100,000 inhabitants, and the mortality rate of 1.7 per 100,000 inhabitants. In Romania the estimated incidence for 2000 was 2.32 per 100,000 population and mortality of 2.04 per 100,000 inhabitants. More than 90% of the patients diagnosed with esophageal cancer die of the illness.

Risk Factors

1. Alcohol and Tobacco smoking is the strongest risk factor Notice for esophageal cancer (squamous cell carcinoma as well as for both adenocarcinomas). The risk of esophageal cancer was 5 times higher among smokers than nonsmokers.

2. A diet rich in fat, low in protein, low in calories

Alcohol consumption is a cause of esophageal cancer. The risk is multiplied when alcohol consumption is associated with smoking.

Non-starch vegetables, fruits and vegetables containing beta carotene and / or vitamin C may have a protective role.

Mate -a herbal infusion drank too hot through a metal straw (in South America) is probably a cause of this cancer.

There is limited evidence to suggest that foods containing dietary fiber, Folates, pyridoxine or vitamin E protects against this cancer and that red meat, processed meat and drinks with high temperatures causes this cancer. Esophageal adenocarcinoma is associated with an increase in body fat.

3. Occupational factors were found to be an increased risk among workers exposed to asbestosis, painters, textile industry.

4. Infectious Agents HPV infection types 16 and 18 inspections can play an important role in the pathogenesis of squamous carcinoma cellule especially in areas with high incidence, China and South Africa. Infection with HPV is a necessary but not sufficient cause.

5. Esophageal postcaustic stenosis

6. Esophageal achalasia

7. Barrett’s esophagus (intestinal metaplasia of the lower esophagus) There are 5% chance of progression to cancer in 5 years and de10-12% prevalence of adenocarcinoma.

8. Iron deficiency anemia (Plummer-Vinson syndrome)

Histological Types

More than 50% of tumors of the esophagus are formed in the lower third of the esophagus or gastrointestinal junction, while the average 1/3 1/3 develops. Junction tumors are most commonly gastrointestinal adenocarcinomas and squamous tumors predominate in the rest of the esophagus.

Locating: esophageal cancer is cervical esophagus 10%, 40% and 50% higher thoracic esophagus to the lower thoracic esophagus.

I. epithelial tumors:

1. 60% squamous cell carcinoma

2. Adenocarcinoma 40%

3. Small cell carcinoma 1%

4. Malignant melanoma

II. Sarcoma (leiomyosarcoma) – 1%

III. Lymphomas

IV. Metastatic disease

For patients with locally advanced or metastatic disease, adenocarcinoma histology and who is considered trastuzumab therapy is recommended for evaluation of Her2 neu overexpression by immunohistochemistry or FISH (fluorescence in situ hibridisation) or other methods of in situ hybridization recommended. It is recommended that the technique cazurilre which immunohistochemistry (IHC) is less than the value of 3+ and FISH technique to be carried out. Cases the values ​​obtained by the method IHC 3+ or FISH are positive are considered positive.

Chromosomal abnormalities. Esophageal carcinoma is probably the result of the accumulation of multiple mutations in suppressor genes and proto-oncogenes.

It has been associated with multiple fractures and deletions of chromosome 13q including, 5q, 18q, 3p, 9p, 17p, 16p. Often it detected and significant aneuploidy.

P53 and p53 genes or mutations or aberrations oncosupressor overexpression were observed in 50% of esophageal carcinomas. Mutation in p53 is an early event in the progression of esophageal cancer. Also found disappearance suppressor genes Rb in 48%, 66% and DCC APC in 24%.

Cytological screening has been established for patients with Barrett’s esophagus (intestinal metaplasia in the distal esophagus) and moderate and severe dysplasia. This implies multiple endoscopic biopsies at varying time intervals, 12-18 months.

Signs and symptoms: progressive dysphagia, initially for solid and then for liquid food, salivation and regurgitation when the tumor becomes obstructive, weight loss, diet-induced cough, retrosternal pain, dysphonia, recurrent nerve by direct invasion or lymph node metastases. On examination in advanced stages adenopaties may be palpable supraclavicular, cervical, abdominal tumor mass by celiac lymphadenopathy or hepatomegaly tumor.

Tumor markers useful in the detection and monitoring of disease are ACE is increased in 70% of patients and that 50 to 40% of patients increased.

Esophagoscopy with biopsy or tumor formation brushing histological or cytological followed to establish the diagnosis. By these two methods, the biopsy associated with brushing, it is diagnosed in 90% of cases.

Diagnosis on examination must be histopatolgically confirmed.

Diagnosis and staging are done by:

– History, clinical examination, blood count, biochemistry profile,

– Chest X-ray, esogastric barium x-ray,

– CT thorax and upper abdomen,

– Bronchoscopy for all patients with tumors above the gastroesophageal junction (Karen) and patients have metastases.

The staging can also be used:

– Endoscopic ultrasound with FNA (fine needle puncture tumor) if no metastases.

– PET / CT if there are no signs of metastasis.

– Biopsy of metastatic disease if clinically indicated

– Test Her2 / neu in metastatic adenocarcinoma case

TNM Classification esophageal cancer

Primary Tumor (T)

Tx – primary tumor cannot be assessed

How- no evidence of primary tumor

Tis -Displasia with high-grade HGD- (carcinoma in situ)

T1a -Tumor invades lamina propria, muscularis mucosae

T1b- tumor invading the submucous

T2 – Tumor invades muscle

T3 – Tumor invades adventitia

T4 – Tumor invades adjacent structures

T4a-resected tumors invade the pleura, pericardium, or diaphragm

T4b-tumor invades unresectable aorta, vertebral corpus or trachea

Regional lymph nodes (M)

Nx – regional lymph nodes cannot be assessed

No – no regional lymph node metastases

N1 regional lymph nodes within 1-2 -metastază

N2 Metastasis in regional lymph node 3-6

N3 metastasis 7 or more regional lymph nodes

Distant metastasis (M)

Mx – distant metastasis can not be assessed

M0 – no distant metastases

M1 – distant metastases

Staging

Squamous carcinoma cell or mixed histology with squamous component

    Mo St 0 Tis No 1, X                 any

    St IA T1 No Mo 1, X                 any

    No Mo St IB 2.3 T1                  any

                                       T2,3 No Mo 1 lower X, X

    St II T2-3 No Mo 1, X upper, middle

                                     No Mo 2.3 T2-3 lower X

    St IIB T2-3 2.3 No Mo upper, middle

                                       T1-2 N1 Mo any any

    St IIIA N2 Mo T1-2 any any

                                       T3 N1 M0 any any

                                       No Mo T4 any any

   Mo St III B T3 N2 any any

   St IIIC T4a Mo N1,2 any any

                                     Mo N T4b any any any

                                    3 Mo TN any any any

   IV Any T 0rice St N M1 Any any

         Adenocarcinoma

                                                                                                              G

    Mo St 0 Tis No 1, X

    St IA T1 No Mo 1-2, X

    St IB T1 No Mo 3

                                       T2 No Mo 1-2, X

    St II T2 No Mo 3

    St IIB T3 No Mo all

                                       T1-2 N1 Mo all

    St IIIA N2 Mo T1-2 any

                                       T3 N1 M0 any

                                       No Mo T4a any

   Mo St III B T3 N2 any

   St IIIC T4a Mo N1,2 any

                                     Mo N T4b any any

                                    any 3 Mo TN any

   IV Any T 0rice St N M1 Any

TREATMENT

Therapeutic Indication

I.                    Barrett’s esophagus with high grade dysplasia

High grade dysplasia is a premalignant condition which was not documented regression and the associated adenocarcinoma in 45-50% of patients who underwent esophagectomy.

For patients with high grade dysplasia there are 3 options:

– Esophagectomy in patients with good medical condition

– Following endoscopic biopsies at regular intervals

– Photoablative argon laser with Barrett mucosa associated with antacid therapy (omeprazole) that causes a type of squamous re-epithelialization.

II. Invasive Cancer, st I, II and III

Surgical resection is the mainstay of treatment for tumors st I and st II of the thoracic esophagus and gastroesophageal junction.

For treatment of primary tumors of the cervical esophagus can be surgical resection or radiation therapy.

It can be done neoadjuvant chemotherapy or chemoradiotherapy followed by surgical resection.

Tis: – EMR (endoscopic mucosal resection) or ablation

T1a: – EMR or esophagectomy ablation

T1b, No: – esophagectomy

Tib, N +: – esophagectomy for esophagus and noncervical

              -Chemoradiotherapy For cervical esophagus

T2-4, any N: – final chemoradiotherapy for cervical esophagus. If the disease persists recommend saving or palliative treatment oesophagectomy

                       – Preoperative chemoradiotherapy distal esophagus or adenocarcinoma JEG followed by esogectomy.

                     – Preoperative chemoradiotherapy. If there are no signs of illness either do a esophagectomy or maintain under observation. If disease is persistent indicate oesophagectomy or palliative treatment. If the disease progresse, indicate palliative therapy.

T4b: definitive chemoradiotherapy (50 Gy plus concurrent chemotherapy)

Oesophageal cancer therapeutic indication

III. Invasive carcinoma st IV

Survival in these patients is short and recommended treatment is palliative. Surgical treatment is not recommended.

It is recommended chemotherapy with Cisplatin and 5 FUR associated with palliative radiotherapy. Associating mandatory palliative treatment consisting of endoscopic electrofulguration , laser therapy for esophageal lumen release or intraluminal intubation.

Metastatic disease: a). ECOG performance status of 0-2 (or Karnofsky 60-100) testing is recommended Her2 / neu in case of metastatic adenocarcinoma. Recommended treatment is chemotherapy and / or BSC.

                               b). ECOG performance status ≥3 (or Karnofsky <60) who recommended treatment is best supportive care (BSC).

Therapeutic Modalities

Principles of Surgery

Before surgery staging should be performed to assess resectability through CT thorax and abdomen, general PET and ultrasound endoscopy. Esophageal resection should be considered for all patients physiologically adequate to support this intervention.

Siewert tumor type should be assessed in all patients with adenocarcinoma involving esogastric junction.

– Siewert type I: adenocarcinoma of the distal esophagus whose center is located 1cm above and 5 cm below the junction esogastric (JEG) anatomy.

– Sievert type II carcinoma of cardia true with center located at 1 cm above and 2 cm below the JEG.

– Siewert type III: subcardial carcinoma tumor center between 2cm and 5cm in JEG JEG infiltrating and distal esophagus below it. Siewert type I and II Treatment consists of a variety of surgical approaches. Siewert III lesions are considered gastric cancers and treat accordingly.

Laparoscopy can be useful in some patients in radiological detection of occult metastatic disease, particularly in patients with tumors Siewert type II and III.

Peritoneal positive cytology (performed in the absence of visible peritoneal implants) is associated with a poor prognosis and metastatic disease is defined as M1. Patients with advanced tumors, clinical T3 or N + should be considered for staging laparoscopic peritoneal lavage.

Carcinomas of the cervical esophagus or cervicotoracic at <5cm cricofaringes be treated by final chemoradiotherapy.

Eso- gastric esophageal cancers or resectable cancers:

– T1a tumors defined as tumors that involve the submucosa mucosa but are considered to EMR (endoscopic mucosal resection) or ablation plus esophagectomy in experienced centers.

– Tumors affecting the submucosa (T1b) or deeper can be treated with esophagectomy.

– T1-T3 tumors even when there are resectable lymph node invasion N +, although massive lymph node invasion or a contraindication multiple surgical and must take into account the relative age and performance status of the patient.

– T4 tumors involving the pericardium, pleura or diaphragm are resectable.

Unresectable esophageal cancers:

– T4 tumors with invasion of heart, great vessels, trachea, liver, pancreas, lung, spleen are unresectable.

– Most patients with bulky lymphadenopathy, multiple, although it must consider as inoperable account for age, performance status and treatment response.

– Patients with tumors of supraclavicular lymph node metastases JEG should be considered inoperable.

– Most patients with distant metastases are considered inoperable.

– In patients who cannot feed due to swallowing disorder and which must be maintained in a state of good nutrition during induction therapy of esophageal dilations be necessary or jejunostomy tube (gastrostomy not alter the integrity gastric needed for reconstruction).

– In patients fare esophagectomy is done induction chemoradiotherapy for a correct staging at least 15 nodes should be removed.

– Patients who develop localized disease after chemoradiotherapy resection can be considered for proper salvage esophagectomy.

Oesophageal resection is a major procedure with significant morbidity and mortality. Operative mortality is 10-20% and 20-40% mortality major. 85-90% of patients will die of recurrent disease.

Laser therapy may alleviate the obstruction and bleeding with a mortality rate of less than 1%.

15% of patients with malignant esophageal obstruction are candidates for placement of tubes to expand the stenosed part of the esophagus.

The limit expandable intraluminal diameter provides a larger and more patients were able to resume a normal diet after tube placement limiter.

Radiotherapy

Expanded tumor volume includes primary tumor and regional lymph nodes. Planned target volume includes upper and lower tumor plus 5cm tumor and 1,5-2cm in addition to radial edges. IMRT (intensity modulated radiotherapy) can be used in some cases to reduce the doses administered to the heart and lung. Normal lung should not receive more than 40 Gy. Personalized protection is needed to reduce doses to normal organs: heart 1/3 <50Gy, spinal cord <45Gy, kidney <20Gy, 60% of the liver <30Gy.

Dosage: 45 to 50.4 Gy preoperatively or postoperatively (1,8-2Gy / day)

Definitive therapy: 50 to 50.4 Gy (1,8-2Gy).

Radiation therapy has been used as an alternative to surgery in the primary treatment of esophageal cancer. It is used in patients with extensive disease and patients ineligible for surgery. Provide a temporary palliative. Survival at 1 year is 18% and at 5 years is 6%.

Supportive therapy

Discontinuation or dose reduction should be avoided. Careful monitoring of the patient and aggressive supportive therapy are preferable to treatment interruption. During irradiation of patients are investigated at least once a week noting vital signs, weight and vital signs. If caloric intake is less than 1500kcal / day oral and / or enteral nutrition should be considered.

When indicated it is recommended placement of nasogastric feeding tube or jejunostomy feeding to ensure caloric intake. Parenteral or oral hydration is necessary throughout the chemoradiotherapy.

Principles of Chemotherapy

Chemotherapy regimens should be chosen based on performance status, comorbidities medical term toxicity profile and Her2 / neu (for adenocarcinoma).

Using three drug regimens for advanced disease should be reserved for patients without medical problems, with good performance status (ECOG 0-1) and access to a common assessment of toxicity.

You can change regimes Category 1 or Category 2A or 2B regimes may be preferred to obtain a more favorable toxicity profile without compromising efficacy.

Dosages and timing of administration for any regime that is not derived from Category 1 regime, are a suggestion and are subject to appropriate modifications depending on the specific circumstances.

They allowed alternating chemotherapy regimens and timing of administration according to drug availability, preference and contraindications practice.

5 Fluorouracil and capecitabine can replace one another (except where specified). The infusion is the preferred route for 5 fluorouracil bolus administration in place.

Cisplatin and Oxaliplatin can substitute for one another depending on the specific toxic profile.

Preoperative chemoradiation for localized adenocarcinoma JEG is preferred therapeutic method. Preoperative chemotherapy is an option only for adenocarcinoma of the distal esophagus and JEG.

Cisplatin-based chemotherapy is most commonly used. Response rates vary  between 25% and 50%.

I Chemo-radiotherapy Preoperative

1. carboplatin AUC 2 IV day 1

Paclitaxel 50 mg / m2 IV day 1

Weekly for 5 weeks

2. cisplatin 15mg / m2 iv day 1-5

Fluorouracil 800mg IV 24 hours continuous infusion on days 1-5

Repeat in 21 days, 2 cycles

3. Cisplatin 30 mg / m2 IV day 1

Capecitabine 800mg / m2 po x 2 / day on days 1-5

Week for 5 weeks

II perioperative chemotherapy (3 cycles 3 cycles preoperatively and postoperatively)

1.ECF Epirubicin 50 mg / m2 IV day 1

Cisplatin 60 mg / m2 IV day 1

5 fluoruacil 200mg / m2 IV continuous infusion of 24 hours days 1-21

Repeat 3 weeks, 3 cycles are administered preoperatively and postoperatively 3 cycles

Two modified ECF

a) Epirubicin 50 mg / m2 IV day 1

Oxaliplatin 130 mg / m2 IV day 1

5 fluoruacil 200mg / m2 IV continuous infusion of 24 hours days 1-21

Repeat 3 weeks, 3 cycles are administered preoperatively and postoperatively 3 cycles

b) Epirubicin 50 mg / m2 IV day 1

Cisplatin 60 mg / m2 IV day 1

Capecitabine 625 mg / m 2 x 2 / day po days 1-21

Repeat 3 weeks, 3 cycles are administered preoperatively and postoperatively 3 cycles

c) Epirubicin 50 mg / m2 IV day 1

Oxaliplatin 130 mg / m2 IV day 1

Capecitabine 625 mg / m 2 x 2 / day po days 1-21

Repeat 3 weeks, 3 cycles are administered preoperatively and postoperatively 3 cycles

III Chemo-radiotherapy postoperative

————————————————– ——————

1,3 and 4 cycles before and after radiotherapy

1. 5 FU and leucovorin bolus

5 fluorouracil 425mg / m2 IV days 1-5

Leucovorin 20 mg / m 2 IV days 1-5

Repeat after 28 days

CLCL 2 (radiotherapy)

5 fluorouracil 400 mg / m2 IV days 1-4 and 31-33

Leucovorin 20 mg / m2 IV days 1-5 and 31-33

Repeat 35 days

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2. LV 5 FU2

1 cycle before and two after radiotherapy

Leucovorin 400 mg / m2 IV days 1, 2, 15, 16

5 FU 400mg / m2 IV days 1,2,15,16

5 FU 1200 mg / m2 IV continuous infusion for 24 hours on days 1,2,15,16

Repeat in 28 days

With radiotherapy

5 FU 200-250 mg / m2 IV continuous infusion for 24 hours on days 1-5

Repeat every week, 5 weeks

With radiotherapy

Capecitabine 625-825 mg / m2 po x 2 / day on days 1-5

Repeat weekly 5 weeks

III chemotherapy in metastatic esophageal cancer

For adenocarcinomas neu overexpressing HER2 Trastuzumab is recommended in combination with cisplatin and fluoropyrimidine. Not recommended association with anthracyclines.

At patients that overexpression of HER2 is associated Trastuzumab chemotherapy belts

Trastuzumab (with chemotherapy) 8mg / kg IV on day 1 of ciclului1 as a loading dose, then 6 mg / kg IV at 21 days.

1.       DCF Docetaxel 75 mg / m2 / day i.v. Day 1

Cisplatin 75 mg / m2 / day i.v. Day 1

5 fluoruacil 1000 mg / m 2 IV continuous infusion of 24 hours on days 1-5

It is repeated every 4 weeks.

————————————————– ——–

 2. DOF Docetaxel 50 mg / m2 / day i.v. Day 1

 Oxaliplatin 85 mg / m2 / day i.v. Day 1

 Leucovorin 200 mg / m2 IV day 1

 Fluoruacil May 2600 mg / m2 IV continuous infusion for 24 hours on day 1

 Repeat every 2 weeks.

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3. ECF Epirubicin 50 mg / m2 IV day 1

Cisplatin 60 mg / m2 IV day 1

5 fluoruacil 200mg / m2 IV continuous infusion of 24 hours days 1-21