Esophageal and Esophagogastric Junction Cancer

- Executive Summary

This guidance provides a data-supported approach to the primary prevention, screening, diagnosis, staging, treatment and follow up of patients diagnosed with Esophageal and Esophagogastric Junction Cancer. This guideline intended only for malignant esophageal tumors of epithelial origin, and not for any other non‐epithelial malignant tumors of the esophagus or metastatic malignant esophageal tumors.

- Recommendations

1.Primary preventions

         The following intervention may help to reduce the risk of esophageal cancer:

·        Treating gastroesophageal reflux disease (GERD) and Barrett's esophagus early

·        Prevention of injury to the esophagus

·        Avoidance of tobacco and alcohol

·        Avoidance of meat, processed food intake, hot beverages.

·        Diet rich in fruits and vegetables

·        Avoid obesity

       Good practice statement

      2.Secondary prevention (Screening)

•        Screening of esophageal and GEJ tumors in the general population is not cost effective and should not be done.

     Strong recommendation, high grade evidence (1).

     3.Diagnosis

         3A. All patients with new dysphagia, gastrointestinal bleeding, recurrent aspiration or emesis,

   weight loss and/or loss of appetite should undergo an upper gastrointestinal endoscopy.

     Strong recommendation, moderate grade evidence (2).

         3B. The location of the tumor relative to the lower incisors and GEJ, the length of the tumor, the

                extent of circumferential involvement, the presence of Barrett esophagus and the degree of

                obstruction should be carefully recorded to assist with treatment planning.

       Strong recommendation, moderate grade evidence (3)

         3C. Multiple biopsies, six to eight, using standard size endoscopy forceps should be performed to

                provide sufficient material for histologic and molecular interpretation. Larger forceps is

                recommended during surveillance endoscopy of Barrett esophagus for the detection of

               dysplasia.

     Strong recommendation, moderate grade evidence (4)

      3D. Diagnosis should be based on endoscopic biopsies (Chromo-endoscopy if available) with the

             histological tumor type classified according to the World Health Organization (WHO) criteria.

             The differentiation between esophageal SCC and AC is of prognostic and therapeutic relevance.                                  

      Strong recommendation, high grade evidence (5)

      3E. Laparoscopy + washings could be done to exclude occult metastatic disease involving

             peritoneum/diaphragm, especially in locally advanced (T3/T4) adenocarcinoma of the GEJ

             infiltrating the anatomical cardia.

             Good practice statement

4.Pathology

     4A. Histological diagnosis should be reported according to the WHO criteria.

 Good practice statement.

     4B. Immuno-histochemical staining including HER2 is recommended in poorly differentiated and   

            undifferentiated cancers when differentiation between SCC and AC using morphological

            characteristics is not possible.

Good practice statement.

5.Staging and risk assessment

      5A. Consider Multidisciplinary team meetings (MDTs) for patients with esophageal cancer.

            MDTs often include surgeons, radiologist, pathologists, medical oncologists, radiation

            oncologists, gastroenterologists, dietitians, rehabilitation physicians, palliative care specialists 

            and dedicated cancer nurse specialists.

Conditional recommendation, moderate grade evidence (6).

      5B. Staging should include a complete clinical examination, Complete blood count (CBC) and

           comprehensive chemistry profile, endoscopy, chest /abdomen /pelvis CT with oral and IV

           contrast.

  Strong recommendation, high grade evidence (7).

   5C. Consider 18F-fluoro-2-deoxy-D-glucose (FDG)-positron emission tomography (PET)

           in patients who are candidates for esophagectomy.

Conditional recommendation, moderate grade evidence (8).

5D. Endoscopic ultrasound (EUS) is recommended in early lesions in order to assess tumor depth and

      lymph node status in patients amenable to upfront surgery or candidates for tri-modality

      treatment (T3N0, T1-4a and any locoregional N). If not available refer to a specialized center.

 Strong recommendation, high grade evidence (9).

5E. We recommend bronchoscopy for tumors located at or above the carina in the initial staging,

       which can help in both surgery and radiotherapy treatments.

 Strong recommendation, moderate grade evidence (10).

5F. Esophageal cancer should be staged according to the American Joint Committee on Cancer

      AJCC/UICC TNM (tumor/node/metastases) 8th edition staging system

  Strong recommendation, high grade evidence (11).

6.Nutrition

6A. All patients with esophageal cancer should be screened regularly for malnutrition by evaluating   

       nutritional intake, weight change and BMI, beginning with diagnosis and repeated depending on the

       stability of the clinical situation. 

Strong recommendation, moderate grade evidence (12)

6B. Patients at nutritional risk should be promptly referred for comprehensive nutritional assessment and

        support clinical nutrition services.

 Good practice statement.

6C. We recommend that during radiotherapy an adequate nutritional intake should be ensured primarily

        by individualized nutritional counseling and/or with use of ONS, to avoid nutritional deterioration,  

         maintain intake and avoid radiotherapy interruptions.

    Strong recommendation, high grade evidence (13-14).

    6D. In patients at nutritional risk, we recommend feeding jejunostomy in operable patients and 

           percutaneous gastrostomy tubes for inoperable patients..

     Strong recommendation, moderate grade evidence (15-16).

     6E. We recommend that vitamins and minerals be supplied in amounts approximately equal to the   

            recommended daily allowance and discourage the use of high-dose micronutrients in the absence  

            of specific deficiencies.

      Strong recommendation, high grade evidence (17-18).

      6F. Parentral nutrition is only recommended if adequate oral/EN is not possible or insufficient e.g.  

            severe mucositis, intractable vomiting, ileus, severe malabsorption, protracted diarrhea or

            symptomatic gastrointestinal graft versus host disease.

Strong recommendation, moderate grade evidence (19-20).

      6G. For all cancer patients undergoing either curative or palliative surgery we recommend  

              management within an enhanced recovery after surgery (ERAS) program; within this program

              every patient should be screened for malnutrition and if deemed at risk, given additional

              nutritional support

   Strong recommendation, high Grade evidence (21).

7. Early disease (cT1 N0 M0)

7A. Multidisciplinary assessment and planning before any treatment is mandatory.

Good clinical practice

7B. We recommend endoscopic en bloc resection of lesions with intraepithelial high-grade dysplasia and most T1 tumors using either endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD).

Conditional recommendation, low grade evidence (22,23).

7C. Examination of the specimen provides accurate staging and endoscopic resection is considered definitive treatment, unless the deep resection margin is involved or there are significant risk factors for lymph node metastases (e.g. depth of invasion, lymph-vascular invasion, low differentiation grade, ulceration and large tumor size).

Conditional recommendation, Low quality evidence (22-25).

7D. Patients with involved deep endoscopic resection margins or significant risk factors for lymph node metastases should be offered further respective surgery with appropriate lymphadenectomy.

Conditional recommendation low grade evidence (25).

8. Locally advanced and resectable disease (cT2-T4 or cN1-3 M0)

Squamous cell carcinoma

8A. Locally advanced esophageal SCC should be treated with CRT (see 10D) followed by surgery, or definitive CRT with close surveillance and salvage surgery for local tumor persistence or progression.

Strong recommendation, high grade evidence (26,27).

8B. For patients not willing to undergo esophageal surgery or who are medically unfit for major surgery, definitive CRT should be preferred as CRT is superior to RT alone.

Strong recommendation, high grade evidence (28)

8C. Definitive CRT is recommended for cervically localized tumors where surgery would entail a laryngectomy

Good clinical practice

Adenocarcinoma

8D. We recommend the use of perioperative chemotherapy or neoadjuvant CRT (see 10D).

Strong recommendation, high grade evidence (29)

9. Surgery

9A. Esophageal surgery should be carried out in experienced centers only.

Good clinical practice

9B. We recommend Ivor Lewis procedure, (abdominal and right chest access is used, and reconstruction is carried out with a gastric tube conduit with esophagi-gastric anastomosis in the upper mediastinum) for esophagi-gastric tumors.

Strong recommendation, low grade evidence (30).

9C. We recommend McKeown procedure, (abdominal, right chest and cervical access is used with a similar reconstruction to the cervical esophagus) for esophageal tumors.

Strong recommendation, low grade evidence (30).

9D. We recommend transhiatal esophagectomy without transthoracic access with a similar reconstruction to the cervical esophagus in frail patients with distal tumors.

Strong recommendation, low grade evidence (30).

9E. The Siewert tumor type should be assessed in all patients with adenocarcinoma involving the EGJ.

The surgical approach for Siewert type 1 and type 2 should be similar to those described in esophageal cancer. Also, Siewert type III tumors should be considered gastric cancer and surgical approach for these tumors should be similar to those described in gastric cancer.

Good clinical practice.

10. Chemoradiotherapy

10A. The recommended traditional standard regimen for definitive CRT is four cycles of cisplatin5-FU (or capecitabine) combined with RT to a dose of 50.4 Gy in 28 fractions (or 50 Gy in 25 fractions).

Strong recommendation, high grade evidence (31)

10B. Weekly carboplatin - paclitaxel, as used in the CROSS regimen, combined with RT as definitive treatment is also recommended

Strong recommendation, high grade evidence (32)

10C. RT should be delivered using 3D conformal RT, but intensity modulated RT or volumetric arc therapy are preferred if available.

Strong recommendation, moderate grade evidence (33)

10D. We recommend against the use of RT dose >50.4 Gy in the definitive treatment of mid and distal 

         esophageal cancer specially if salvage esophagectomy is considered as a therapeutic strategy.

         We recommend the use of dose up to 60 Gy in cervical esophageal cancer.

Strong recommendation, high grade evidence (34,35).

11. Preoperative chemotherapy in adenocarcinoma of the esophagus and GEJ

11A. In patients with c T2, N0(with high-risk lesions: LVI≥ 3cm, poorly differentiated) or 

   cT1b-cT2N+ or cT3-cT4a, any N who are scheduled to receive surgery as the primary

   treatment, pre-operative chemotherapy regimens are recommended.

Strong recommendation, high grade evidence (36).

11B. FLOT regimen (4 cycles before and after surgery) is the preferred perioperative 

chemotherapy regimen for patients with good performance status. Cisplatin and 5-fluorouracil (CF) or oxaliplatin-based doublets FOLFOX or CAPOX are also valid options.

Strong recommendation, high grade evidence (37,38)

 12. Adjuvant chemotherapy in adenocarcinoma of the esophagus and GEJ (who have not 

             received preoperative chemotherapy)

12A. In patients operated without neoadjuvant treatment, postoperative CT is recommended,

        particularly in case of R1 resection, N+ lesion, or PT3, T4.

 Strong recommendation, high grade evidence (39).

12B. Postoperative chemotherapy with capecitabine and oxaliplatin is an option in patients with

       resectable esophageal or GEJ cancers who had not received preoperative therapy. FOLFOX regimen is also a valid option.  

   Strong recommendation, high grade evidence (40).

13. First- line systemic therapy for unresectable, metastatic, recurrent adenocarcinoma of the esophagus and GEJ.

     13A. Trastuzumab should be added to first-line chemotherapy for patients with advanced 

              HER2 overexpression-positive adenocarcinoma (combination with a fluoropyrimidine 

              and a platinum   agent is preferred).

     Strong recommendation, high grade evidence (41).

       13B. The preferred regimens for HER2-negative disease also include a fluoropyrimidine 

               (Fluorouracil or capecitabine) combined with either oxaliplatin or cisplatin

      Strong recommendation, high grade evidence (42).

13C.We recommend FOLFOX for elderly or frail patients due to lower toxicity.

        Strong recommendation, high grade evidence (42,43).

14. Second line and subsequent systemic therapy for unresectable, metastatic, recurrent   adenocarcinoma of esophagus and GEJ

        14A. Single-agent docetaxel, paclitaxel, and irinotecan are preferred options for second-line

             subsequent therapy

        Strong recommendation, high grade evidence (43,44).

14B.  FOLFIRI is a preferred treatment option that can be safely used in the second-line setting  

             if it was not previously used in first-line therapy.

        Strong recommendation, moderate grade evidence (45).

15. First line systemic therapy for unresectable, metastatic, recurrent esophageal and GEJ squamous cell carcinoma

15A.  Standard first-line Chemotherapy for advanced untreated   esophageal SCC is a 

           platinum-Fluoropyrimidine doublet chemotherapy.

        Strong recommendation, moderate grade evidence (46).

15B.  For patients with advanced esophageal SCC, who are unfit for full- dose 

              chemotherapy due to advanced age or frailty, dose-reduced oxaliplatin/capecitabine is 

              an alternative option.

             Strong recommendation, high grade evidence (47).

 16. Second line and subsequent systemic therapy for unresectable, metastatic and 

                   recurrent SCC

       Taxanes (paclitaxel or docetaxel) or irinotecan monotherapies are recommended as 

                    further-line treatment options

               Strong recommendation, moderate grade evidence (48,49).

- Acknowledgments

• We would like to acknowledge the Oncology Committee of the Egyptian Health Council (EHC) Guidelines, for adapting these Guidelines. 
• Chair of the Oncology Committee of Egyptian Health Council Guidelines: Prof Hussein Khaled. 
• The Oncology Committee Members: Emad Hamada, Samir Shehata, Hesham Elghazaly, Hesham Tawfik, Fouad Abuotaleb, Ebtesam Saad Eldin, Ihab Khalil, Khaled Abdelkarim, Lobna EZZ Elarab, Mary Gamal, Mohamed Abdel Mooti, Mohamed Gamil, Nervana Hussein, Ola Khorshid, Omar Sherif Omar, Rasha Fahmi, Rasha Shaltout, Yousri Wasef & Yousri Rostom.

·       Chair of the GIT Cancer Scientific Committee: Prof Yousri Rostom 

• The Esophageal and Esophagogastric Junction Cancer Scientific Group Members: (Alphabitical order): Ahmed EL Kassed, Doaa Gennena, Fouad Aboutaleb, Heba Fadlol,  Hussein Okasha, Khaled Abdelkarim, Manal EL Mahdy, Mary Gamal, Mohammed Eid, Omar S. Omar, and Yousri Wasef.

- Abbreviations

AC     adenocarcinoma

BE        Barret’s esophagus

BMI   body mass index

C        clinical

CHT  chemotherapy

CT      Computed tomography

EMR       Endoscopic Mucosal Resection

EN     enteral nutrition

ERAS   Enhanced recovery after surgery

ESD       Endoscopic submucosal dissection

ESGE     European Society of Gastrointestinal Endoscopy

EUS    Endoscopic Ultrasound

FNA/FNB   Fine needle aspiration/biopsy

GEJ       Esophagogastric Junction

GERD    Gastroesophageal reflux disease

GI      gastrointestinal

MRI    Magnetic Resonance imaging

ONS  oral nutritional supplements

PEG  percutaneous endoscopic gastrostomies

PET/CT     Positron Emission tomography

PN     parenteral nutrition

RHT   radiotherapy

SCC.   squamous cell carcinoma

- Introduction

Esophageal cancer is a familiar malignancy with high incidence and mortality, and the overall prognosis is poor. esophageal cancer has become an urgent global health challenge and the growing trend of esophageal cancer cases is expected to continue for the next two decades and beyond. In Egypt, there were an estimated 1543 new cases of esophageal cancer and 1510  deaths occurred because of this disease based on GLOBOCAN 2022.

- Purpose and scope

These guidelines are developed to improve the quality of care for Esophageal and GJ cancer via providing a uniform standard of care across the country to help in  primary prevention, screening, early diagnosis, treatment and follow up for esophageal and GEJ cancer so more optimal treatment options and improved clinical outcomes. 

- Target audience

Clinicians who are involved in the care and treatment of patients with esophageal and GEJ cancer, including medical oncologists, radiation oncologists, clinical oncologist, gastroenterologists, surgeons, clinical dietrition interventional radiologists, radiologists, pathologists, and palliative care specialists. 

- Methodology

A comprehensive search for guidelines was undertaken to identify the most relevant guidelines to consider for adaptation.   inclusion/exclusion criteria followed in the search and retrieval of guidelines to be adapted: 

-  Selecting only evidence-based guidelines (guidelines must include a report on systematic literature searches and explicit links between individual recommendations and their supporting evidence). - Selecting only national and/or international guidelines. 

-  Specific range of dates for publication (using Guidelines published or updated 2015 and later). 

-  Selecting peer reviewed publications only.

-  Selecting guidelines written in English language.

-  Excluding guidelines written by a single author not on behalf of an organization to be valid and comprehensive, a guideline ideally requires multidisciplinary input. 

-  Excluding guidelines published without references as the panel needs to know whether a thorough literature review was conducted and whether current evidence was used in the preparation of the recommendations. 

All retrieved Guidelines were screened and appraised using AGREE II instrument (www.agreetrust.org) by at least two members. the panel decided a cutoff point or rank the guidelines (any guideline scoring above 50% on the rigor dimension was retained)  The NCCN, ESMO, NICE guidelines are the main sources used while formulating the national guidelines for bladder cancer (1-3). 

Ø  Evidence assessment 

According to WHO handbook for Guidelines we used the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach to assess the quality of a body of evidence, develop and report recommendations. GRADE methods are used by WHO because these represent internationally agreed standards for making transparent recommendations. Detailed information on GRADE is available through the on the following sites: 

. GRADE working group: https://www.gradeworkinggroup.org/

 . GRADE online training modules: http://cebgrade.mcmaster.ca/

 . GRADE profile software: http://ims.cochrane.org/revman/gradepro 

Table 1: Quality of evidence in GRADE  

Table 2: Significance of the four levels of evidence

Table 3: Factors that determine How to upgrade or downgrade the quality of evidence  

Ø  The strength of the recommendation 

The strength of a recommendation communicates the importance of adherence to the recommendation: 

Strong recommendations: With strong recommendations, the guideline communicates the message that the desirable effects of adherence to the recommendation outweigh the undesirable effects. This means that in most situations the recommendation can be adopted as policy. 

Conditional recommendations: These are made when there is greater uncertainty about the four factors above (Table 2) or if local adaptation must account for a greater variety in values and preferences, or when resource use makes the intervention suitable for some, but not for other locations. This means that there is a need for substantial debate and involvement of stakeholders before this recommendation can be adopted as policy. 

When not to make recommendations; when there is lack of evidence on the effectiveness of an intervention, it may be appropriate not to make a recommendation.

- Clinical indicators for monitoring

For patients newly diagnosed with esophageal & EGJ cancer:

• laboratory evaluation (CBC, LFT, and KFT)  
• imaging
• endoscopic biopsy for pathological confirmation &IHC

- Research gaps

§  Systematic inclusion of cost-benefit analyses in clinical trial with collection of health economic analysis such as incremental cost effectiveness ratio in order to facilitate clinical decision-making. 

§  Predictive biomarkers: response to specific systemic targeted therapies and immunotherapy. 

§  Improve models for pre-clinical testing of novel drugs. 

§  Search for tools to assess quality of life and in clinical trials.

§  Dietary supplements, nutritional counselling, physical activity recommendations and psychological support as part of an integrative healthcare approach to care for people with esophageal cancer. 

- Update of this guideline

§  This guideline will be updated whenever there is new evidence. 

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- Annexes

AJCC Cancer Staging Manual, Eighth Edition (2017)