# Guideline Resource Unit

# Background
There are two common distinct histologies of esophageal cancer. Chronic gastroesophageal reflux predisposes to Barrett's metaplasia and the development of adenocarcinoma 1 . Typically, it develops within the distal esophagus; in North America, it is now more prevalent than the other histology, squamous cell carcinoma 2 . The recognized risk factors for squamous cell carcinoma include tobacco and alcohol exposure. 3 Guideline Questions 

# Target Population
The recommendations outlined in this guideline apply to adults over the age of 18 years with esophageal cancer, including both squamous cell and adenocarcinoma. Different principles may apply to pediatric patients.

# Recommendations
Recommended Diagnostic Work-Up
- Esophagogastroduodenoscopy with biopsy establishes the tumour's location (distance from incisors) and histology. - An augmented CT scan of the thorax, abdomen and pelvis also helps to establish the tumour's Guideline Resource Unit location, depth of penetration into the esophageal wall, invasion into adjacent structures, and involvement of regional and non-regional lymph nodes. Metastatic disease confers an incurable situation for which only palliative maneuvers would be appropriate.
- Blood work identifies any end-organ dysfunction that may preclude the safe administration of chemotherapy. - if no metastatic disease is seen on the baseline CT, F-fluorodeoxy-D-glucose (FDG) PET scan can complement an augmented CT scan and help to identify radiologically-occult metastatic disease  .
Optional Investigations:
- In the absence of metastatic disease (based upon the above investigations), the following tests may be of additional value if it would influence treatment decisions: o Bronchoscopy if tumor is located at or above the level of the carina.  o Endoscopic ultrasound (establishes the depth of penetration into the esophageal wall, invasion into adjacent structures, and involvement of regional and non-regional lymph nodes) for clinically node negative, T1 or T2 tumors.  o Pulmonary function testing (required prior to surgical resection and may be necessary prior to chemoradiotherapy). - Bone scans can be done for patients suspected of having bone metastases, CT head or MRI for patients suspected of having brain metastases

# Stage Information
Tumors involving the esophagogastric junction (EGJ) with the tumor epicenter no more than 2 cm into the proximal stomach are staged as esophageal rather than gastric cancers. In contrast, EGJ tumors with their epicenter located more than 2 cm into the proximal stomach are staged as stomach cancers (refer to gastric cancer guideline). Guideline Resource Unit Regional- Lymph Node Involvement (N Stage): N0 No regional lymph node involvement N1 Involvement of one or two regional lymph nodes N2 Involvement of three to six regional lymph nodes N3 Involvement of seven or more regional lymph nodes gastric cancer for all other tumours (epicenter in stomach more than 5 cm from the esophagogastric junction and without extension into esophagus).  
0 0 0 NA Any Stage 0 is 0 NA Stage IA 0 0 1 1 Any Stage IA 1a 0 1 1a 0 0 X Any 1a 0 X Stage IB 1a 0 0 2-3 Any Stage IB 1a 0 2 1b 0 0 1-3 Any 1b 0 1-2 1b 0 0 X Any 1b 0 X 2 0 0 1 Any Stage IC 1 0 3 Stage IIA 2 0 0 2-3 Any 2 0 1-2 2 0 0 X Any Stage IIA 2 0 3 3 0 0 Any L 2 0 X 3 0 0 1 U/M Stage IIB 1 1 Any Stage IIB 3 0 0 2-3 U/M 3 0 Any 3 0 0 X Any Stage IIIA 1 2 Any 3 0 0 Any X 2 1

# Goals of Therapy
To render the patient free of disease, to relieve symptoms (e.g.: dysphagia), and to improve or prolong survival, if possible.
Guideline Resource Unit Recommendations 14 :
- Complete the work-up (as described above).
- For patients who do not have metastatic disease: o Early referral to a surgeon trained in esophageal surgery is important to assess for resectability. o Patients should be referred for a multidisciplinary discussion including radiation oncologists and medical oncologists prior to surgery for patients with resectable disease. - Assess the degree of dysphagia and consult with a dietician to optimize the patient's nutritional status. Consider placement of a nasogastic (NG) feeding tube. If the NG feeding tube insertion is technically difficult, placement should be performed radiographically. - In a curative situation, avoid placement of an endoluminal stent as it increases the complication and mortality rate with radical chemoradiotherapy 15 . - Patients who receive preoperative chemoRT should have a CT scan prior to surgery. In certain cases, FDG-PET can provide an assessment of response but should only be done if clinically warranted  . - There is limited data to support the use of imaging after definitive chemoRT or after surgical resection for non-metastatic patients, however, individualized discussion regarding imaging after definitive chemoRT or after surgical resection for non-metastatic patients may be appropriate in select clinical cases. - For patients on palliative systemic treatment, CT chest, abdomen, and pelvis should be done every 2-3 months depending on the clinical situation. - Consider treatment on a clinical trial, if available.  - Multidisciplinary discussion regarding chemoRT vs chemotherapy recommended For gastric cancers, refer to the Gastric Cancer Guidelines. For more details, refer to table 2. Note: EGJ was redefined in the AJCC 8th edition: adenocarcinomas with epicenters no more than 2cm into the gastric cardia are staged as esophageal adenocarcinomas, and those extending further are staged as stomach cancers. 55 Table 3. Curative therapy recommendations for patients with esophageal cancer.

# Stage Recommendations TisN0 or T1aN0 Disease
Endoscopic Therapy for Superficial Cancers: - Endoscopic mucosal resection (EMR) 22, , submucosal dissection (ESD) and various ablation techniques (e.g.: photo-dynamic therapy 23 , argon plasma coagulation, radiofrequency ablation 24 , cryotherapy) can preserve the integrity of the esophagus and provide a potentially curative option for superficial cancers. - Provided careful endoscopic surveillance can be performed, consider for patients with favorable mucosal tumours- who are interested in an esophagus-sparing approach or who are elderly, with multiple comorbidities, or otherwise high surgical risk. *Note: Favorable mucosal tumours include non-invasive (in situ) lesions or disease that invades into the mucosa (but not submucosa). Invasion into deepest third of submucosa 49%
Esophagectomy:
- Resect disease if both technically and medically feasible. Aim to achieve an "R0"resection (no gross or microscopic residual tumour). - Post-operative morbidity and survival are significantly better when surgery is completed in an experienced centre 25 . T1bN0 Disease

# Preferred

# Esophagectomy:
- Esophagectomy is the preferred treatment choice for fit patients with superficial esophageal cancers invading the submucosa.

# Alternate
Endoscopic therapy:
- For most patients with favorable intramucosal tumors, who are interested in an esophagus-sparing approach or are older with multiple comorbidities or are otherwise high surgical risk are candidates for endoscopic resection rather than surgical resection.
- If a patient is not medically operable, declines surgery, or is not a candidate for EMR/ESD, refer to  17 . This protocol improves the R0 resection rate (92% versus 69%) and overall survival (HR 0.657, CI95% 0.495-0.871, p = 0.003) when compared to surgery alone. It prolongs median survival from 24.0 months to 49.4 months and increases the one-, two-, three-, and five-year survival rates from 70% to 82%, 50% to 67%, 44% to 58%, and 34% to 47% respectively. It offers a pCR rate of 23%. 75% of the patients enrolled had adenocarcinoma. About 25% of patients had disease at the esophagogastric junction. - Aim to achieve an "R0"resection (no gross or microscopic residual tumour).
- Post-operative morbidity and survival are significantly better when surgery is completed in an experienced centre 25 .

# Post-operative Adjuvant Therapy:
The Checkmate 577 trial randomized patients who received preoperative CROSS chemoradiotherapy followed by surgery with residual pathological disease (> ypT1 and/or >ypN1) to nivolumab (240 mg/m 2 IV q 2 weekly for up to 1 year) or placebo.
- Note that esophagectomy alone is an option in low risk cT2N0 patients. 56 

# Preferred

# Alternate

# Guideline Resource Unit
Disease free survival (DFS) was significantly improved in the nivolumab group compared to the placebo (median 22.4 months versus 11.0 months, HR 0.69, 95% CI 0.56-0.86, p=0.003). 48 Nivolumab is not currently funded for this indication in Alberta.
- No randomized trial (and at least two meta-analyses 26,27 has demonstrated a survival advantage for preoperative chemoradiotherapy over chemotherapy alone - One network meta-analysis concluded that there is a survival benefit for neoadjuvant chemoradiotherapy over neoadjuvant chemotherapy 28 . 

# Alternatives for patients not candidates for FLOT
- MAGIC: When compared to surgery alone in patients with good performance status (ECOG 1) and T2-4N0-3M0 adenocarcinoma of the distal third of the esophagus, gastro-esophageal junction, or stomach, peri-operative chemotherapy improves the five-year progression-free (HR 0.66, CI95% 0.53-0.81, p < 0.001) and overall survival (from 23.0% to 36.3%, HR 0.74, CI95% 0.59-0.93, p = 0.008 19 ).
- Pre-Operative Phase: Three three-week cycles of Epirubicin 50 mg/m 2 and Cisplatin 60 mg/m 2 IV on day one plus a continuous intravenous infusion of 5-Fluorouracil 200 mg/m 2 /day over twenty-one days.

# Chemotherapy
- Operative Phase: Perform surgical resection with oncologic principles.
- Post-Operative Phase: As described in the pre-operative phase (above). Alternative for patients not candidates for epirubicin (MAGIC): cisplatin 5FU has been evaluated in patients with operable adenocarcinoma of the esophagus and gastroesophageal junction - The FFCD trial six peri-operative cycles of Cisplatin and infusional fluorouracil improves the five-year disease-free survival (34% versus 19%, HR 0.65, CI95% 0.48-0.89, p = 0.003), overall survival (38% versus 24%, HR 0.69, CI95% 0.50-0.95, p = 0.02), and rate of curative resection (84% versus 73%, p = 0.04) compared to surgery alone. Chemotherapy was given every 4 weeks and was comprised of cisplatin 100 mg/m 2 IV on day one plus 5-Fluorouracil 800 mg/m 2 /day over days one through five days, every 28 days 29 . - The OE5 trial randomized patients to 4 cycles of ECX or 2 cycles of cisplatin and infusional fluorouracil prior to surgery. The pathological complete response rate was higher in the ECX arm compared to cisplatin/fluoruracil (11% vs 3%). However, there was no significant difference in overall survival (23.4 months vs 26.1 months, HR 0.90 0.77-1.05, p = 0.19) 21 - These regimens require placement of a central venous catheter (CVC), peripherally inserted central catheter (PICC line), or port. - For patients in whom it is not possible to resect disease due to medical or technical issues, refer to Table 3 Guideline Resource Unit 

# Preferred Recommendation
In whom it is not possible to resect disease due to medical or technical issues: Primary ('Definitive') Chemoradiotherapy: - The two treatment options are: - Preferred: Deliver 5,000 cGy in twenty-five fractions over five weeks plus Oxaliplatin 85 mg/mg 2 IV and Leucovorin 200 mg/m 2 IV followed by 5-Fluorouracil 400 mg/m 2 IV bolus followed by 5-Fluorouracil 800 mg/m 2 /day over days one and two on weeks one, three, five, seven, nine, and eleven. This regimen is associated with less mucositis, alopecia, and renal toxicity plus numerically fewer toxic and sudden deaths but without a difference in overall survival, progression-free survival, and pCR rate 30 . (Level 1 evidence) - Alternatively deliver 5,000 cGy in twenty-five fractions over five weeks plus Cisplatin 75 mg/m 2 IV over one hour and 5-Fluorouracil 4,000 mg/m 2 IV over ninetysix hours on weeks one, five, eight, and eleven. This protocol offers an five-year overall survival rate of 27% (compared to 0% for radiotherapy alone) 31 . Note: 82% of the patients enrolled had squamous cell carcinoma of the esophagus. - These regimens require placement of a central venous catheter (CVC), peripherally inserted central catheter (PICC line), or port.

# Alternate
Radiotherapy Alone:
- Consider for patients who decline chemotherapy or in whom chemotherapy is deemed unsafe.

# Guideline Resource Unit

# Recommendations for Incurable Situations
Provide palliative maneuvers to maintain and/or improve quality of life:
- Relieve pain, bleeding, and/or dysphagia with radiotherapy (30 Gy in 10 fractions is preferred, alternatively 40 Gy in 15 fractions or 50 Gy in 20 fractions). 2. Consider placement of an endoluminal stent 32,33 or photodynamic therapy 34 to relieve dysphagia. 3. Patients with advanced esophageal cancer who have a self expanding metal stent inserted for the primary management of dysphagia do not gain additional benefit from concurrent palliative radiotherapy (Level 1 evidence). Palliative radiotherapy may be indicated for bleeding. 49 4. Consider palliative chemotherapy to control disease and prolong survival in patients with a satisfactory performance status (ECOG  2) 35-41 5. Consider treatment on a clinical trial if available. 6. Consider early referral to palliative care. (Symptom management guidelines can be found here). 7. Refer to dieticians and consider psychosocial referral. Early interdisciplinary care with the addition of psychologists and dieticians improved survival compared to standard oncology care in phase III trial of untreated patients with metastatic upper GI cancers (median overall survival 14.8 months vs 11.9 months, HR 0.68; 95% CI 0.51-0.9,; = 0.021). 58 

# Metastatic Adenocarcinoma of the Esophagus or Gastroesophageal Junction
Many phase III clinical trials for metastatic gastric cancer also included patients with adenocarcinoma of the gastroesophageal junction. By extrapolation, patients with metastatic adenocarcinoma of the esophagus and gastroesophageal junction are treated as per metastatic gastric cancers. .
Evaluation of HER2 protein expression via immunohistochemistry or in situ hybridization is recommended to select patients with metastastic esophageal/gastroesophageal adenocarcinoma for trastuzumab based treatment 42 .

# Metastatic Squamous Cell Cancer of the Esophagus
There is limited data to guide systemic therapy for metastatic squamous cell cancer of the esophagus. The combination of a platinum with a fluoropyrimidine is the preferred first line regimen 42,43 .
- The benefit was seen in all patients, but primarily driven by the patients with squamous cell cancer. 50 Pembrolizumab is not currently funded for this indication in Alberta.

# Guideline Resource Unit
Second Line Therapy 47 The ATTRACTION-3 study randomized patients with advanced esophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy to nivolumab versus chemotherapy of physician's choice (paclitaxel 100 mg/m2 q week for 6 weeks followed by 1 week off) or docetaxel (75 mg/m2 q3 weeks). Overall survival was significantly improved in the nivolumab group compared to chemotherapy (median 10.9 months versus 8.4 months, HR 0.77, 95% CI 0.62-0.96; p=0.019). There was no significant difference in progression free survival for nivolumab versus chemotherapy (median 1.7 months versus 3.4 months, HR 108, 95% CI 087-1 34). The prespecified interaction analysis indicated no significant interaction of treatment effect by PD-L1 status. Nivolumab is not currently available on the Alberta CancerCare Drug Benefit List.
Taxane based chemotherapy would be a reasonable alternative option and is available through the Alberta CancerCare Drug Benefit List.

# Development and Revision History
This guideline was reviewed and endorsed by the Alberta GI Tumour Team. Members of the Alberta GI Tumour Team include surgical oncologists, radiation oncologists, medical oncologists, gastroenterologists, nurses, pathologists, and pharmacists. Evidence was selected and reviewed by a working group comprised of members from the Alberta GI Tumour Team, external participants identified by the Working Group Lead, and a Knowledge Management Specialist from the Guideline Resource Unit. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook.
This guideline was originally developed in 2010.

# Maintenance
A formal review of the guideline will be conducted in 2022. If critical new evidence is brought forward before that time, however, the guideline working group members will revise and update the document accordingly. 

# Abbreviations