Management of Malignancy of the Lower One-Third of the Esophagus

What Is It?

Figure: Stage distribution and 5-year survival for esophageal cancer. Localized disease = 48.8% 5-year survival; distant disease = only 5.6%

STEP 1 - Initial Assessment and Staging Workup

A. History and Physical Examination

• Main symptom: progressive dysphagia (first solids, then liquids)
• Weight loss, odynophagia (pain on swallowing), regurgitation, hoarseness (suggests recurrent laryngeal nerve involvement)
• History of GERD / Barrett's esophagus (risk factor for adenocarcinoma)
• Tobacco and alcohol use (risk for SCC)

B. Endoscopy (Upper GI Endoscopy + Biopsy)

• First investigation
• Confirms diagnosis by tissue biopsy
• Assesses tumor location, length, and relation to GEJ
• Determines histologic type (adenocarcinoma vs SCC)

C. TNM Staging (AJCC 8th Edition - from Sabiston)

D. Staging Investigations (in order)

1. CT scan of chest, abdomen, and pelvis - assesses local invasion and distant metastases (lung, liver, adrenals)
2. FDG-PET/CT scan - detects occult distant metastases not seen on CT; changes management in ~20% of patients
3. Endoscopic Ultrasound (EUS) - gold standard for T and N staging; determines depth of tumor invasion and regional lymph node involvement
4. Diagnostic laparoscopy - for GEJ (junction) tumors to exclude peritoneal metastases

STEP 2 - Multidisciplinary Team (MDT) Discussion

• Surgeon (thoracic/upper GI)
• Medical oncologist
• Radiation oncologist
• Gastroenterologist
• Radiologist
• Pathologist

STEP 3 - Treatment Based on Stage

GROUP A: Very Early Disease (Tis, T1a - High-grade dysplasia or mucosal cancer)

1. Endoscopic Mucosal Resection (EMR) - removes the full thickness of mucosa for lesions <2 cm
2. Endoscopic Submucosal Dissection (ESD) - for larger lesions or when en bloc removal needed
3. Radiofrequency Ablation (RFA) - burns away remaining Barrett's tissue after resection
4. EMR successfully eradicates 91-98% of T1a cancer (Sabiston)
5. After successful endoscopic therapy - regular endoscopic surveillance

Esophagectomy is reserved for patients with high-risk features (lymphovascular invasion, deep submucosal invasion >500 µm, or poor differentiation) or failed endoscopic therapy.

GROUP B: Locally Advanced Resectable Disease (T2-T3, N0-N1, M0)

Step 3B-1: Neoadjuvant (Pre-operative) Chemoradiotherapy (CRT) - STANDARD OF CARE

• Regimen: Carboplatin + Paclitaxel given weekly, concurrent with 41.4 Gy radiation in 23 fractions
• Then surgery 4-6 weeks after completing CRT
• Results: Rate of complete (R0) resection = 92% vs 69% surgery alone
• Median overall survival: 48.6 months (CRT + surgery) vs 24 months (surgery alone)
• In adenocarcinoma patients: pathologic complete response (pCR) in ~23%

• The FLOT4 trial showed perioperative FLOT (5-FU + Leucovorin + Oxaliplatin + Docetaxel) was superior to ECF/ECX regimens
• 4 cycles pre-op + 4 cycles post-op
• Median OS: 50 months (FLOT) vs 35 months (ECF)
• Preferred by many centers for lower esophageal/GEJ adenocarcinoma

Step 3B-2: Restaging Before Surgery

• FDG-PET/CT at 5-8 weeks after completing neoadjuvant therapy - mandatory to confirm no new distant disease before proceeding to surgery

Step 3B-3: Surgery - ESOPHAGECTOMY

1. Mobilize and resect the esophagus with adequate proximal margin
2. Remove regional lymph nodes (2-field lymphadenectomy - mediastinal + abdominal)
3. Create a gastric conduit (stomach tubularized to replace the esophagus)
4. Anastomose (join) conduit to remaining esophagus in the chest (Ivor Lewis)

Step 3B-4: Adjuvant (Post-operative) Therapy

• If pCR (no cancer left in surgical specimen): surveillance only
• If residual disease after neoadjuvant CRT: Adjuvant Nivolumab (immunotherapy, PD-1 inhibitor) for 1 year - shown to improve disease-free survival in the CheckMate-577 trial
• If perioperative chemotherapy (FLOT) used: complete remaining 4 cycles post-surgery

GROUP C: Unresectable or Patient Unfit for Surgery

• Standard regimen: Cisplatin + 5-FU concurrent with 50.4 Gy radiation
• Aim: cure without surgery
• Complete response rates ~25-30%; long-term survival is achievable in responders

GROUP D: Metastatic / Stage IV Disease

Systemic Chemotherapy (First-line):

• HER2-positive adenocarcinoma: Trastuzumab (Herceptin) + chemotherapy (ToGA trial)
• HER2-negative / PD-L1 positive: Nivolumab + chemotherapy (CheckMate-649 trial) - first-line immunotherapy + chemo
• Standard chemo backbone: FOLFOX (5-FU + Oxaliplatin) or CF (Cisplatin + 5-FU)

Palliative Procedures for Dysphagia:

1. Endoscopic stenting - self-expanding metal stent (SEMS) - fastest relief of dysphagia
2. Palliative radiotherapy - helps shrink tumor to relieve obstruction
3. Laser therapy / PDT (Photodynamic therapy) - recanalize the lumen
4. Feeding jejunostomy or gastrostomy - nutritional support

STEP 4 - Surgical Complications to Know (Post-Esophagectomy)

STEP 5 - Follow-Up and Surveillance

• History, examination, and CT scan every 3-6 months for first 2 years, then annually
• Endoscopy if symptoms suggest recurrence
• PET-CT if recurrence suspected
• Nutritional support - dietitian involvement throughout
• Watch for and treat complications of surgery and treatment

Summary Flowchart (Simple)

Lower 1/3 Esophageal Cancer Confirmed
           |
           v
   STAGING (CT + PET + EUS)
           |
    ________|________
   |                 |
Tis/T1a           T2-T3/N+ (resectable)
   |                 |
Endoscopy          Neoadjuvant CRT (CROSS)
(EMR/ESD)          or Periop chemo (FLOT)
   |                 |
Surveillance    Esophagectomy (Ivor Lewis)
                     |
             Residual disease?
               YES -> Nivolumab
               NO  -> Surveillance
                     |
             Metastatic?
               -> Systemic chemo ± immunotherapy
               -> Palliative stenting/RT

Key Points to Remember

• Lower 1/3 cancer = mainly adenocarcinoma (from Barrett's/GERD)
• EUS is gold standard for T and N staging
• CROSS trial regimen (carboplatin/paclitaxel + 41.4 Gy) is standard neoadjuvant CRT
• FLOT is the preferred perioperative chemo for GEJ/lower esophageal adenocarcinoma
• Surgery = Ivor Lewis esophagectomy for lower third tumors
• Goal of surgery = R0 resection + ≥15 lymph nodes
• Nivolumab adjuvant therapy if residual disease after CRT + surgery (CheckMate-577)
• Metastatic disease: check HER2 status - trastuzumab if HER2-positive
• Palliative: SEMS stenting is fastest treatment for dysphagia in metastatic disease

Fecal Calprotectin in Brucellosis

Short Answer: It may NOT be elevated - even when GI involvement is present.

What the Evidence Says

• 4 months of colicky abdominal pain, diarrhea, night sweats, anorexia
• Fever, splenomegaly, anaemia, leukopenia
• Abdominal CT showed diffuse thickening of the ileum and swollen locoregional lymph nodes - i.e., clear evidence of intestinal involvement
• Blood cultures and Brucella serology were positive (Rose-Bengal positive, ELISA IgM positive, Huddleson titer 1:320)

Why Is This Clinically Important?

• 89-98% sensitive and 81-91% specific for IBD (Crohn's disease, ulcerative colitis)
• Elevated in colorectal cancer, intestinal infections with mucosal disruption (e.g., Clostridioides difficile, Campylobacter, Salmonella)

1. Brucellosis causes a different type of intestinal inflammation - it is primarily a systemic reticuloendothelial infection (affecting liver, spleen, lymph nodes, bone marrow), not a primary mucosal/luminal intestinal disease
2. The ileal thickening likely reflects reactive lymphoid hyperplasia and submucosal inflammation rather than mucosal granulocyte infiltration - which is what calprotectin measures
3. Brucella species invade macrophages (intracellular pathogen) - the dominant immune response is monocyte/macrophage-mediated, not a neutrophilic mucosal response
4. Normal calprotectin + CT ileal thickening in a patient from an endemic area = think brucellosis as a differential, not IBD

Practical Takeaway

Limitation