Esophageal and EGJ Cancers

Work up:

• CT CAP with IV and oral contrast

• EGD with biopsy

• Endoscopic Ultrasound (EUS)

  • If no M1 unresectable disease

• Bronchoscopy for tumors at/above the carina to rule out fistula

• PET/CT scan

• Consider staging laparoscopy:

  • To assess peritoneal metastases (mostly in signet ring histology)

  • At least 15 LNs need to be removed during surgery

• Biomarker testing:

  • MSI/MMR in all newly diagnosed patients

  • PD-L1 in all newly diagnosed patients

  • HER-2 if advanced/metastatic adenocarcinoma is documented/suspected

  • CLDN18.2 if advanced/metastatic adenocarcinoma is documented/suspected

  • NGS should be considered

Staging:

T1a: Tumor invades the lamina propria or muscularis mucosae

T1b: Tumor invades the submucosa

T2: Tumor invades the muscularis propria

T3: Tumor invades the adventitia

T4: Tumor invades the adjacent structures

Pathology:

• SCC:

  • Usually in the upper part of esophagus

  • Predominates in Eastern Europe and Asia

  • Associated with tobacco use, EtOH use, achalasia, lye ingestion, plummer-vinson syndrome

• Adenocarcinoma:

  • Usually in the lower part of the esophagus/GE Junction

  • Common in North America and Western Europe

  • Associated with obesity, GERD and Barrett's esophagus

Treatment:

High-grade dysplasia/ Barrett's esophagus:

• Endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) → radiofrequency ablation (RFA)

  • Complete eradication of intestinal metaplasia in ~73% of patients

  • + Anti reflux therapy → repeat EGD in 6-12 months

• Esophagectomy is reserved for patients with characteristics unfavorable for endoscopic therapy

Localized/ Locally Advanced Resectable:

• Carcinoma in situ (Tis), T1a:

  • ESD or esophagectomy

• T1b:

  • Esophagectomy

• T2N0 (if low risk, <3 cm, well diff, not located in cervical esophagus):

  • Esophagectomy

• T2N0 (if high risk, LVI, >3 cm, poorly diff, located in cervical esophagus) or anyTN+:

  • Neoadjuvant chemoRT (Carbo/taxol) → Surgery (CROSS trial)

    • If residual pathologic disease after neoadjuvant chemoRT → adjuvant Nivolumab x1 year (Checkmate-577)

    • Preferred approach for SCC (SCC is more radiosensitive)

  • Perioperative FLOT ± durvalumab → Surgery (ESOPEC, Matternhorn trial)

    • Perioperative FLOT: 4 cycles pre-op + 4 cycles post-op

      • FLOT: Fluorouracil (5-FU), Leucovorin, Oxaliplatin, Docetaxel

    • Preferred approach for adenocarcinoma (superior overall survival)

    • If not candidate for FLOT: Replace with perioperative FOLFOX or CAPEOX

      • FOLFOX: Leucovorin (Folinic acid), Fluorouracil (5-FU), Oxaliplatin

      • CAPEOX: Capecitabine, Oxaliplatin

  • Definitive chemoRT:

    • Those who decline surgery

    • Preferred for cervical esophagus

  • Consider IO if MSI-H/dMMR

Metastatic Disease/Locally Advanced Unresectable:

If SCC:

Immunotherapy is independent of PD-L1 status.

• First line:

  • ChemoIO: Preferred

    • FOLFOX (or CAPEOX) + PD-L1 inhibitor (Nivo, Pembro, Tislelizumab)

  • If IO is contraindicated:

    • FOLFOX (or CAPEOX)

    • Carboplatin (or Cisplatin) ± Taxol

  • If MSI-high/dMMR (independent of PD-L1 status):

    • Pembrolizumab

    • Dostarlimab

    • Nivolumab + Ipilimumab

  • If NTRK gene fusion positive:

    • Entrectinib

    • Larotrectinib

    • Repotrectinib:

• Subsequent line:

  • Nivolumab

  • Docetaxel/ Paclitaxel

  • Irinotecan +/- 5FU

  • Tislelizumab-jsgr

  • Dabrafenib/Trametinib (if BRAF V600E mutated)

  • Selpercatinib (if RET positive)

If adenocarcinoma:

Immunotherapy depends on PD-L1 status, unlike SCC.

• HER-2 positive:

  • If PD-L1 CPS ≥1:

    • FOLFOX (or CAPEOX) + Trastuzumab + Pembro

  • If PD-L1 CPS 0 or IO is contraindicated:

    • FOLFOX (or CAPEOX) + Trastuzumab

• HER-2 negative:

  • If PD-L1 CPS ≥1:

    • FOLFOX (or CAPEOX) + PD-L1 inhibitor (Nivo, Pembro, Tislelizumab)

  • If PD-L1 CPS 0 or IO is contraindicated:

    • FOLFOX (or CAPEOX)

  • If CLDN 18.2 positive:

    • FOLFOX (or CAPEOX) + Zolbetuximab

  • If MSI-high/dMMR (independent of PD-L1 status):

    • Pembrolizumab

    • Dostarlimab

    • Nivolumab + Ipilimumab

  • If NTRK gene fusion positive:

    • Entrectinib

    • Larotrectinib

    • Repotrectinib:

• Subsequent line:

  • Ramucirumab + Paclitaxel

  • Enhertu (if HER-2 positive)

  • Docetaxel/ Paclitaxel

  • Irinotecan ± 5-FU

  • Dabrafenib/ Trametinib (if BRAF V600E mutated)

  • Selpercatinib (if RET positive)

  • Lonsurf (trifluridine/Tipiracil): 3rd line