Management of Esophago-Gastric Junction Carcinoma: A Narrative Multidisciplinary Review
Abstract
:Simple Summary
Abstract
1. Introduction
2. Lymphatic Flow of EGJ Cancer
2.1. Mediastinal Lymph Node
2.2. Perigastric Lymph Node
2.3. Para-aortic Lymph Node
3. Principles of surgery of EGJ Cancer
Surgical Management of EGJ Cancer Must Respect Some Principles
4. Type of Surgical Procedures
4.1. Thoracoabdominal Esophagectomy (Ivor Lewis Esophagogastrectomy)
4.2. Thoracoabdominal Esophagectomy with Cervical Anastomosis (McKeown Esophagectomy or 3-hole Esophagectomy)
4.3. Transhiatal Esophagogastrectomy
4.4. Transhiatal Distal Esophagectomy with Total Gastrectomy
4.5. Transhiatal vs. Transthoracic Esophagectomy
4.6. Total vs. Partial Gastrectomy
5. The Role of Endoscopic Management
6. Multidisciplinary Treatment of Locally Advanced EGJ Cancer
6.1. Preoperative Chemoradiation
6.2. Perioperative Chemotherapy
6.3. Current Guidelines: The Choice of the Best Multimodal Approach
6.4. Definitive Chemoradiation
6.5. Adjuvant Multimodal Treatments
- EGJ adenocarcinoma should be evaluated for adjuvant therapy in R0 resection if pathologically proved positive nodes are found or in the case of the pT3–pT4a stage. R0 pT2 pN0 EGJ adenocarcinoma should be evaluated for adjuvant chemoradiation only if high-risk factors are detected, such as poor differentiation, high-grade disease, lymphovascular/perineural invasion, or in the case of patients younger than 50 years.
- R1 resected EGJ adenocarcinoma without any preoperative treatment should be evaluated for chemoradiation. In the case of R2 resection, chemoradiation or palliative management is recommended.
- Complete the three cycles of chemotherapy if received perioperatively after surgery in the case of negative margins.
- Undergo re-resection or chemoradiation—if not previously performed—in the case of microscopic positive margins.
- Undergo chemoradiation—if not previously performed—or best supportive care in the case of macroscopic positive margins.
7. Future Perspectives and Ongoing Studies
- A phase III study that compares, in patients affected by esophageal or EGJ adenocarcinoma, neoadjuvant chemoradiation with perioperative chemotherapy followed by surgery is the ESOPEC trial, and the primary endpoint is the overall survival [64]; this study evaluates, on the chemotherapy arm, four cycles of FLOT-schedule chemotherapy in preoperative settings and for cycles of the same chemotherapy after surgery versus neoadjuvant chemoradiotherapy according to the CROSS protocol [58].
- Neo-AEGIS [65] is another randomized phase III trial that compares, in patients affected by adenocarcinoma of the esophagus or EGJ, perioperative radiotherapy according to the MAGIC scheme [61] with neoadjuvant chemoradiation according to the CROSS study [58]; the survival outcomes are the measured primary endpoint.
- In the PREACT study, perioperative S-1- and oxaliplatin-based chemotherapy is compared to neoadjuvant chemoradiotherapy in EGJ adenocarcinoma and gastric cancer [66]; the primary endpoint is represented by the 3-year disease-free survival of patients.
- The RACE study is a randomized phase III trial that studies progression-free survival in resectable patients affected by EGJ who are randomized to receive four cycles of preoperative FLOT chemotherapy followed by surgery and four cycles of postoperative chemotherapy versus two cycles of FLOT chemotherapy plus chemoradiation (with fluoropyrimidine and oxaliplatin concomitant to 45 Gy radiotherapy) followed by surgery and four cycles of postoperative FLOT chemotherapy [67].
- The TOPGEAR trial compares, in patients affected by EGJ or gastric cancer, perioperative chemotherapy according to the MAGIC scheme (three preoperative and three postoperative cycles) with a multimodal approach based on the same scheme of perioperative chemotherapy plus fluoropyrimidine-based chemoradiation (two cycles plus chemoradiation in the preoperative phase, and three cycles in the postoperative phase) [68].
- The PROTECT trial is a prospective randomized phase II study that evaluates different chemotherapy regimens (FOLFOX versus paclitaxel and carboplatin) as concomitant to the same radiotherapy schedule (41.4 Gy), measuring the short-term complete resection rate and safety in the neoadjuvant treatment of esophageal and EGJ (Siewert I-II) cancer [69].
- As has been the case with many other malignancies, where the introduction of immunotherapy has changed the standard of care and patient prognosis, in the multimodal treatments of EGJ cancer, the evaluation of the role of immune checkpoints is in progress. The main evidence is directed toward assessing the role of immunotherapy in gastric and gastroesophageal cancer, cumulatively recruiting patients with gastric cancer and EGJ cancer [72]. Moreover, the KEYNOTE975 trial aims to evaluate the impact of pembrolizumab in combination with definitive FOLFOX or Cisplatin plus fluoropyrimidine chemoradiation to treat patients affected by esophageal or EGJ cancer [73].
Name of the Trial | Phase | Site | Endpoint | Setting | Enrollment | Arm A | Arm B | Estimated Completation Data |
---|---|---|---|---|---|---|---|---|
ESOPEC [64] | III | EC ADC EGJ ADC (Sievert I-III) | OS | NeoAdj | 438 | Neoadjuvant CRT (CROSS) RT (41.4Gy/23fractions) and concurrent CT with Carboplatin and Paclitaxel (5 weeks). | Perioperative CT (FLOT) 5-Fluorouracil, Leucovorin, Oxaliplatin and Docetaxel. Repetition every 2 weeks (d15, q2w). 4 neoadjuvant cycles (8 weeks) prior to surgery and 4 adjuvant cycles (8 weeks) postoperatively are given. | June 2024 |
Neo-AEGIS [65] | III | EC ADC EGJ ADC | OS | NeoAdj | 366 | Perioperative CT (Modified MAGIC or FLOT) Modified MAGIC: 3 cycles of CT pre-surgery and 3 cycles post-surgery. Epirubicin, cisplatin or oxaliplatin and a choice of 5-fluorouracil or capecitabine. Each cycle lasts 21 days. FLOT: 8 cycles of CT in total, 4 cycles of CT pre-surgery and a further 4 cycles of CT post-surgery. Each cycle of CT lasts 14 days/2 weeks. | Neoadjuvant CRT (CROSS) RT (41.4Gy/23 fractions) and concurrent CT with Carboplatin and Paclitaxel (5 weeks) prior to surgery. | March 2023 |
PREACT [66] | III | GC ADCEGJ ADC (Sievert II-III) | DFS | NeoAdj | 682 | Perioperative CT (SOX) 3 cycles of neoadjuvant CT with S-1 and oxaliplatin Surgery 3 cycles of adjuvant CT with S-1 and oxaliplatin | Neoadjuvant CRT 1 cycles of S-1 + Concomitant S1 RT (45 Gy in 25 fr) + 1 cycles of S-1 Surgery 3 cycles of adjuvant CT with S-1 and oxaliplatin | December 2023 |
PROTECT [69] | II | EC (located under the carena, beyond 25 cm from the incisors) EGJ (Siewert I-II) | CRR and severe (grade ≥ 3) postop. morbidity/mortality | NeoAdj | 106 | Neoadjuvant CRT (FOLFOX) RT (41.4Gy/23 fractions) and concurrent every two weeks CT with Folfox scheme (5-Fluorouracil; Oxaliplatin and Folinic acid). | Neoadjuvant CRT (Carbo-Paclitaxel) RT (41.4Gy/23 fractions) and concurrent weekly CT with Carboplatin and Paclitaxel. | June 2023 |
RACE [67] | III | EGJ ADC | PFS | NeoAdj | 340 | Perioperative CT (FLOT) 4 cycles of neoadjuvant CT with FLOT | Perioperative CT + Neoadjuvant CRT 2 cycles of neoadjuvant FLOT. CRT consists of oxaliplatin 45 mg/m² weekly and continuous infusional 5-FU 225 mg/m² plus concurrent radiotherapy given in 5/week fractions with 1.8 Gy to a dose of 45 Gy over 5 weeks. 4 cycles of adjuvant FLOT | May 2028 |
TOPGEAR [68] | III | GC ADC EGJ ADC (Sievert II-III) | OS | NeoAdj | 574 | Perioperative CT (ECF) 3 Cycles of epirubicin, cisplatin and 5-FU Surgery 3 Cycles of epirubicin, cisplatin and 5-FU | Perioperative CT + Neoadjuvant CRT 2 cycles of neoadjuvant ECF. CRT consists of continuous infusional 5-FU 200 mg/m² (or Capecitabine 825 mg/m²) plus concurrent radiotherapy given in 5/week fractions with 1.8 Gy to a dose of 45 Gy over 5 weeks. 3 cycles of adjuvant ECF. | December 2026 |
KEYNOTE O59 [73] | II–III | EC ADC EC SCC EGJ | OS EFS | Def | 700 | Pembrolizumab + Definitive CRT 8 cycles of Pembrolizumab 200 mg q3w + 5 cycles 400 mg q6w Def CRT FOLFOX of FP (Cisplatin + 5-FU) and 50 vs. 60 Gy in 25 vs. 30 fractions. | Placebo + Definitive CRT 8 cycles of Placebo q3w + 5 cycles q6w Def CRT FOLFOX of FP (Cisplatin + 5-FU) and 50 vs. 60 Gy in 25 vs. 30 fractions. | February 2027 |
8. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Conflicts of Interest
References
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Lymph Node Station | Median of Reported Incidence |
---|---|
No. 1 (Right cardiac) | 40.9% |
No. 2 (Left cardiac) | 25.2% |
No. 3 (Lesser gastric curve) | 43.4% |
No. 4 (Greater gastric curve) 4sa 4sb 4d | 2.3% 2.2% 0.4% |
No. 5 (Supra-pyloric) | 1.2% |
No. 6 (Infra-pyloric) | 0.9% |
No. 7 (Left gastric artery) | 25.0% |
No. 8 (Common hepatic artery) | 4.9% |
No. 9 (Coeliac axis) | 10.9% |
No. 10 (Splenic hilus) | 4.7% |
No. 11 (Splenic artery) 11p 11d | 15.4% 2.9% |
No. 12 (hepato-duodenal ligament) | 0.7% |
No. 16 (Para-aortic) | 4.8% |
Abdominal hiatal field No. 19 No. 20 | 4.9% 1.5% |
Upper mediastinal No. 105 No. 106 | 0.5% 0% |
Middle mediastinal No. 107 No. 108 No. 109 | 0.4% 2.0% 1.7% |
Lower mediastinal No. 110 No. 111 No. 112 | 12.0% 3.7% 1.9% |
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Tondolo, V.; Casà, C.; Rizzo, G.; Leone, M.; Quero, G.; Alfieri, V.; Boldrini, L.; Bulajic, M.; Corsi, D.; Micciché, F. Management of Esophago-Gastric Junction Carcinoma: A Narrative Multidisciplinary Review. Cancers 2023, 15, 2597. https://doi.org/10.3390/cancers15092597
Tondolo V, Casà C, Rizzo G, Leone M, Quero G, Alfieri V, Boldrini L, Bulajic M, Corsi D, Micciché F. Management of Esophago-Gastric Junction Carcinoma: A Narrative Multidisciplinary Review. Cancers. 2023; 15(9):2597. https://doi.org/10.3390/cancers15092597
Chicago/Turabian StyleTondolo, Vincenzo, Calogero Casà, Gianluca Rizzo, Mariavittoria Leone, Giuseppe Quero, Virginia Alfieri, Luca Boldrini, Milutin Bulajic, Domenico Corsi, and Francesco Micciché. 2023. "Management of Esophago-Gastric Junction Carcinoma: A Narrative Multidisciplinary Review" Cancers 15, no. 9: 2597. https://doi.org/10.3390/cancers15092597