With advances in state-of-the-art technology, trendy diagnostic and prognostic molecular markers, and cutting-edge surgical techniques, the overall survival for patients with many types of cancers has improved. However, there is a disconnect between esophageal cancer and the acceleration in cancer care seen in other malignancies. Based on data reported by Surveillance, Epidemiology, and End Results Program (SEER), the 5-year survival rate for patients with esophageal cancer is only 19.9% . Poor prognosis is likely due to an overwhelming number of patients with advanced disease during the time of diagnosis, and is also reflective of the unsatisfactory outcomes from current treatments.
In this article, we will review the epidemiology and the recently revised staging of esophageal and esophagogastric junction cancers. We will discuss the current roles of endoscopic resection, surgery, radiation therapy, and systemic therapy used individually, or as components of multimodality treatment. We will describe the changes in treatment landscape with targeted therapy and immunotherapy. The focus of clinical investigations continues to shift from the traditional empiric chemotherapy to more individualized treatments based on molecular oncology and use of immunotherapy. Further identification of prognostic values may help clarify the optimal approach to treatment and management for patients with esophageal cancer, and hopefully improve survival.
Upper midline laparotomy and left neck incisions allow dissection of the middle and distal thirds of the esophagus. Thoracic esophagus is mobilized and blunt dissection through the diaphragmatic hiatus is performed. A gastric tube is created, and anastomosis is made with cervical esophagus. Some studies have shown that transhiatal esophagectomy is associated with a lower 30-day morbidity and mortality compared to the transthoracic approach; however, some studies report better oncologic outcomes with en bloc transthoracic esophagectomy [20-23].
This technique involves right thoracotomy and abdominal laparotomy. Esophagus is divided at or above the level of the azygous vein. Gastric tube, like the one employed in transhiatal esophagectomy, is created and anastomosed at this location.
Three incisions are made, combining thoracotomy, laparotomy, and neck incision. Thoracotomy allows en bloc resection including esophagus and mediastinal and upper abdominal lymph nodes. Laparotomy is utilized for abdominal exploration and stomach mobilization for gastric conduit. Lastly, neck incision allows exposure to create an esophagogastric anastomosis.
A minimally invasive technique, as compared to the aforementioned open esophagectomy approaches, provides smaller incisions, less blood loss, decreased postoperative pain, faster return to bowel function, decreased ICU and hospital stay, and improved cosmetic appearance compared to the conventional open procedures . With this technique, surgeons are able to perform with or without thoracoscopic dissection of intrathoracic esophagus.
Table 1: Esophagectomy Techniques.
- SEER Cancer Stat Facts: Esophageal Cancer. National Cancer Institute. Bethesda.
- Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, et al. (2015) Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136: E359-386.
- Dulak AM, Stojanov P, Peng S, Lawrence MS, Fox C, et al. (2013) Exome and whole-genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity. Nat Genet 45: 478-486.
- Arnold M, Laversanne M, Brown LM, Devesa SS, Bray F (2017) Predicting the Future Burden of Esophageal Cancer by Histological Subtype: International Trends in Incidence up to 2030. Am J Gastroenterol 112: 1247-1255.
- Cancer Genome Atlas Research N, Analysis Working Group: Asan U, Agency BCC, Greater Poland Cancer Centre, Harvard Medical School, et al. (2017) Integrated genomic characterization of oesophageal carcinoma. Nature 541: 169-175.
- Rice TW, Gress DM, Patil DT, Hofstetter WL, Kelsen DP, et al. (2017) Cancer of the esophagus and esophagogastric Junction-Major changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin 67: 304-317.
- Rice TW, Apperson-Hansen C, DiPaola LM, Semple ME, Lerut TE, et al. (2016) Worldwide Esophageal Cancer Collaboration: clinical staging data. Dis Esophagus 29: 707-714.
- Berry MF, Zeyer-Brunner J, Castleberry AW, Martin JT, Gloor B, et al. (2013) Treatment modalities for T1N0 esophageal cancers: a comparative analysis of local therapy versus surgical resection. Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 8: 796-802.
- National Comprehensive Cancer Network. Esophageal and Esophagogastric Junction 2019.
- Rustgi AK, El-Serag HB (2014) Esophageal carcinoma. N Engl J Med 371: 2499-2509.
- Manner H, Pech O (2015) Measurement of the tumor invasion depth into the submucosa in early adenocarcinoma of the esophagus (pT1b): Can microns be the new standard for the endoscopist? United European gastroenterology journal 3: 501-504.
- Peyre CG, Hagen JA, DeMeester SR, Van Lanschot JJ, Hölscher A, et al. (2008) Predicting systemic disease in patients with esophageal cancer after esophagectomy: a multinational study on the significance of the number of involved lymph nodes. Ann Surg 248: 979-985.
- Rizk NP, Ishwaran H, Rice TW, Chen LQ, Schipper PH, et al. (2010) Optimum lymphadenectomy for esophageal cancer. Ann Surg 251: 46-50.
- Groth SS, Virnig BA, Whitson BA, DeFor TE, Li ZZ, et al. (2010) Determination of the minimum number of lymph nodes to examine to maximize survival in patients with esophageal carcinoma: data from the Surveillance Epidemiology and End Results database. J Thorac Cardiovasc Surg 139: 612-620.
- Birkmeyer JD, Siewers AE, Finlayson EV, Stukel TA, Lucas FL et al. (2002) Hospital volume and surgical mortality in the United States. N Engl J Med 346: 1128-1137.
- Dimick JB, Wainess RM, Upchurch GR, Jr., Iannettoni MD, Orringer MB (2005) National trends in outcomes for esophageal resection. Ann Thorac Surg 79: 212-216.
- Moraca RJ, Low DE (2006) Outcomes and health-related quality of life after esophagectomy for high-grade dysplasia and intramucosal cancer. Arch Surg 141: 545-549.
- Viklund P, Wengstrom Y, Rouvelas I, Lindblad M, Lagergren J (2006) Quality of life and persisting symptoms after oesophageal cancer surgery. Eur J Cancer 42: 1407-1414.
- Reynolds JV, McLaughlin R, Moore J, Rowley S, Ravi N, et al. (2006) Prospective evaluation of quality of life in patients with localized oesophageal cancer treated by multimodality therapy or surgery alone. Br J Surg 93: 1084-1090.
- Hulscher JB, Tijssen JG, Obertop H, van Lanschot JJ (2001) Transthoracic versus transhiatal resection for carcinoma of the esophagus: a meta-analysis. Ann Thorac Surg 72: 306-313.
- Hulscher JB, van Sandick JW, de Boer BPL, Tijssen JGP, et al. (2002) Extended transthoracic resection compared with limited transhiatal resection for adenocarcinoma of the esophagus. N Engl J Med 347: 1662-1669.
- Omloo JM, Lagarde SM, Hulscher JB, Reitsma JB, Fockens P, et a. (2007) Extended transthoracic resection compared with limited transhiatal resection for adenocarcinoma of the mid/distal esophagus: five-year survival of a randomized clinical trial. Ann Surg 246: 992-1000.
- Omloo JM, Law SY, Launois B, Le Prisé E, Wong J, et al. (2009) Short and long-term advantages of transhiatal and transthoracic oesophageal cancer resection. Eur J Surg Oncol 35: 793-797.
- Santillan AA, Farma JM, Meredith KL, Shah NR, Kelley ST (2008) Minimally invasive surgery for esophageal cancer. J Natl Compr Canc Netw 6: 879-884.
- Shapiro J, van Lanschot JJB, Hulshof M, van Hagen P, van Berge Henegouwen MI, et al. (2015) Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial. Lancet Oncol 16: 1090-1098.
- Newaishy GA, Read GA, Duncan W, Kerr GR (1982) Results of radical radiotherapy of squamous cell carcinoma of the oesophagus. Clin Radiol 33: 347-352.
- Okawa T, Kita M, Tanaka M, Ikeda M (1989) Results of radiotherapy for inoperable locally advanced esophageal cancer. Int J Radiat Oncol Biol Phys 17: 49-54.
- Sun DR (1989) Ten-year follow-up of esophageal cancer treated by radical radiation therapy: analysis of 869 patients. Int J Radiat Oncol Biol Phys 16: 329-334.
- Sjoquist KM, Burmeister BH, Smithers BM, Zalcberg JR, Simes RJ, et al. (2011) Survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal carcinoma: an updated meta-analysis. Lancet Oncol 12: 681-692.
- Pasquali S, Yim G, Vohra RS, Mocellin S, Nyanhongo D, et al. (2017) Survival After Neoadjuvant and Adjuvant Treatments Compared to Surgery Alone for Resectable Esophageal Carcinoma: A Network Meta-analysis. Ann Surg 265: 481-491.
- Oppedijk V, Gaast Avd, Lanschot JJB, van Hagen P, van Os R, et al. (2014) Patterns of Recurrence After Surgery Alone Versus Preoperative Chemoradiotherapy and Surgery in the CROSS Trials. Journal of Clinical Oncology 32: 385-391.
- Tepper J, Krasna MJ, Niedzwiecki D, Hollis D, Reed CE, et al. (2008) Phase III trial of trimodality therapy with cisplatin, fluorouracil, radiotherapy, and surgery compared with surgery alone for esophageal cancer: CALGB 9781. J Clin Oncol 26: 1086-1092.
- Mariette C, Dahan L, Mornex F, Maillard E, Thomas PA, et al. (2014) Surgery alone versus chemoradiotherapy followed by surgery for stage I and II esophageal cancer: final analysis of randomized controlled phase III trial FFCD 9901. J Clin Oncol 32: 2416-2422.
- Messager M, Mirabel X, Tresch E, Paumier A, Vendrely V, et al. (2016) Preoperative chemoradiation with paclitaxel-carboplatin or with fluorouracil-oxaliplatin-folinic acid (FOLFOX) for resectable esophageal and junctional cancer: the PROTECT-1402, randomized phase 2 trial. BMC Cancer 16: 318.
- Smalley SR, Benedetti JK, Haller DG, Hundahl SA, Estes NC, et al. (2012) Updated Analysis of SWOG-Directed Intergroup Study 0116: A Phase III Trial of Adjuvant Radiochemotherapy Versus Observation After Curative Gastric Cancer Resection. Journal of Clinical Oncology 30: 2327-2333.
- Herskovic A, Martz K, al-Sarraf M, Leichman L, Brindle J, et al. (1992) Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus. N Engl J Med 326: 1593-1598.
- Cooper JS, Guo MD, Herskovic A, Macdonald JS, Martenson JA Jr, et al. (1999) Chemoradiotherapy of locally advanced esophageal cancer: long-term follow-up of a prospective randomized trial (RTOG 85-01). Radiation Therapy Oncology Group. JAMA 281: 1623-1627.
- Minsky BD, Pajak TF, Ginsberg RJ, Pisansky TM, Martenson J, et al. (2002) INT 0123 (Radiation Therapy Oncology Group 94-05) phase III trial of combined-modality therapy for esophageal cancer: high-dose versus standard-dose radiation therapy. J Clin Oncol 20: 1167-1174.
- Bedenne L, Michel P, Bouche O, Milan C, Mariette C, et al. (2007) Chemoradiation followed by surgery compared with chemoradiation alone in squamous cancer of the esophagus: FFCD 9102. J Clin Oncol 25: 1160-1168.
- Vellayappan BA, Soon YY, Ku GY, Leong CN, Lu JJ, et al. Chemoradiotherapy versus chemoradiotherapy plus surgery for esophageal cancer. Cochrane Database Syst Rev 8: CD010511.
- Li QQ, Liu MZ, Hu YH, Liu H, He ZY, et al. (2010) Definitive concomitant chemoradiotherapy with docetaxel and cisplatin in squamous esophageal carcinoma. Dis Esophagus 23: 253-259.
- Ruppert BN, Watkins JM, Shirai K, Wahlquist AE, Garrett-Mayer E, et al. (2010) Cisplatin/Irinotecan versus carboplatin/paclitaxel as definitive chemoradiotherapy for locoregionally advanced esophageal cancer. Am J Clin Oncol 33: 346-352.
- Conroy T, Galais MP, Raoul JL, Bouché O, Gourgou-Bourgade S, et al. (2014) Definitive chemoradiotherapy with FOLFOX versus fluorouracil and cisplatin in patients with oesophageal cancer (PRODIGE5/ACCORD17): final results of a randomised, phase 2/3 trial. Lancet Oncol 15: 305-314.
- Kelsen DP, Ginsberg R, Pajak TF, Sheahan DG, Gunderson L, et al. (1998) Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer. N Engl J Med 339: 1979-1984.
- Medical Research Council Oesophageal Cancer Working G (2002) Surgical resection with or without preoperative chemotherapy in oesophageal cancer: a randomised controlled trial. Lancet 359: 1727-1733.
- Boige V, Pignon J, Saint-Aubert B, Lasser P, Conroy T, et al. (2007) Final results of a randomized trial comparing preoperative 5-fluorouracil (F)/cisplatin (P) to surgery alone in adenocarcinoma of stomach and lower esophagus (ASLE): FNLCC ACCORD07-FFCD 9703 trial. Journal of Clinical Oncology 25: 4510-4510.
- Alderson D, Langley RE, Nankivell MG, Blazeby JM, Griffin M, et al. (2015) Neoadjuvant chemotherapy for resectable oesophageal and junctional adenocarcinoma: Results from the UK Medical Research Council randomised OEO5 trial (ISRCTN 01852072). Journal of Clinical Oncology 33: 4002-4002.
- Kidane B, Coughlin S, Vogt K, Malthaner R (2015) Preoperative chemotherapy for resectable thoracic esophageal cancer. Cochrane Database Syst Rev 2015: CD001556.
- Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, et al. (2006) Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 355: 11-20.
- Ychou M, Boige V, Pignon JP, Conroy T, Bouché O, et al. (2011) Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial. J Clin Oncol 29: 1715-1721.
- Al-Batran S-E, Homann N, Schmalenberg H, Kopp HG, Haag GM, et al. (2017) Perioperative chemotherapy with docetaxel, oxaliplatin, and fluorouracil/leucovorin (FLOT) versus epirubicin, cisplatin, and fluorouracil or capecitabine (ECF/ECX) for resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma (FLOT4-AIO): A multicenter, randomized phase 3 trial. Journal of Clinical Oncology 35: 4004-4004.
- Al-Batran SE, Homann N, Pauligk C, Goetze TO, Meiler J, et al. (2019) Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2019.
- Van Cutsem E, Moiseyenko VM, Tjulandin S, Majlis A, Constenla M, et al. (2006) Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin Oncol 24: 4991-4997.
- Flejou JF, Paraf F, Muzeau F, Fékété F, Hénin D, et al. (1994) Expression of c-erbB-2 oncogene product in Barrett's adenocarcinoma: pathological and prognostic correlations. J Clin Pathol 47: 23-26.
- Reichelt U, Duesedau P, Tsourlakis M, Quaas A, Link BC, et al. (2007) Frequent homogeneous HER-2 amplification in primary and metastatic adenocarcinoma of the esophagus. Mod Pathol 20: 120-129.
- Vakiani E (2015) HER2 testing in gastric and gastroesophageal adenocarcinomas. Adv Anat Pathol 22: 194-201.
- Mimura K, Kono K, Hanawa M, Mitsui F, Sugai H, et al. (2005) Frequencies of HER-2/neu expression and gene amplification in patients with oesophageal squamous cell carcinoma. Br J Cancer 92: 1253-1260.
- Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, et al. (2010) Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 376: 687-697.
- Soularue E, Cohen R, Tournigand C, Zaanan A, Louvet C, et al. (2015) Efficacy and safety of trastuzumab in combination with oxaliplatin and fluorouracil-based chemotherapy for patients with HER2-positive metastatic gastric and gastro-oesophageal junction adenocarcinoma patients: a retrospective study. Bull Cancer 102: 324-331.
- Fondevila C, Metges JP, Fuster J, Grau JJ, Palacín A, et al. (2004) p53 and VEGF expression are independent predictors of tumour recurrence and survival following curative resection of gastric cancer. Br J Cancer 90: 206-215.
- Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, et al. (2014) Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 383: 31-39.
- Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, et al. (2014) Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol 15: 1224-1235.
- Sasaki T, Hiroki K, Yamashita Y (2013) The Role of Epidermal Growth Factor Receptor in Cancer Metastasis and Microenvironment. BioMed Research International 2013: 8.
- Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, et al. (2009) Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol 27: 663-671.
- Lordick F, Kang YK, Chung HC, Salman P, Oh SC, et al. (2013) Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): a randomised, open-label phase 3 trial. Lancet Oncol 14: 490-499.
- Waddell T, Chau I, Cunningham D, Gonzalez D, Okines AF, et al. (2013) Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): a randomised, open-label phase 3 trial. Lancet Oncol 14: 481-489.
- Tebbutt NC, Price TJ, Ferraro DA, Wong N, Veillard AS, et al. (2016) Panitumumab added to docetaxel, cisplatin and fluoropyrimidine in oesophagogastric cancer: ATTAX3 phase II trial. Br J Cancer 114: 505-509.
- Chen L, Xiong Y, Li J, Zheng X, Zhou Q, et al. (2017) PD-L1 Expression Promotes Epithelial to Mesenchymal Transition in Human Esophageal Cancer. Cell Physiol Biochem 42: 2267-2280.
- Kelly RJ (2017) Immunotherapy for Esophageal and Gastric Cancer. Am Soc Clin Oncol Educ Book 37: 292-300.
- Muro K, Chung HC, Shankaran V, Geva R, Catenacci D, et al. (2016) Pembrolizumab for patients with PD-L1-positive advanced gastric cancer (KEYNOTE-012): a multicentre, open-label, phase 1b trial. Lancet Oncol 17: 717-726.
- Fuchs CS, Doi T, Jang RW, et al. (2018) Safety and Efficacy of Pembrolizumab Monotherapy in Patients with Previously Treated Advanced Gastric and Gastroesophageal Junction Cancer: Phase 2 Clinical KEYNOTE-059 Trial. JAMA Oncol 4: e180013.
- Doi T, Piha-Paul SA, Jalal SI, Saraf S, Lunceford J, et al. (2018) Safety and Antitumor Activity of the Anti-Programmed Death-1 Antibody Pembrolizumab in Patients with Advanced Esophageal Carcinoma. J Clin Oncol 36: 61-67.
- Kojima T, Muro K, Francois E, Hsu CH, Moriwaki T, et al. (2019) Pembrolizumab versus chemotherapy as second-line therapy for advanced esophageal cancer: Phase III KEYNOTE-181 study. Journal of Clinical Oncology 37: 2-2.
- Shitara K, Ozguroglu M, Bang YJ, Di Bartolomeo M, Mandalà M, et al. (2018) Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial. Lancet 392: 123-133.
- Timmermann B, Kerick M, Roehr C, Fischer A, Isau M, et al. (2010) Somatic mutation profiles of MSI and MSS colorectal cancer identified by whole exome next generation sequencing and bioinformatics analysis. PLoS One 5: e15661.
- Eshleman JR, Lang EZ, Bowerfind GK, Parsons R, Vogelstein B, et al. (1995) Increased mutation rate at the hprt locus accompanies microsatellite instability in colon cancer. Oncogene 10: 33-37.
- Dolcetti R, Viel A, Doglioni C, Russo A, Guidoboni M, et al. (1999) High prevalence of activated intraepithelial cytotoxic T lymphocytes and increased neoplastic cell apoptosis in colorectal carcinomas with microsatellite instability. Am J Pathol 154: 1805-1813.
- Peltomaki P (2005) Lynch syndrome genes. Fam Cancer 4: 227-232.
- Boland CR, Goel A (2010) Microsatellite instability in colorectal cancer. Gastroenterology 138: 2073-2087.
- Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, et al. (2015) PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. New England Journal of Medicine 372: 2509-2520.
- Fuchs CS, Doi T, Jang RW-J, Muro K, Satoh T, et al. (2017) KEYNOTE-059 cohort 1: Efficacy and safety of pembrolizumab (pembro) monotherapy in patients with previously treated advanced gastric cancer. Journal of Clinical Oncology 35: 4003-4003.
- Kang Y-K, Satoh T, Ryu M-H, Chao Y, Kato K, et al. (2017) Nivolumab (ONO-4538/BMS-936558) as salvage treatment after second or later-line chemotherapy for advanced gastric or gastro-esophageal junction cancer (AGC): A double-blinded, randomized, phase III trial. Journal of Clinical Oncology 35: 2-2.
- Janjigian YY, Ott PA, Calvo E, Kim JW, Ascierto PA, et al. (2017) Nivolumab ± ipilimumab in pts with advanced (adv)/metastatic chemotherapy-refractory (CTx-R) gastric (G), esophageal (E), or gastroesophageal junction (GEJ) cancer: CheckMate 032 study. Journal of Clinical Oncology 35: 4014-4014.
- Bang YJ, Ruiz EY, Van Cutsem E, Lee KW, Wyrwicz L, et al. (2018) Phase III, randomised trial of avelumab versus physician's choice of chemotherapy as third-line treatment of patients with advanced gastric or gastro-oesophageal junction cancer: primary analysis of JAVELIN Gastric 300. Ann Oncol 29: 2052-2060.
- Bang YJ, Cho JY, Kim YH, Kim JW, Di Bartolomeo M, et al. (2017) Efficacy of Sequential Ipilimumab Monotherapy versus Best Supportive Care for Unresectable Locally Advanced/Metastatic Gastric or Gastroesophageal Junction Cancer. Clin Cancer Res 23: 5671-5678.