Infectious complications after esophagectomy for esophageal cancer: Comparison
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Please note this is a comparison between Version 2 by Bruce Ren and Version 1 by Hiroya Takeuchi.

Despite advances in the perioperative management of esophagectomy, it is still a highly invasive procedure for esophageal cancer and is associated with severe postoperative complications. The two major postoperative infectious complications after esophagectomy are pulmonary complications and anastomotic leakage. 

  • postoperative complication
  • esophageal cancer
  • esophagectomy
  • CXCL8
  • CXCR2

1. Introduction

Esophageal cancer is the sixth leading cause of cancer-related mortality globally because of its high malignant potential and poor prognosis [1]. The postoperative 5-year survival rate in patients with American Joint Committee on Cancer stage I esophageal cancer is approximately 90%. This rate decreases to 45%, 20%, and 10% in patients with stages II, III, and IV diseases, respectively [2]. Esophagectomy is still the most effective treatment option, although chemoradiotherapy may be effective in treating esophageal cancer treatment [3]. Despite developments in extended lymph node dissection and perioperative management of esophagectomy, it remains a highly invasive procedure associated with severe postoperative complications [4]. The Japanese national database, including 5354 esophagectomy patients in 713 hospitals in 2011, indicated an overall morbidity rate of 41.9% and a 30-day and surgery-related mortality of 1.2% and 3.4%, respectively [5].
The effect of postoperative complications on long-term survival has been investigated in many cancers [4[4][6],6], including a recent meta-analysis of colorectal cancer studies [7]. Some reports have shown the adverse effect of postoperative esophagectomy complications on long-term survival [4[4][8],8], whereas others have reported that postoperative esophagectomy complications did not affect long-term survival [9]. We previously conducted a meta-analysis to investigate the effect of postoperative complications after esophagectomy on long-term survival [10].
The two major postoperative infectious complications after esophagectomy are pulmonary complications and anastomotic leakage [11].

2. The Effect of Postoperative Complications after Esophagectomy for Cancer on Survival

2.1. Pulmonary Complications

Using information recorded between 2011 and 2012 from a nationwide database in Japan, we reported that the rate of pulmonary complications after esophagectomy was 14.8% (1419/9584) [5]. Additionally, Ancona et al., reported that postoperative pulmonary complications (25.2%, 110/437) after esophagectomy did not affect long-term survival [12]. However, Baba et al., and Saeki et al., recently reported postoperative pulmonary complications (19.7%, 99/502 and 10.2%, 59/580, respectively) after esophagectomy had a significant negative effect on long-term survival [13,14][13][14].
We previously reported that, within a single institution, postoperative pneumonia after esophagectomy (22.5%, 64/284) had a significant negative effect on overall survival (OS) (p = 0.035). Furthermore, multivariate analysis revealed that the presence of pneumonia was predictive of poorer OS; the multivariate hazard ratio (HR) was 1.456 (95% confidence interval (CI) 1.020–2.079, p = 0.039)4. Furthermore, we analyzed the data from a randomized controlled trial (JCOG9907 trial); the OS of patients with pneumonia (14.5%, 22/152) was shorter than that of patients without pneumonia (HR: 1.82, 95% CI: 1.01–3.29), and progression-free survival (PFS) tended to be shorter in patients with pneumonia (HR: 1.50, 95% CI: 0.85–2.62) [8]. Additionally, we conducted a meta-analysis to investigate the impact of pulmonary complications after esophagectomy on survival [10]. Patients with pulmonary complications had significantly worse five-year OS (HR: 1.37, 95% CI: 1.16–1.62, p = 0.0003), five-year cancer-specific survival (CSS) (HR: 1.60, 95% CI: 1.35–1.89, p < 0.00001), and five-year disease-free survival (DFS) (HR: 1.18, 95% CI: 1.00–1.38, p = 0.04).

2.2. Anastomotic Leakage

Using information recorded between 2011 and 2012 from a nationwide database in Japan, we reported that the anastomotic leakage rate after esophagectomy was 12.6% (1203/9584) [5]. Additionally, Markar et al., reported that using a multicenter database in France, postoperative severe anastomotic leakage (8.5%, 208/2439) negatively affected long-term survival significantly [15].
In contrast, we previously reported that, in a single institution, anastomotic leakage after esophagectomy (19.4%, 55/284) did not affect OS [4]. Furthermore, we analyzed data from the JCOG9907 trial; OS of patients with anastomotic leakage (13.8%, 21/152) was nearly identical to that of patients without leakage (HR: 1.06, 95% CI: 0.52–2.13); PFS showed the same tendency (HR: 1.28, 95% CI: 0.71–2.32) [8]. However, we conducted a meta-analysis to investigate the impact of anastomotic leakage after esophagectomy on survival and reported that patients with anastomotic leakage had significantly worse five-year OS (HR: 1.18, 95% CI: 1.04–1.33, p = 0.01), five-year CSS (HR: 1.81, 95% CI: 1.11–2.95, p = 0.02), and five-year DFS (HR: 1.13, 95% CI: 1.03–1.25, p = 0.01) [10].

2.3. Overall Complications

Using information recorded between 2011 and 2012 from a nationwide database in Japan, we reported that the rate of overall morbidity after esophagectomy was 42.8% (4102/9584) [5]. Ancona et al., and Ferri et al., reported that overall postoperative complications did not affect long-term survival (16.3%, 85/522 and 22.6%, 98/434, respectively) [12,16][12][16]. However, Baba et al., and Saeki et al., recently reported that overall postoperative complications negatively affected long-term survival (43.2%, 217/502 and 26.6%, 154/580, respectively) [13,14][13][14].
We conducted a meta-analysis to investigate the impact of overall morbidity after esophagectomy on survival and reported that the overall postoperative morbidity had significantly worse five-year OS (HR: 1.16, 95% CI: 1.06–1.26, p = 0.001) and five-year CSS (HR: 1.28, 95% CI: 1.11–1.48, p = 0.0009) [10].
It was possible that the worsening of the general condition after postoperative complications lead to a delay or cessation of additional therapy after esophagectomy and led to esophageal cancer recurrence [4].

3. Clinical Significance of Proinflammatory Cytokines

Persistent infection or chronic inflammation significantly contributes to tumorigenesis and tumor progression. C-X-C motif ligand 8 (CXCL8) is a chemokine that acts as an important multifunctional cytokine to modulate tumor proliferation, invasion, and migration in an autocrine or paracrine manner [17]. CXCL8 and its cognate receptors, C-X-C chemokine receptor 1 (CXCR1) and C-X-C chemokine receptor 2 (CXCR2), may mediate the initiation and development of various cancers, including breast cancer [18], prostate cancer [19], lung cancer [20], colorectal carcinoma [21], and melanoma [22]. Further, CXCL8 integrates with multiple intracellular signaling pathways to produce coordinated effects. Additionally, neovascularization, which provides a basis for fostering tumor growth and metastasis, is now recognized as a critical function of CXCL8 in the tumor microenvironment [17].
The complication-specific factors that negatively affected long-term survival included pulmonary complications, involving a generalized infection that produced strong impairment of the immunological system leading to esophageal cancer recurrence [4]. Furthermore, we previously reported that infectious postoperative esophagectomy complications significantly increased the levels of inflammatory cytokines, such as CXCL6 and CXCL8 [23]. Increased expression of CXCL8 and its receptor, CXCR2, has been correlated with tumor progression after esophagectomy [24,25][24][25]. Thus, pulmonary complications may be related to tumor progression by promoting inflammatory cytokines, such as CXCL8, which negatively affects CSS and DFS [4]. Additionally, anastomotic leakage could result in the spread of viable tumor cells locally from stapled or sutured anastomoses. Locoregional recurrence after anastomotic leakage could be related to a proinflammatory response that promotes tumor growth [15]. Pulmonary infectious complications and anastomotic leakage have been related to tumor progression by developing inflammatory cytokines, such as CXCL8 [10]. Moreover, anastomotic leakage after esophagectomy have been shown to negatively affect CSS and DFS.

References

  1. Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries 2021. CA Cancer J. Clin. 2021, 71, 209–249.
  2. Ando, N.; Ozawa, S.; Kitagawa, Y.; Shinozawa, Y.; Kitajima, M. Improvement in the results of surgical treatment of advanced squamous esophageal carcinoma during 15 consecutive years. Ann. Surg. 2000, 232, 225–232.
  3. Cooper, J.S.; Guo, M.D.; Herskovic, A.; Macdonald, J.S.; Martenson, J.A., Jr.; Al-Sarraf, M.; Byhardt, R.; Russell, A.H.; Beitler, J.J.; Spencer, S.; et al. Chemoradiotherapy of locally advanced esophageal cancer: Long-term follow-up of a prospective randomized trial (RTOG 85-01). Radiation Therapy Oncology Group. JAMA 1999, 281, 1623–7162.
  4. Booka, E.; Takeuchi, H.; Nishi, T.; Matsuda, S.; Kaburagi, T.; Fukuda, K.; Nakamura, R.; Takahashi, T.; Wada, N.; Kawakubo, H.; et al. The Impact of Postoperative Complications on Survivals After Esophagectomy for Esophageal Cancer. Medicine 2015, 94, e1369.
  5. Takeuchi, H.; Miyata, H.; Gotoh, M.; Kitagawa, Y.; Baba, H.; Kimura, W.; Tomita, N.; Nakagoe, T.; Shimada, M.; Sugihara, K.; et al. A Risk Model for Esophagectomy Using Data of 5354 Patients Included in a Japanese Nationwide Web-Based Database. Ann. Surg. 2014, 260, 259–266.
  6. Tokunaga, M.; Tanizawa, Y.; Bando, E.; Kawamura, T.; Terashima, M. Poor survival rate in patients with postoperative intra-abdominal infectious complications following curative gastrectomy for gastric cancer. Ann. Surg. Oncol. 2013, 20, 1575–1583.
  7. McSorley, S.T.; Horgan, P.G.; McMillan, D.C. The impact of the type and severity of postoperative complications on long-term outcomes following surgery for colorectal cancer: A systematic review and meta-analysis. Crit. Rev. Oncol. Hematol. 2016, 97, 168–177.
  8. Kataoka, K.; Takeuchi, H.; Mizusawa, J.; Igaki, H.; Ozawa, S.; Abe, T.; Nakamura, K.; Kato, K.; Ando, N.; Kitagawa, Y. Prognostic impact of postoperative morbidity after esophagectomy for esophageal cancer: Exploratory analysis of JCOG9907. Ann. Surg. 2017, 265, 1152–1157.
  9. Martin, L.W.; Swisher, S.G.; Hofstetter, W.; Correa, A.M.; Mehran, R.J.; Rice, D.C.; Vaporciyan, A.A.; Walsh, G.L.; Roth, J.A. Intrathoracic leaks following esophagectomy are no longer associated with increased mortality. Ann. Surg. 2005, 242, 392–399.
  10. Booka, E.; Takeuchi, H.; Suda, K.; Fukuda, K.; Nakamura, R.; Wada, N.; Kawakubo, H.; Kitagawa, Y. Meta-analysis of the impact of postoperative complications on survival after oesophagectomy for cancer. BJS Open 2018, 2, 276–284.
  11. Takeuchi, H.; Miyata, H.; Ozawa, S.; Udagawa, H.; Osugi, H.; Matsubara, H.; Konno, H.; Seto, Y.; Kitagawa, Y. Comparison of short-term outcomes between open and minimally invasive esophagectomy for esophageal cancer using a nationwide database in Japan. Ann. Surg. Oncol. 2017, 24, 1821–1827.
  12. Ancona, E.; Cagol, M.; Epifani, M.; Cavallin, F.; Zaninotto, G.; Castoro, C.; Alfieri, R.; Ruol, A. Surgical Complications Do Not Affect Longterm Survival after Esophagectomy for Carcinoma of the Thoracic Esophagus and Cardia. J. Am. Coll. Surg. 2006, 203, 661–669.
  13. Baba, Y.; Yoshida, N.; Shigaki, H.; Iwatsuki, M.; Miyamoto, Y.; Sakamoto, Y.; Watanabe, M.; Baba, H. Prognostic impact of postoperative complications in 502 patients with surgically resected esophageal squamous cell carcinoma: A retrospective single-institution study. Ann. Surg. 2016, 264, 305–311.
  14. Saeki, H.; Tsutsumi, S.; Tajiri, H.; Yukaya, T.; Tsutsumi, R.; Nishimura, S.; Nakaji, Y.; Kudou, K.; Akiyama, S.; Kasagi, Y.; et al. Prognostic Significance of Postoperative Complications After Curative Resection for Patients with Esophageal Squamous Cell Carcinoma. Ann. Surg. 2017, 265, 527–533.
  15. Markar, S.; Gronnier, C.; Duhamel, A.; Mabrut, J.-Y.; Bail, J.-P.; Carrere, N.; Lefevre, J.H.; Brigand, C.; Vaillant, J.-C.; Adham, M.; et al. The Impact of Severe Anastomotic Leak on Long-term Survival and Cancer Recurrence After Surgical Resection for Esophageal Malignancy. Ann. Surg. 2015, 262, 972–980.
  16. Ferri, L.E.; Law, S.; Wong, K.H.; Kwok, K.F.; Wong, J. The influence of technical complications on postoperative outcome and survival after esophagectomy. Ann. Surg. Oncol. 2006, 13, 557–564.
  17. Liu, Q.; Li, A.; Tian, Y.; Wu, J.D.; Liu, Y.; Li, T.; Chen, Y.; Han, X.; Wu, K. The CXCL8-CXCR1/2 pathways in cancer. Cytokine Growth Factor Rev. 2016, 31, 61–71.
  18. Zuccari, D.A.P.D.C.; Leonel, C.; Castro, R.; Gelaleti, G.B.; Jardim, B.V.; Moscheta, M.G.; Regiani, V.R.; Ferreira, L.C.; Lopes, J.R.; Neto, D.D.S.; et al. An immunohistochemical study of interleukin-8 (IL-8) in breast cancer. Acta Histochem. 2012, 114, 571–576.
  19. Araki, S.; Omori, Y.; Lyn, D.; Singh, R.K.; Meinbach, D.M.; Sandman, Y.; Lokeshwar, V.B.; Lokeshwar, B.L. Interleukin-8 Is a Molecular Determinant of Androgen Independence and Progression in Prostate Cancer. Cancer Res. 2007, 67, 6854–6862.
  20. Masuya, D.; Huang, C.; Liu, D.; Kameyama, K.; Hayashi, E.; Yamauchi, A.; Kobayashi, S.; Haba, R.; Yokomise, H. The intratumoral expression of vascular endothelial growth factor and interleukin-8 associated with angiogenesis in nonsmall cell lung carcinoma patients. Cancer 2001, 92, 2628–2638.
  21. Brew, R.; Erikson, J.S.; West, D.C.; Kinsella, A.R.; Slavin, J.; Christmas, S.E. Interleukin-8 as an autocrine growth factor for human colon carcinoma cells in vitro. Cytokine 2000, 12, 78–85.
  22. Singh, S.; Varney, M.; Singh, R.K. Host CXCR2-dependent regulation of melanoma growth, angiogenesis, and experimental lung metastasis. Cancer Res. 2009, 69, 411–415.
  23. Okamura, A.; Takeuchi, H.; Matsuda, S.; Ogura, M.; Miyasho, T.; Nakamura, R.; Takahashi, T.; Wada, N.; Kawakubo, H.; Saikawa, Y.; et al. Factors Affecting Cytokine Change After Esophagectomy for Esophageal Cancer. Ann. Surg. Oncol. 2015, 22, 3130–3135.
  24. Ogura, M.; Takeuchi, H.; Kawakubo, H.; Nishi, T.; Fukuda, K.; Nakamura, R.; Takahashi, T.; Wada, N.; Saikawa, Y.; Omori, T.; et al. Clinical significance of CXCL-8/CXCR-2 network in esophageal squamous cell carcinoma. Surgery 2013, 154, 512–520.
  25. Inoue, M.; Takeuchi, H.; Matsuda, S.; Nishi, T.; Fukuda, K.; Nakamura, R.; Takahashi, T.; Wada, N.; Kawakubo, H.; Kitagawa, Y. IL-8/CXCR2 signalling promotes cell proliferation in oesophageal squamous cell carcinoma and correlates with poor prognosis. Anticancer. Res. 2021, 41, 783–794.
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