Abstract
Background:
The aim of this study was to establish a new preoperative staging classification and evaluate its comparability to the post-operative tumour stage, lymph node invasion and metastasis (TNM) classification. To date, adequate, preoperative staging in patients with oesophageal carcinoma (EC) is still missing but urgently needed. Systemic inflammation and disseminated tumour load have a pivotal role in recurrence and oncological outcome. To improve the clinical staging, we merged the Glasgow Prognostic Score (GPS) and disseminated tumour cells (DTC) into a new sufficient preoperative staging classification, the Hamburg-Glasgow classification (HGC).
Methods:
In this prospective, single-centre study, 326 patients following curative oesophagectomy were included. From all patients preoperative bone marrow was aspirated from the iliac crest to detect DTCs by immunostaining with the pan-keratin antibody A45-B/B3. HGC was subdefined into four prognostic groups on the basis of C-reactive protein (CRP), albumin and DTC. The three prognostic groups of the GPS were supplemented by DTC detection status. Results were correlated with clinicopathological parameters and clinical outcome.
Results:
Increasing HGC significantly correlated with lymph node invasion (P=0.022), post-operative pathohistological TNM staging (P=0.001) and tumour recurrence (P=0.001). The four HGC prognostic groups displayed a gradual decrease in overall as well as disease-free survival (P<0.001, each). Hamburg-Glasgow classification was a strong, significant independent predictor of overall survival and disease-free survival (P<0.001, both) in multivariate analysis.
Conclusions:
Hamburg-Glasgow classification seems to be a promising preoperative additive staging classification for accurate and simple outcome stratification.
Similar content being viewed by others
Main
Oesophageal cancer (EC) is an aggressive disease and the sixth most frequent cause of cancer death worldwide (Siegel et al, 2015). Five-year survival rates following curative oesophagectomy in a multimodal treatment approach have increased but locoregional recurrence and distant metastasis remain a significant problem even in node-negative patients (Hulscher et al, 2002; Allum et al, 2009). Neoadjuvant treatment regimes have been introduced for improving long-term locoregional as well as systemic tumour control (Cunningham et al, 2006; Sjoquist et al, 2011; van Hagen et al, 2012). However, indication for neoadjuvant therapy is based on insufficient preoperative staging tools like computed tomography (CT) and endoscopic ultrasound (EUS) with poor sensitivities and significant proportion of under- and over-staging (Kutup et al, 2007; Allum et al, 2011). Disseminated tumour load and systemic inflammation have a pivotal role in cancer progression and tumour recurrence (O'Sullivan et al, 1999; Pantel et al, 2008). Oesophageal adenocarcinoma is an exemplar model of an inflammation-associated cancer (O'Sullivan et al, 2014). Several studies and our own previous work have shown a significant prognostic impact and clinical significance of disseminated tumour cells (DTC) in the bone marrow of patients with EC (Thorban et al, 2000; Macadam et al, 2003; Vashist et al, 2012). In addition, systemic inflammation (SI) also correlates to cancer progression but the interaction between tumour cells and host inflammatory response is still poorly understood (Zhang et al, 2007; Boffetta, 2010; Sgambato and Cittadini, 2010; Terzic et al, 2010). The Glasgow Prognostic Score (GPS) based on two acute phase proteins albumin and C-reactive protein (CRP), represents an indicator of SI and is a useful tool for risk stratification in cancer patients (O'Gorman et al, 1999; McMillan, 2009). Several studies and our own work validated the GPS in several tumour entities including EC (Brown et al, 2007; Ishizuka et al, 2007, 2009; Kobayashi et al, 2008; Sharma et al, 2008; Roxburgh et al, 2009; Vashist et al, 2011).
We merged GPS and DTC status to a new sufficient preoperative staging classification (Hamburg-Glasgow classification (HGC)) substratifying four preoperative prognostic groups. HGC is based on three preoperatively, easily available and objective parameters, whereas the routinely used variables like tumour stage, lymph node invasion and metastasis (TNM) can only be accurately determined by post-operative histological analysis.
The aim of this prospective investigation was to evaluate the preoperative prognostic impact of HGC in patients with EC.
Materials and methods
Patients characteristics
The study was approved by the Medical Ethical Committee, Hamburg, Germany. All patients enrolled in this study underwent oesophageal resection at the Department of General, Visceral and Thoracic surgery at the University Medical Center Hamburg-Eppendorf. Informed consent was obtained from all patients before study inclusion.
Routine workup of patients included patient’s history, physical examination, routine blood tests, studies of tumour markers (carcinoembryonic antigen and CA 19-9), abdominal ultrasonography, endoscopy and thoracic and abdominal CT scans as well as PET scans in selected cases from 2006 forward.
The database included 605 patients. 360 patients had available DTC and GPS status. Only patients without neoadjuvant therapy and histologically proven EC as well as tumour-free resection margins and without distant metastasis (M0) with complete follow up data were included in the study (N=326).
Disseminated tumour cell detection
Bone marrow was aspirated from the right upper iliac crest before primary oesophageal cancer surgery. Mononuclear cells were enriched using the Ficoll-Hypaque gradient. Bone marrow samples were immunocytochemically assessed for DTC using the monoclonal anticytokeratin antibody A45-B/B3 (mouse IgG1; AS Diagnostics, Hückeswagen, Germany). The A45-B/B3 antibody has been established for disseminated tumour cell detection in EC earlier (Izbicki et al, 1997). As an isotype-specific negative control the MOPC-21 monoclonal antibody (Sigma Chemical, St Louis, MO, USA), lacking any known reactivity for epithelial cells or bone marrow cells, was used at the same concentration as the A45-B/B3. This immunocytochemical assay for DTC in bone marrow is state-of-the-art and has a false-positive rate of maximum 1% in control cases (Braun et al, 2000). Criteria applied for the disseminated tumour cell analysis were extensively analyzed by Fehm et al (2006). Disseminated tumour cells detection, staining and interpretation were performed in the same way as described before (Vashist et al, 2012).
Hamburg-Glasgow classification
For evaluation of the HGC blood test results containing albumin and CRP from the day before surgery or test results not older than 1 week before surgery were used. Abnormalities were defined as follows: DTC status positive (DTC⩾1), elevated CRP (>10 g l−1) and hypoalbuminemia (<35 g l−1). Glasgow Prognostic Score prognostic groups were expanded by DTC status and four HGC prognostic groups were defined. Table 1 depicts details of HGC classification.
Statistical analysis
For statistical analysis, SPSS 20.0 (Chicago, IL, USA) was used. Descriptive statistics were used to describe patient baseline characteristics. To evaluate a potential association between the HGC and clinicopathological parameters, the χ2-test was applied. Survival curves for disease-free and overall survivals of the patients were plotted using the Kaplan–Meier method and analyzed using the log-rank test. Results are presented as median survival in months with 95% confidence interval (CI) and number of patients at risk. Post-operative follow-up was conducted at 3-month intervals for the first 2 years, including physical examination, plain chest radiography, abdominal ultrasonography, endoscopy, endoscopic ultrasonography and computed tomography of the chest and abdomen. Studies of tumour markers (carcinoembryonic antigen and cancer antigen 19-9) and bone scans were also performed. The overall survival was computed as the time period from the date of surgery to either the date of death or last follow-up, whichever occurred first. The disease-free survival was defined as the time period from the date of surgery to the date of recurrence, last follow-up or date of death, whichever occurred first. Patients alive without recurrence at the last follow-up dates were censored. Cox regression hazard model was used for multivariate analysis to assess the independent influence of HGC and other covariates on tumour recurrence and overall survival. Results are presented as hazard ratio (HR) with 95% CI. Significant statements refer to P-values of two-tailed tests that were P<0.05.
Results
Patient characteristics and HGC correlations
Three hundred and twenty six patients following curative oesophagectomy with tumour-free resection and preoperative available DTC, albumin and CRP status were finally included. There were 154 patients with adenocarcinomas (AC) and 172 patients with squamous cell carcinomas (SCC). Of the 326 patients, 260 were men and 66 were women, and their median age was 61 years (range 34–83 years). Ninety-day mortality rate was 3.3%. None of the patients received adjuvant treatment.
We assessed the correlation of HGC with gender, age and the following histopathological parameters: tumour depth, lymph node stage, post-operative Union for International Cancer Control (UICC) TNM classification, histological type, tumour grading, surgical approach and tumour recurrence. No correlations were found between HGC stages and gender, age, tumour depth, histological type, tumour grading and surgical approach (P=n.s.). Hamburg-Glasgow classification was significantly correlated with the presence of lymph node invasion (P=0.022), post-operative TNM classification (P=0.001) and tumour recurrence (P=0.001). Table 2 depicts the tumour-specific patient characteristics and the results of the correlation analysis. Further, we analyzed the positive predictive value, negative predictive value as well as accuracy concerning lymph node metastasis. The results were 68%, 47.3% and 55.2%, respectively.
Univariate survival analysis
The median follow-up time of surviving patients was 60 months. The median survival time was 21.97 months (95% CI, 18.05–25.89 months). Hamburg-Glasgow classification showed significant preoperative risk stratification between the four prognostic groups for overall as well as disease-free survival (P<0.001, each) (Figure 1). Hamburg-Glasgow classification showed significant overall survival stratification for SCC and AC subgroup analyses (P<0.001, each). These results were comparable to the significant survival stratification of the post-operative UICC TNM classification (P<0.001, each) (Figure 1). Pairwise log rank analyses showed significant survival stratification by each HGC stage as well as pTN stages. In a subgroup analysis including only pT1–2 N0 patients (N=129), HGC groups III/IV showed significant shorter overall as well as disease-free survival in comparison to HGC groups I/II (P<0.001, each) (Figure 2).
Multivariate survival analysis
We analyzed the independent prognostic impact of the HGC on overall and disease-free survival by multivariate stratified analysis including age, gender, post-operative UICC TNM classification, tumour grading and histological type. The HGC prognostic groups were identified as strong independent prognostic markers for overall survival (P<0.001; HR 3.19, 95% CI, 2.06–4.93) and disease-free survival (P<0.001; HR 2.24, 95% CI, 1.36–3.68; Table 3).
Discussion
The results of the present study show for the first time that the preoperative combination of disseminated tumour load in bone marrow indicated by DTC and systemic inflammation evaluated by GPS are associated with poor overall survival and disease-free survival after potentially curative resection in EC. Furthermore, the new defined preoperative HGC is a strong predictor of oncological outcome of patients with EC and showed comparable survival stratification to the post-operative UICC TNM classification. The HGC has several advantages compared with conventional preoperative TNM staging (Sobin and Compton, 2010; Allum et al, 2011). Based on the primary staging an interdisciplinary planning and therapy decision making is mandatory in EC patients. Several multicentric randomised studies showed that surgery alone in patients with advanced disease (T3 N+) results in poor survival rates (Cunningham et al, 2006; Allum et al, 2009; Sjoquist et al, 2011; Ychou et al, 2011; van Hagen et al, 2012). These patients need neoadjuvant chemotherapy or radiochemotherapy which lead to prolonged survival in comparison to surgery as monotherapy. Therefore, accurate preoperative diagnosis and prognostic staging are imperative before multimodal treatment. Indication for neoadjuvant treatment regime is still only based on the commonly used diagnostic techniques, computed tomography, endoscopy and endoscopic ultrasound (Stahl et al, 2010; Allum et al, 2011). Sensitivities of N-staging which is the most important prognostic parameter are given between 42–68% for EUS and between 33 and 35% for CT that results in under but also overstaging in a significant number of patients (Kelly et al, 2001; Lowe et al, 2005; Kutup et al, 2007; van Vliet et al, 2008; Takizawa et al, 2009; Choi et al, 2010; Pech et al, 2010; Konieczny et al, 2013). Thus, accurate pretreatment staging remains inconsistent. However, an improvement of the current staging system by adding other significant and objective prognosticators like disseminated tumour load and SI inherit the potential for defining adequate treatments regimes based on better risk-stratification in patients with EC.
Disseminated tumour cells are described to be an early event in tumour progression which is independent of tumour depth and lymph node invasion (Pantel et al, 2008). Tumour recurrence and metastasis supposedly result from clinically occult, minimal residual disease like DTC (Pantel et al, 2008). In this context, several studies reported a prognostic value of DTC in patients with EC (Thorban et al, 2000; Macadam et al, 2003; Vashist et al, 2012). The advantage of this tool is the easily accessibility preoperatively in contrast to lymph nodes or other distant sites. Thus, we included DTC as a significant prognostic biomarker in the new defined, preoperative HGC. Further, we included the acute phase proteins CRP and albumin based GPS as a well-known parameter for systemic inflammation (O'Gorman et al, 1999; McMillan, 2009). The underlining mechanisms of SI leading to aggressive tumour biology and decreased survival are only partially understood. Elevated CRP levels are associated with proangiogenic environment based on increased levels of vascular growth factors (Krzystek-Korpacka et al, 2008; McMillan, 2009). Furthermore, impaired lymphocyte function correlates to elevated CRP and poor survival in several tumour entities (Jain et al, 2009). In addition, several studies postulated the association between increasing CRP and poor survival in various tumour types (Crumley et al, 2006; Glen et al, 2006; Brown et al, 2007; McMillan et al, 2007; Ramsey et al, 2007). A decrease in albumin level was verified in several tumour entities. Hypoalbuminemia is a well-known negative prognosticator in cancer patients and is a surrogate parameter for SI (Forrest et al, 2003; McMillan, 2008). Several studies reported on prognostic significance of GPS on survival in various cancers including EC (Crumley et al, 2006; Glen et al, 2006; McMillan et al, 2007; Vashist et al, 2011).
Due to the prognostic significance of DTC, CRP and albumin, we constructed the HGC as a new and promising preoperative staging classification which should be additionally used in staging of patients with EC. Hamburg-Glasgow classification seems to be an objective, easily available and significant prognosticator for survival of patients with EC. Even in patients with pT1–2 N0-tumours, HGC showed significant survival stratification between the groups I/II and III/IV. The patients of the prognostic groups HGC III/IV had similar survival as patients with pT3/4 N+. In consequence, these patients (pT1–2 N0 and HGC III/IV) should have been treated by neoadjuvant treatment, which underlines the urgent need of improvement of the current TNM staging system. We could show that the HGC is independent of the TNM system. However, the HGC measures other relevant biological parameters with significant clinical impact in contrast to the TNM staging system. The implementation of the HGC into standard clinical preoperative staging might add significant information of tumour biology to the TNM classification. This have to be evaluated, prospective designed studies should evaluate the prognostic value and its role in neoadjuvant treated patients.
Although we were able to present a new and promising staging classification, our study is biased by the lack of comparative data, for example, preoperative clinical TNM stages or ASA score. However, we report on a homogenous and large study population which underwent surgery alone for EC and neither DTC status nor SI were affected by neoadjuvant systemic therapy. However, this aspect opens another future issue to be evaluated whether HGC could be used for response prediction after neoadjuvant therapy.
In conclusion, HGC is a new and promising preoperative staging classification which showed significant risk stratification for overall survival and disease-free survival in patients with non-metastatic EC. Our results suggest that HGC can enable accurate preoperative staging in addition to the TNM classification which might improve treatment of patients with EC.
References
Allum WH, Blazeby JM, Griffin SM, Cunningham D, Jankowski JA, Wong R Association of Upper Gastrointestinal Surgeons of Great Britain and Ireland, The British Society of Gastroenterology, The British Association of Surgical Oncology (2011) Guidelines for the management of oesophageal and gastric cancer. Gut 60: 1449–1472.
Allum WH, Stenning SP, Bancewicz J, Clark PI, Langley RE (2009) Long-term results of a randomized trial of surgery with or without preoperative chemotherapy in esophageal cancer. J Clin Oncol 27: 5062–5067.
Boffetta P (2010) Exploring a cancer biomarker: the example of C-reactive protein. J Natl Cancer Inst 102: 142–143.
Braun S, Pantel K, Muller P, Janni W, Hepp F, Kentenich CR, Gastroph S, Wischnik A, Dimpfl T, Kindermann G, Riethmuller G, Schlimok G (2000) Cytokeratin-positive cells in the bone marrow and survival of patients with stage I, II, or III breast cancer. N Engl J Med 342: 525–533.
Brown DJ, Milroy R, Preston T, McMillan DC (2007) The relationship between an inflammation-based prognostic score (Glasgow Prognostic Score) and changes in serum biochemical variables in patients with advanced lung and gastrointestinal cancer. J Clin Pathol 60: 705–708.
Choi J, Kim SG, Kim JS, Jung HC, Song IS (2010) Comparison of endoscopic ultrasonography (EUS), positron emission tomography (PET), and computed tomography (CT) in the preoperative locoregional staging of resectable esophageal cancer. Surg Endosc 24: 1380–1386.
Crumley AB, McMillan DC, McKernan M, McDonald AC, Stuart RC (2006) Evaluation of an inflammation-based prognostic score in patients with inoperable gastro-oesophageal cancer. Br J Cancer 94: 637–641.
Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, Scarffe JH, Lofts FJ, Falk SJ, Iveson TJ, Smith DB, Langley RE, Verma M, Weeden S, Chua YJ Magic Trial Participants (2006) Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 355: 11–20.
Fehm T, Braun S, Muller V, Janni W, Gebauer G, Marth C, Schindlbeck C, Wallwiener D, Borgen E, Naume B, Pantel K, Solomayer E (2006) A concept for the standardized detection of disseminated tumor cells in bone marrow from patients with primary breast cancer and its clinical implementation. Cancer 107: 885–892.
Forrest LM, McMillan DC, McArdle CS, Angerson WJ, Dunlop DJ (2003) Evaluation of cumulative prognostic scores based on the systemic inflammatory response in patients with inoperable non-small-cell lung cancer. Br J Cancer 89: 1028–1030.
Glen P, Jamieson NB, McMillan DC, Carter R, Imrie CW, McKay CJ (2006) Evaluation of an inflammation-based prognostic score in patients with inoperable pancreatic cancer. Pancreatology 6: 450–453.
Hulscher JB, van Sandick JW, de Boer AG, Wijnhoven BP, Tijssen JG, Fockens P, Stalmeier PF, ten Kate FJ, van Dekken H, Obertop H, Tilanus HW, van Lanschot JJ (2002) Extended transthoracic resection compared with limited transhiatal resection for adenocarcinoma of the esophagus. N Engl J Med 347: 1662–1669.
Ishizuka M, Nagata H, Takagi K, Horie T, Kubota K (2007) Inflammation-based prognostic score is a novel predictor of postoperative outcome in patients with colorectal cancer. Ann Surg 246: 1047–1051.
Ishizuka M, Nagata H, Takagi K, Kubota K (2009) Influence of inflammation-based prognostic score on mortality of patients undergoing chemotherapy for far advanced or recurrent unresectable colorectal cancer. Ann Surg 250: 268–272.
Izbicki JR, Hosch SB, Pichlmeier U, Rehders A, Busch C, Niendorf A, Passlick B, Broelsch CE, Pantel K (1997) Prognostic value of immunohistochemically identifiable tumor cells in lymph nodes of patients with completely resected esophageal cancer. N Engl J Med 337: 1188–1194.
Jain RK, Duda DG, Willett CG, Sahani DV, Zhu AX, Loeffler JS, Batchelor TT, Sorensen AG (2009) Biomarkers of response and resistance to antiangiogenic therapy. Nat Rev Clin Oncol 6: 327–338.
Kelly S, Harris KM, Berry E, Hutton J, Roderick P, Cullingworth J, Gathercole L, Smith MA (2001) A systematic review of the staging performance of endoscopic ultrasound in gastro-oesophageal carcinoma. Gut 49: 534–539.
Kobayashi T, Teruya M, Kishiki T, Endo D, Takenaka Y, Tanaka H, Miki K, Kobayashi K, Morita K (2008) Inflammation-based prognostic score, prior to neoadjuvant chemoradiotherapy, predicts postoperative outcome in patients with esophageal squamous cell carcinoma. Surgery 144: 729–735.
Konieczny A, Meyer P, Schnider A, Komminoth P, Schmid M, Lombriser N, Weishaupt D (2013) Accuracy of multidetector-row CT for restaging after neoadjuvant treatment in patients with oesophageal cancer. Eur Radiol 23: 2492–2502.
Krzystek-Korpacka M, Matusiewicz M, Diakowska D, Grabowski K, Blachut K, Kustrzeba-Wojcicka I, Terlecki G, Gamian A (2008) Acute-phase response proteins are related to cachexia and accelerated angiogenesis in gastroesophageal cancers. Clin Chem Lab Med 46: 359–364.
Kutup A, Link BC, Schurr PG, Strate T, Kaifi JT, Bubenheim M, Seewald S, Yekebas EF, Soehendra N, Izbicki JR (2007) Quality control of endoscopic ultrasound in preoperative staging of esophageal cancer. Endoscopy 39: 715–719.
Lowe VJ, Booya F, Fletcher JG, Nathan M, Jensen E, Mullan B, Rohren E, Wiersema MJ, Vazquez-Sequeiros E, Murray JA, Allen MS, Levy MJ, Clain JE (2005) Comparison of positron emission tomography, computed tomography, and endoscopic ultrasound in the initial staging of patients with esophageal cancer. Mol Imaging Biol 7: 422–430.
Macadam R, Sarela A, Wilson J, MacLennan K, Guillou P (2003) Bone marrow micrometastases predict early post-operative recurrence following surgical resection of oesophageal and gastric carcinoma. Eur J Surg Oncol 29: 450–454.
McMillan DC (2008) An inflammation-based prognostic score and its role in the nutrition-based management of patients with cancer. Proc Nutr Soc 67: 257–262.
McMillan DC (2009) Systemic inflammation, nutritional status and survival in patients with cancer. Curr Opin Clin Nutr Metab Care 12: 223–226.
McMillan DC, Crozier JE, Canna K, Angerson WJ, McArdle CS (2007) Evaluation of an inflammation-based prognostic score (GPS) in patients undergoing resection for colon and rectal cancer. Int J Colorectal Dis 22: 881–886.
O'Gorman P, McMillan DC, McArdle CS (1999) Longitudinal study of weight, appetite, performance status, and inflammation in advanced gastrointestinal cancer. Nutr Cancer 35: 127–129.
O'Sullivan GC, Shanahan F, Talwalkar J, Van Dam J (1999) Setback for systemic therapy of esophageal cancer: right concept, disappointing result. Gastroenterology 117: 1020–1022.
O'Sullivan KE, Phelan JJ, O'Hanlon C, Lysaght J, O'Sullivan JN, Reynolds JV (2014) The role of inflammation in cancer of the esophagus. Expert Rev Gastroenterol Hepatol 8: 749–760.
Pantel K, Brakenhoff RH, Brandt B (2008) Detection, clinical relevance and specific biological properties of disseminating tumour cells. Nat Rev Cancer 8: 329–340.
Pech O, Gunter E, Dusemund F, Origer J, Lorenz D, Ell C (2010) Accuracy of endoscopic ultrasound in preoperative staging of esophageal cancer: results from a referral center for early esophageal cancer. Endoscopy 42: 456–461.
Ramsey S, Lamb GW, Aitchison M, Graham J, McMillan DC (2007) Evaluation of an inflammation-based prognostic score in patients with metastatic renal cancer. Cancer 109: 205–212.
Roxburgh CS, Crozier JE, Maxwell F, Foulis AK, Brown J, McKee RF, Anderson JH, Horgan PG, McMillan DC (2009) Comparison of tumour-based (Petersen Index) and inflammation-based (Glasgow Prognostic Score) scoring systems in patients undergoing curative resection for colon cancer. Br J Cancer 100: 701–706.
Sgambato A, Cittadini A (2010) Inflammation and cancer: a multifaceted link. Eur Rev Med Pharmacol Sci 14: 263–268.
Sharma R, Hook J, Kumar M, Gabra H (2008) Evaluation of an inflammation-based prognostic score in patients with advanced ovarian cancer. Eur J Cancer 44: 251–256.
Siegel RL, Miller KD, Jemal A (2015) Cancer statistics, 2015. CA Cancer J Clin 65: 5–29.
Sjoquist KM, Burmeister BH, Smithers BM, Zalcberg JR, Simes RJ, Barbour A, Gebski V Australasian Gastro-Intestinal Trials Group (2011) Survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal carcinoma: an updated meta-analysis. Lancet Oncol 12: 681–692.
Sobin LH, Compton CC (2010) TNM seventh edition: what's new, what's changed: communication from the International Union Against Cancer and the American Joint Committee on Cancer. Cancer 116: 5336–5339.
Stahl M, Budach W, Meyer HJ, Cervantes A ESMO Guidelines Working Group (2010) Esophageal cancer: Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 21 (Suppl 5): v46–v49.
Takizawa K, Matsuda T, Kozu T, Eguchi T, Kato H, Nakanishi Y, Hijikata A, Saito D (2009) Lymph node staging in esophageal squamous cell carcinoma: a comparative study of endoscopic ultrasonography versus computed tomography. J Gastroenterol Hepatol 24: 1687–1691.
Terzic J, Grivennikov S, Karin E, Karin M (2010) Inflammation and colon cancer. Gastroenterology 138: 2101–2114 e2105.
Thorban S, Rosenberg R, Busch R, Roder RJ (2000) Epithelial cells in bone marrow of oesophageal cancer patients: a significant prognostic factor in multivariate analysis. Br J Cancer 83: 35–39.
van Hagen P, Hulshof MC, van Lanschot JJ, Steyerberg EW, van Berge Henegouwen MI, Wijnhoven BP, Richel DJ, Nieuwenhuijzen GA, Hospers GA, Bonenkamp JJ, Cuesta MA, Blaisse RJ, Busch OR, ten Kate FJ, Creemers GJ, Punt CJ, Plukker JT, Verheul HM, Spillenaar Bilgen EJ, van Dekken H, van der Sangen MJ, Rozema T, Biermann K, Beukema JC, Piet AH, van Rij CM, Reinders JG, Tilanus HW, van der Gaast A CROSS Group (2012) Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med 366: 2074–2084.
van Vliet EP, Heijenbrok-Kal MH, Hunink MG, Kuipers EJ, Siersema PD (2008) Staging investigations for oesophageal cancer: a meta-analysis. Br J Cancer 98: 547–557.
Vashist YK, Effenberger KE, Vettorazzi E, Riethdorf S, Yekebas EF, Izbicki JR, Pantel K (2012) Disseminated tumor cells in bone marrow and the natural course of resected esophageal cancer. Ann Surg 255: 1105–1112.
Vashist YK, Loos J, Dedow J, Tachezy M, Uzunoglu G, Kutup A, Yekebas EF, Izbicki JR (2011) Glasgow Prognostic Score is a predictor of perioperative and long-term outcome in patients with only surgically treated esophageal cancer. Ann Surg Oncol 18: 1130–1138.
Ychou M, Boige V, Pignon JP, Conroy T, Bouche O, Lebreton G, Ducourtieux M, Bedenne L, Fabre JM, Saint-Aubert B, Geneve J, Lasser P, Rougier P (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.
Zhang SM, Lin J, Cook NR, Lee IM, Manson JE, Buring JE, Ridker PM (2007) C-reactive protein and risk of breast cancer. J Natl Cancer Inst 99: 890–894.
Acknowledgements
All authors had a substantial contribution to the conception and design, acquisition of data, or analysis and interpretation of data, drafting the article, or revising it critically for important intellectual content and final approval of the version published.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution-NonCommercial-Share Alike 4.0 Unported License.
Rights and permissions
From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/
About this article
Cite this article
Reeh, M., Ghadban, T., Uzunoglu, F. et al. Hamburg-Glasgow classification: preoperative staging by combination of disseminated tumour load and systemic inflammation in oesophageal carcinoma. Br J Cancer 117, 612–618 (2017). https://doi.org/10.1038/bjc.2017.219
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/bjc.2017.219
Keywords
This article is cited by
-
Benefit of a flash dose of corticosteroids in digestive surgical oncology: a multicenter, randomized, double blind, placebo-controlled trial (CORTIFRENCH)
BMC Cancer (2022)
-
Prognostic Utility of the Glasgow Prognostic Score for the Long‐Term Outcomes After Liver Resection for Intrahepatic Cholangiocarcinoma: A Multi‐institutional Study
World Journal of Surgery (2021)