- Email: [email protected]
Inflammation-based prognostic score, prior to neoadjuvant chemoradiotherapy, predicts postoperative outcome in patients with esophageal squamous cell carcinoma
Surgical Outcome Research Inflammation-based prognostic score, prior to neoadjuvant chemoradiotherapy, predicts postoperative outcome in patients with esophageal squamous cell carcinoma Takashi Kobayashi, MD, PhD, Masanori Teruya, MD, PhD, Tomokazu Kishiki, MD, Daisuke Endo, MD, PhD, Yoshiharu Takenaka, MD, Hozumi Tanaka, MD, Kenji Miki, MD, PhD, Kaoru Kobayashi, MD, and Koji Morita, MD, Tokyo, Japan
Background. Recent studies have revealed that Glasgow prognostic score (GPS), an inflammation-based prognostic score, is associated with poor outcome in a variety of tumors. However, few studies have investigated whether GPS measured prior to neoadjuvant chemoradiotherapy (nCRT) is useful for postoperative prognosis of patients with advanced esophageal squamous cell carcinoma (ESCC). Methods. GPS was calculated on the basis of admission data as follows: patients with both an elevated C-reactive protein (>10 mg/L) and hypoalbuminaemia (<35 g/L) were allocated a GPS score of 2. Patients in whom only 1 of these biochemical abnormalities was present were allocated a GPS score of 1, and patients with a normal C-reactive protein and albumin were allocated a score of 0. All patients underwent radical en-bloc resection 3--4 weeks after nCRT. Results. A total of 48 patients with clinical TNM stage II/III were enrolled. Univariate analyses revealed that there were significant differences in cancer-specific survival in relation to grade of response to nCRT (P = .004), lymph node status (P = .0065), lymphatic invasion (P = .0002), venous invasion (P = .0001), pathological TNM classification (P = .015), and GPS (P < .0001). GPS classification showed a close relationship with lymphatic invasion, venous invasion, and number of lymph node (P = .0292, .0473, and .0485, respectively). GPS was found to be the only independent predictor of cancer-specific survival (odds ratio, 0.17; 95% confidence interval, 0.06–0.52; P = .0019). Conclusions. GPS, measured prior to nCRT, is an independent novel predictor of postoperative outcome in patients with advanced ESCC. (Surgery 2008;144:729-35.) From the Department of Surgery, Showa General Hospital, Tokyo, Japan
BECAUSE
OF HIGH RATES OF LOCOREGIONAL AND DISTANT
RECURRENCE, NEOADJUVANT CHEMORADIOTHERAPY
(NCRT) has been proposed, expecting the elimination of potential systemic micrometastases and promoting local ‘‘downstaging’’ that may increase the curative resection rate.1 None of prospective randomized
Accepted for publication August 15, 2008. Reprint requests: Takashi Kobayashi, MD, PhD, Department of Surgery, Showa General Hospital, 2-450 Tenjincho, Kodaira, Tokyo 187-8510, Japan. E-mail: [email protected]. 0039-6060/$ - see front matter Ó 2008 Mosby, Inc. All rights reserved. doi:10.1016/j.surg.2008.08.015
trials of patients with esophageal cancer, however, has demonstrated any benefit for nCRT.2-8 Recently, a multidisciplinary approach including surgery, radiotherapy, and chemotherapy, alone or in combination, has been proposed for locally advanced esophageal cancer.9 Although the addition of surgery to chemotherapy could result in improved local control and survival in selected patients showing complete response to nCRT,10 it is difficult to select precisely those particular patients prior to operation. Moreover, surgery as salvage treatment in patients with no response to nCRT or persistent tumor after definitive chemoradiotherapy is associated with high mortality and morbidity.11 So it would be clinically useful if we SURGERY 729
730 Kobayashi et al
could select patients, prior to treatment, suitable for nCRT in combination with surgery for advanced esophageal squamous cell carcinoma (ESCC) in terms of postoperative cancer-specific survival. It is increasingly recognized that it is not only the intrinsic properties of tumor cells that determine tumor spread but also the host inflammatory response.12,13 Albumin does not only reflect status. Recently, the relationship of measures of systemic inflammation and immunity to cancer outcome has been of increasing interest; however, it has been poorly studied. Glasgow prognostic score (GPS), an inflammation-based prognostic score that includes serum C-reactive protein and serum albumin, has been reported to be one of the most useful scoring systems for the prognosis of patients with advanced cancer.14-16 The present study was conducted to investigate whether GPS, prior to nCRT, could predict postoperative cancer-specific survival in patients with advanced ESCC. PATIENTS AND METHODS Patients. Between March 2000 and March 2007, 81 consecutive patients with esophageal carcinoma underwent surgical resection in the surgical unit of Showa General Hospital. Of these 81 patients, 71 patients were diagnosed as the stage II/III. However, 13 patients among them were excluded from this study, as they showed severe anemia, leukocytopenia (or neutropenia), coronary artery disease, renal dysfunction, or were 80 years or older. The other 10 patients refused nCRT and received surgery alone. As a result, 23 patients were excluded from this study, and 48 patients with ESCC who received nCRT subsequently followed by potentially curative resection were enrolled in this retrospective study. Patients were routinely evaluated by endoscopy, computed tomography, and esophagogastroduodenal barium study, and occasionally FDG-PET before and after nCRT. Clinical TNM (cTNM) stage II/III tumors, excluding T4, were considered to be amenable to this study. Routine laboratory measurements including serum albumin and C-reactive protein, and tumor marker such as squamous cell carcinoma antigen (SCC) were carried out on the same day before nCRT in order to exclude any inflammatory effect of preoperative sequential examinations, such as endoscopy and biopsy. C-reactive protein, and SCC were routinely measured at our laboratory. Briefly, serum C-reactive protein levels were measured with an immunodetection kit (the cutoff values were 10 mg/L). SCC is known to be one of the tumor markers used in esophageal squamous cell
Surgery November 2008
carcinoma. Serum SCC levels were measured using an enzyme immunoassay kit (the cutoff values were 1.5 ng/mL). At this time, no patient showed clinical evidence of infection or any other inflammatory conditions, such as pneumonia and ulcerative colitis. GPS was constructed as previously described.17 Briefly, patients with both an elevated C-reactive protein (>10 mg/L) and hypoalbuminaemia (<35 g/L) were allocated a score of 2. Patients in whom only 1 of these biochemical abnormalities was present were allocated a score of 1. Patients in whom neither of these abnormalities was present were allocated a score of 0. The study was approved by the Research Ethics Committee of Showa General Hospital. Neoadjuvant chemoradiotherapy. nCRT regimen consisted of both fluorouracil, 600 mg/m2 per day delivered by continuous intravenous infusion on days 1 to 5, and cisplatin, 10 mg/body per day on days 1–5 and 5 mg/body per day on days 8–12 and 15–19, respectively, delivered by intravenous infusion in combination with concomitant radiotherapy (30 Gy over 3 weeks). Histological criteria for response to CRT were as follows:18 grade 0, neither necrosis nor cellular or structural changes seen throughout the lesion; grade 1, necrosis or disappearance of tumor in <2/3 of the whole lesion; grade 2, necrosis or disappearance of tumor in $2/3 of the whole lesion, but viable tumor cells still remain; and grade 3, whole lesion is necrotic and/or replaced by fibrosis, with or without granulomatous changes, and no viable tumor cells are observed. CRT was considered effective in patients with histological response of grade 2 or 3. Conversely, CRT was judged ineffective in patients with histological response of grade 0 or 1. The extent of tumor spread was recorded using the TNM classification. Endoscopy, computed tomography were performed again weeks after nCRT in order to determine resectability. As to the indication for operation in our hospital, radical esophageal resection is indicated for clinical stages I, II, and III cancer. If they detect any remote metastasis, radical esophageal resection is not performed. Surgical technique. Surgical resection consisted of radical en-bloc esophagectomy with an extended en bloc mediastinal and abdominal lymphadenectomy 3–4 weeks after nCRT. Cervical lymphadenectomy was not undertaken routinely. Intrathoracic esophagogastric anastomosis for reconstruction using a circular stapler was performed after esophagectomy. Statistical analysis. Data are presented as mean and range (95% confidence interval [CI]).
Kobayashi et al 731
Surgery Volume 144, Number 5
Table I. Clinical characteristics in patients with esophageal squamous cell carcinoma Patients (n = 48) Age (yr) < 70 $70 Sex Male Female GPS 0 1 2 Tumor site Ut Mt Lt SCC <1.5 ng/ml $1.5 ng/ml cTNM classification IIA IIB III Grade of response to nCRT 1 2 3
Table II. Clinical characteristics and cancerspecific survival in patients with esophageal squamous cell carcinoma: univariate analysis Survival Survival P Patients (months) (months) (n = 48) mean (95% CI) value
36 12 39 9 27 16 5 5 26 17 26 14 13 7 28 29 16 3
GPS, Glasgow Prognostic Score; nCRT, neoadjuvant chemoradiotherapy.
Univariate survival analysis was performed using the Kaplan-Meier method with the log-rank test. Multivariate survival analysis and calculation of odds ratios with 95% CI was performed Cox proportional hazard regression model, including all covariates that were significant on univariate analysis. Correlation between GPS classification and age, sex, tumor site, SCC, grade of response to nCRT, number of lymph nodes metastasis, lymphatic invasion, venous invasion, and pTNM classification were analyzed by v2 test or Fisher exact test as appropriate. Analysis was performed using software package Stat View version 5.0 for Windows (SAS Institute Inc., Cary, NC). RESULTS The classified background characteristics of the 48 patients who under went nCRT followed by surgery for ESCC are shown in Table I. There were 39 men and 9 women. Twenty-nine patients were categorized into grade 1 of response to nCRT, 16 into grade 2, and 3 into grade 3. Results of univariate analysis of cancer-specific survival are shown in Table II. The present study showed that mean survival times in all 48 patients
Overall Age(yr) < 70 $70 Sex Male Female GPS 0 1 and 2 Tumor site Ut Mt Lt SCC <1.5 ng/ml $1.5 ng/ml Grade of response to nCRT 1 2, 3 Number of lymph nodes metastasis 5$ $6 Lymphatic invasion negative positive Venous invasion negative positive pTNM classification 0+I II+III
48
24.6
19.1–30.0
36 12
21.6 33.3
16.0–27.3 18.8–47.9 .4961
39 9
24.3 25.8
18.3–30.3 9.6–42.0 .3652
27 21
31.3 16.0
23.4–39.1 9.8–22.1 <.0001
5 26 17
15.2 20.7 33.3
6.2–24.2 14.0–27.3 22.2–44.4 .0589
26 14
24.5 21.8
16.8–32.1 12.4–31.2 .4812
29 19
19.7 32.1
12.6–26.8 23.9–40.2 .004
39 9
27.7 11.1
21.4–34.0 6.5–15.7 .0065
24 24
30.3 18.8
11.0–26.7 22.9–37.7 .0002
23 25
31.0 18.6
23.5–38.6 11.0–26.2 .0001
9 39
36.4 21.8
23.2–49.7 15.9–27.8 .0150
GPS, Glasgow Prognostic Score; nCRT, neoadjuvant chemoradiotherapy; Ut, upper thoracic; Mt, middle thoracic; Lt, lower thoracic.
were 24.6 months (95% CI, 19.1–30.0 months), with 3- and 5-year survival rates of 36.4 % and 29.1%, respectively. There were no significant differences in overall survival in terms of age (<70/$70), sex, tumor site, or SCC. On the other hand, significant differences were observed in relation to grade of response to nCRT (1/2 and 3), number of lymph node metastasis (5$/$6), lymphatic invasion, venous invasion, pTNM (0+I/II+III) classification, and GPS (0/1 and 2). Table III shows the relationships between GPS and clinicopathological characteristics. Age, sex,
732 Kobayashi et al
Surgery November 2008
Table III. Relationships between clinicopathological characteristics and GPS in patients with esophageal squamous cell carcinoma GPS 0 GPS 1 GPS 2 P (n = 27) (n = 16) (n = 5) value 21 6
11 5
4 1
21 6
15 1
3 2
3 13 11
2 9 5
0 4 1
.7285
18 6
6 5
2 3
.2280
.7745
.1886
P Grade of nCRT response (1/2 and 3) Lymphatic invasion (negative/positive) Venous invasion (negative/positive) Number of lymph nodes metastasis (5$/$6) pTNM (stage 0+I/II+III) GPS (0/1 and 2)
Odds Ratio 95% CI
.6711
1.340
0.34–5.27
.2828
0.540
0.18–1.66
.4743
0.640
0.19–2.18
.0778
0.263
0.06–1.16
.6476 .0019
0.685 0.170
0.14–3.46 0.06–0.52
GPS, Glasgow Prognostic Score; nCRT, neoadjuvant chemoradiotherapy.
(%)
23 4
14 2
2 3
GPS 0
100
.0485
15 12
9 7
5 0
17 10
7 9
0 5
.0292
16 11
7 9
0 5
.0473
7 20
2 14
0 5
.1605
Cancer-specific survival rate
Age (yr) <70 $70 Sex Male Female Tumor site Ut Mt Lt SCC <1.5 ng/ml $1.5 ng/ml Number of lymph nodes metastasis 5$ $6 Grade of response to nCRT 1 2 and 3 Lymphatic invasion Negative Positive Venous invasion Negative Positive pTNM classification 0+I II+III
Table IV. Multivariate logistic regression analysis in relation to survival in patients with esophageal squamous cell carcinoma
GPS 1
80 GPS 2
60
40
20
0 0
10
20
30
40
50
60
70
80
Months after surgery
.2899
GPS, Glasgow Prognostic Score; nCRT, neoadjuvant chemoradiotherapy; Ut, upper thoracic; Mt, middle thoracic; Lt, lower thoracic.
tumor site, SCC, pTNM, and grade of response to CRT showed no significant relationship with GPS classification. On the other hand, lymphatic invasion, venous invasion, and number of lymph node metastasis showed a close relationship with GPS classification. Multivariate analyses using the same factors as those in Table III revealed that GPS was associated with postoperative mortality (odds ratio, 0.17; 95% CI, 0.06–0.52; P = .0019) (Table IV). Kaplan-Meier analysis demonstrated significant differences among the 3 groups: GPS 0 (mean survival, 31.3 months; 95% CI, 23.4--39.1 months), GPS 1 (mean survival, 19.1 months; 95% CI, 11.7-26.6 months), and GPS 2 (mean survival, 5.8 months; 95% CI, 3.8--7.8 months). Thus the use of the GPS classification was able to clearly divide patients with SCCE into 3 independent groups (Figure). As to the mortality and morbidity after
Figure. Cancer-specific survival curves according to Glasgow prognostic score (GPS) 0–2. There were significant differences between GPS 0 and GPS 1 (P < .0001), and between GPS 1 and 2 (P = .0006). 5-year survival rates were 62.0% in patients with GPS 0, 7.8% in those with GPS 1, and 0% in those with GPS 2.
surgery, there was no mortality. There were complications in 10 patients (20.8%) as follows: anastomotic leakage in 3 patients, hematoma in 2, vocal cord palsy in 3, pneumonia in 1, chyrothorax in 1, and sepsis in 1. As to the morbidity in each group, postoperative complications were observed in 6 out of 27 patients of GPS 0, 1 out of 16 patients in GPS 1, and 3 out of 5 patients in GPS 2. Just for reference, we present our data on the 23 patients with stage II/III, who were excluded from this study and received surgery alone without nCRT. Eleven patients were graded into GPS 0 (mean survival, 26.0 months; 95% CI, 12.9--39.1 months), 7 patients into GPS 1 (mean survival, 16.1 months; 95% CI, 10.4--21.9 months), and 5
Surgery Volume 144, Number 5
patients into GPS 2 (mean survival, 12.2 months; 95% CI, 3.6--20.8 months). Especially, postoperative prognosis of GPS 2 group of this study (mean survival, 5.8 months) was worse than that of GPS 2 group without nCRT (mean survival, 12.2 months), albeit statistically not significant. As to the mortality and morbidity after surgery, there was no mortality. There were complications in 5 patients (21.7%) as follows: anastomotic leakage in 3 patients, vocal cord palsy in 2, and chyrothorax in 1. DISCUSSION This study was undertaken to see whether GPS, measured prior to nCRT, is useful in predicting postoperative outcome in patients with advanced ESCC. Despite the retrospective nature of the study and relatively small patient numbers in a single center, a homogeneous patient population and prospective data collection were sufficient to indicate the significance of GPS as postoperative prognostication of patients with advanced ESCC. The prognosis for patients undergoing radical resection is influenced by various pathological characteristics of the resected tumor specimen. Especially in patients receiving nCRT, the grade of response to CRT based on histopathological examinations is well known to be associated with prognosis.18 Generally, pathological TNM classification is the current gold standard for predicting outcome, and venous/lymphatic involvement, nodal metastases, response to nCRT, and depth of penetration have been accepted as parameters predicting postoperative outcome in the field of esophageal surgery.19,20 Indeed, the univariate analysis in this study showed the similar prognostic values for these conventional parameters. However, these parameters are evaluated only after surgery. Of interest, multivariate analyses revealed that GPS was associated with postoperative mortality, indicating that GPS, measured at admission prior to treatment, might become the useful predictor of postoperative outcome; although, we should be careful in drawing this conclusion on the basis of small number of patients. The presence of an ongoing systemic inflammatory response is caused by infiltration of proinflammatory lymphocytes,21 and is associated with poor outcome in patients with advanced cancer.15,22,23 Recently, several papers have reported that the presence of a systemic inflammatory response appears to be a useful indicator of outcome among patients with esophageal cancer.14,24 However, few studies have investigated whether GPS is useful for predicting postoperative outcome in patients with advanced ESCC. In this point, this study is the first
Kobayashi et al 733
report that revealed the efficacy of GPS as a prognostic variable even in such cases. The cause-effect relationship between a systemic inflammatory response and cancer survival is questionable. However, it may be that the presence of a systemic inflammatory response and the associated nutritional decline25,26 influences tolerance and compliance with active treatment.17,27 An alternative explanation is that an elevated C-reactive protein concentration may identify those patients with a proangiogenic environment, as angiogenesis is associated with poor outcome in patients with gastrointestinal tumors,28,29 and circulating concentrations of vascular endothelial growth factor are directly associated with C-reactive protein.30 Results of the present study showing that GPS had close correlation with venous/lymphatic invasion, as well as lymph node status, may be explained by functional deterioration and/or resistance to nCRT caused by a systemic inflammatory response. Serum albumin is related to the systemic inflammatory response,16 and serum albumin level > 35 g/L is independent predictive factor of complete response to CRT in patients with advanced esophageal cancer treated with definitive CRT.31 It is clinically obvious that patients with elevated C-reactive protein and low albumin correspond to patients with much more advanced stages of the disease. On the contrary, patients with advanced carcinoma with multiple metastatic lymph nodes vascular and lymphatic invasion will have a much worst nutritional status. GPS may thus reflect both the presence of an ongoing systemic inflammatory response (C-reactive protein) and the progressive nutritional decline (albumin) of the patient with advanced cancer. Therefore, systemic inflammatory response reflected by the GPS may lead to malnutrition and functional deterioration, ultimately resulting in increased mortality. The prognosis of patients who showed complete response to nCRT followed by surgery is obviously favorable with 5-year survival rates of 62%.10 Our results also showed that cancer-specific survivals of patients with grades 2 and 3 in terms of response to nCRT were 51.6%, which was significantly better than those with grade 1. However, the precise assessment of response to nCRT has been made by histopathological examination only after a major operation so far. In contrast, mean survival in GPS 2 group was so poor compared with that in GPS 0 and GPS 1 groups. Pathological examination revealed that 3 out of 5 patients in GPS 2 group had many lymph node metastases (more than 6), and all patients in GPS 2 group had both massive lymphatic and venous
734 Kobayashi et al
involvement. Recurrent diseases progressed so rapidly that they could not receive sufficient postoperative treatments. As a result, they died of multiple lymph node metastasis, as well as liver and lung metastasis. In addition, postoperative prognosis of GPS 2 group in this study was worse than that of GPS 2 group without nCRT, although there was insignificant difference. These findings strongly suggested that nCRT to GPS 2 group might do more harm than good. It is noteworthy that GPS measured prior to nCRT was associated with cancer-specific survival, indicating that in a selected case, GPS measured at admission could avoid surgery with little hope beforehand, and it may be useful for making an alternative decision toward treatment strategy. Although this is a relatively small study in a single center and requires verification in large cohorts in other centers, GPS, measured prior to nCRT, may be used as a novel predictor of postoperative outcome in patients with advanced ESCC, and it may be useful in selecting patients suitable for nCRT followed by radical surgery. REFERENCES 1. Lerut T, Coosemans W, De Leyn P, Van Raemdonck D, Deneffe G, Decker G. Treatment of esophageal carcinoma. Chest 1999;116(Suppl):463S-5S. 2. Nygaard K, Hagen S, Hansen HS, Hatlevoll R, Hultborn R, Jakobsen A, et al. Pre-operative radiotherapy prolongs survival in operable esophageal carcinoma: a randomized, multicenter study of pre-operative radiotherapy and chemotherapy. The second Scandinavian trial in esophageal cancer. World J Surg 1992;16:1104-9. 3. Apinop C, Puttisak P, Preecha N. A prospective study of combined therapy in esophageal cancer. Hepatogastroenterology 1994;41:391-3. 4. Le Prise E, Etienne PL, Meunier B, Maddern G, Ben Hassel M, Gedouin D, et al. A randomized study of chemotherapy, radiation therapy, and surgery versus surgery for localized squamous cell carcinoma of the esophagus. Cancer 1994;73: 1779-84. 5. Bosset JF, Gignoux M, Triboulet JP, Tiret E, Mantion G, Elias D, et al. Chemoradiotherapy followed by surgery compared with surgery alone in squamous-cell cancer of the esophagus. N Engl J Med 1997;337:161-7. 6. Urba SG, Orringer MB, Turrisi A, Iannettoni M, Forastiere A, Strawderman M. Randomized trial of preoperative chemoradiation versus surgery alone in patients with locoregional esophageal carcinoma. J Clin Oncol 2001;19:305-13. 7. Burmeister BH, Smithers BM, Gebski V, Fitzgerald L, Simes RJ, Devitt P, et al. Surgery alone versus chemoradiotherapy followed by surgery for resectable cancer of the oesophagus: a randomised controlled phase III trial. Lancet Oncol 2005;6: 659-68. 8. Walsh TN, Noonan N, Hollywood D, Kelly A, Keeling N, Hennessy TP. A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med 1996; 335:462-7.
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9. Mariette C, Piessen G, Triboulet JP. Therapeutic strategies in oesophageal carcinoma: role of surgery and other modalities. Lancet Oncol 2007;8:545-53. 10. Mariette C, Piessen G, Lamblin A, Mirabel X, Adenis A, Triboulet JP. Impact of preoperative radiochemotherapy on postoperative course and survival in patients with locally advanced squamous cell oesophageal carcinoma. Br J Surg 2006;93:1077-83. 11. Gardner-Thorpe J, Hardwick RH, Dwerryhouse SJ. Salvage oesophagectomy after local failure of definitive chemoradiotherapy. Br J Surg 2007;94:1059-66. 12. Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet 2001;357:539-45. 13. Coussens LM, Werb Z. Inflammation and cancer. Nature 2002;420:860-7. 14. Crumley AB, McMillan DC, McKernan M, McDonald AC, Stuart RC. Evaluation of an inflammation-based prognostic score in patients with inoperable gastro-oesophageal cancer. Br J Cancer 2006;94:637-41. 15. McMillan DC, Canna K, McArdle CS. Systemic inflammatory response predicts survival following curative resection of colorectal cancer. Br J Surg 2003;90:215-9. 16. McMillan DC, Elahi MM, Sattar N, Angerson WJ, Johnstone J, McArdle CS. Measurement of the systemic inflammatory response predicts cancer-specific and non-cancer survival in patients with cancer. Nutr Cancer 2001;41:64-9. 17. Forrest LM, McMillan DC, McArdle CS, Angerson WJ, Dunlop DJ. Comparison of an inflammation-based prognostic score (GPS) with performance status (ECOG) in patients receiving platinum-based chemotherapy for inoperable non-small-cell lung cancer. Br J Cancer 2004;90:1704-6. 18. Esophageal Disease Research Society. Guidelines for the Clinical and Pathologic Studies on Carcinoma of the Esophagus. 9th ed. Tokyo: Kanehara; 1999. 19. Roder JD, Busch R, Stein HJ, Fink U, Siewert JR. Ratio of invaded to removed lymph nodes as a predictor of survival in squamous cell carcinoma of the oesophagus. Br J Surg 1994; 81:410-3. 20. Siewert JR, Bottcher K, Stein HJ, Roder JD. Relevant prognostic factors in gastric cancer: ten-year results of the German Gastric Cancer Study. Ann Surg 1998;228:449-61. 21. Canna K, McArdle PA, McMillan DC, McNicol AM, Smith GW, McKee RF, et al. The relationship between tumour Tlymphocyte infiltration, the systemic inflammatory response and survival in patients undergoing curative resection for colorectal cancer. Br J Cancer 2005;92:651-4. 22. Hilmy M, Bartlett JM, Underwood MA, McMillan DC. The relationship between the systemic inflammatory response and survival in patients with transitional cell carcinoma of the urinary bladder. Br J Cancer 2005;92:625-7. 23. Jamieson NB, Glen P, McMillan DC, McKay CJ, Foulis AK, Carter R, et al. Systemic inflammatory response predicts outcome in patients undergoing resection for ductal adenocarcinoma head of pancreas. Br J Cancer 2005;92:21-3. 24. Crumley AB, McMillan DC, McKernan M, Going JJ, Shearer CJ, Stuart RC. An elevated C-reactive protein concentration, prior to surgery, predicts poor cancer-specific survival in patients undergoing resection for gastro-oesophageal cancer. Br J Cancer 2006;94:1568-71. 25. Scott HR, McMillan DC, Forrest LM, Brown DJ, McArdle CS, Milroy R. The systemic inflammatory response, weight loss, performance status and survival in patients with inoperable non-small cell lung cancer. Br J Cancer 2002;87:264-7. 26. McMillan DC, Scott HR, Watson WS, Preston T, Milroy R, McArdle CS. Longitudinal study of body cell mass depletion
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and the inflammatory response in cancer patients. Nutr Cancer 1998;31:101-5. 27. Bromwich E, McMillan DC, Lamb GW, Vasey PA, Aitchison M. The systemic inflammatory response, performance status and survival in patients undergoing alpha-interferon treatment for advanced renal cancer. Br J Cancer 2004;91:1236-8. 28. Tanigawa N, Amaya H, Matsumura M, Shimomatsuya T. Correlation between expression of vascular endothelial growth factor and tumor vascularity, and patient outcome in human gastric carcinoma. J Clin Oncol 1997;15:826-32. 29. Fondevila C, Metges JP, Fuster J, Grau JJ, Palacin A, Castells A, et al. p53 and VEGF expression are independent
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predictors of tumour recurrence and survival following curative resection of gastric cancer. Br J Cancer 2004;90: 206-15. 30. Xavier P, Belo L, Beires J, Rebelo I, Martinez-de-Oliveira J, Lunet N, et al. Serum levels of VEGF and TNF-alpha and their association with C-reactive protein in patients with endometriosis. Arch Gynecol Obstet 2006;273:227-31. 31. Di Fiore F, Lecleire S, Pop D, Rigal O, Hamidou H, Paillot B, et al. Baseline nutritional status is predictive of response to treatment and survival in patients treated by definitive chemoradiotherapy for a locally advanced esophageal cancer. Am J Gastroenterol 2007;102:2557-63.
Background. Recent studies have revealed that Glasgow prognostic score (GPS), an inflammation-based prognostic score, is associated with poor outcome in a variety of tumors. However, few studies have investigated whether GPS measured prior to neoadjuvant chemoradiotherapy (nCRT) is useful for postoperative prognosis of patients with advanced esophageal squamous cell carcinoma (ESCC). Methods. GPS was calculated on the basis of admission data as follows: patients with both an elevated C-reactive protein (>10 mg/L) and hypoalbuminaemia (<35 g/L) were allocated a GPS score of 2. Patients in whom only 1 of these biochemical abnormalities was present were allocated a GPS score of 1, and patients with a normal C-reactive protein and albumin were allocated a score of 0. All patients underwent radical en-bloc resection 3--4 weeks after nCRT. Results. A total of 48 patients with clinical TNM stage II/III were enrolled. Univariate analyses revealed that there were significant differences in cancer-specific survival in relation to grade of response to nCRT (P = .004), lymph node status (P = .0065), lymphatic invasion (P = .0002), venous invasion (P = .0001), pathological TNM classification (P = .015), and GPS (P < .0001). GPS classification showed a close relationship with lymphatic invasion, venous invasion, and number of lymph node (P = .0292, .0473, and .0485, respectively). GPS was found to be the only independent predictor of cancer-specific survival (odds ratio, 0.17; 95% confidence interval, 0.06–0.52; P = .0019). Conclusions. GPS, measured prior to nCRT, is an independent novel predictor of postoperative outcome in patients with advanced ESCC. (Surgery 2008;144:729-35.) From the Department of Surgery, Showa General Hospital, Tokyo, Japan
BECAUSE
OF HIGH RATES OF LOCOREGIONAL AND DISTANT
RECURRENCE, NEOADJUVANT CHEMORADIOTHERAPY
(NCRT) has been proposed, expecting the elimination of potential systemic micrometastases and promoting local ‘‘downstaging’’ that may increase the curative resection rate.1 None of prospective randomized
Accepted for publication August 15, 2008. Reprint requests: Takashi Kobayashi, MD, PhD, Department of Surgery, Showa General Hospital, 2-450 Tenjincho, Kodaira, Tokyo 187-8510, Japan. E-mail: [email protected]. 0039-6060/$ - see front matter Ó 2008 Mosby, Inc. All rights reserved. doi:10.1016/j.surg.2008.08.015
trials of patients with esophageal cancer, however, has demonstrated any benefit for nCRT.2-8 Recently, a multidisciplinary approach including surgery, radiotherapy, and chemotherapy, alone or in combination, has been proposed for locally advanced esophageal cancer.9 Although the addition of surgery to chemotherapy could result in improved local control and survival in selected patients showing complete response to nCRT,10 it is difficult to select precisely those particular patients prior to operation. Moreover, surgery as salvage treatment in patients with no response to nCRT or persistent tumor after definitive chemoradiotherapy is associated with high mortality and morbidity.11 So it would be clinically useful if we SURGERY 729
730 Kobayashi et al
could select patients, prior to treatment, suitable for nCRT in combination with surgery for advanced esophageal squamous cell carcinoma (ESCC) in terms of postoperative cancer-specific survival. It is increasingly recognized that it is not only the intrinsic properties of tumor cells that determine tumor spread but also the host inflammatory response.12,13 Albumin does not only reflect status. Recently, the relationship of measures of systemic inflammation and immunity to cancer outcome has been of increasing interest; however, it has been poorly studied. Glasgow prognostic score (GPS), an inflammation-based prognostic score that includes serum C-reactive protein and serum albumin, has been reported to be one of the most useful scoring systems for the prognosis of patients with advanced cancer.14-16 The present study was conducted to investigate whether GPS, prior to nCRT, could predict postoperative cancer-specific survival in patients with advanced ESCC. PATIENTS AND METHODS Patients. Between March 2000 and March 2007, 81 consecutive patients with esophageal carcinoma underwent surgical resection in the surgical unit of Showa General Hospital. Of these 81 patients, 71 patients were diagnosed as the stage II/III. However, 13 patients among them were excluded from this study, as they showed severe anemia, leukocytopenia (or neutropenia), coronary artery disease, renal dysfunction, or were 80 years or older. The other 10 patients refused nCRT and received surgery alone. As a result, 23 patients were excluded from this study, and 48 patients with ESCC who received nCRT subsequently followed by potentially curative resection were enrolled in this retrospective study. Patients were routinely evaluated by endoscopy, computed tomography, and esophagogastroduodenal barium study, and occasionally FDG-PET before and after nCRT. Clinical TNM (cTNM) stage II/III tumors, excluding T4, were considered to be amenable to this study. Routine laboratory measurements including serum albumin and C-reactive protein, and tumor marker such as squamous cell carcinoma antigen (SCC) were carried out on the same day before nCRT in order to exclude any inflammatory effect of preoperative sequential examinations, such as endoscopy and biopsy. C-reactive protein, and SCC were routinely measured at our laboratory. Briefly, serum C-reactive protein levels were measured with an immunodetection kit (the cutoff values were 10 mg/L). SCC is known to be one of the tumor markers used in esophageal squamous cell
Surgery November 2008
carcinoma. Serum SCC levels were measured using an enzyme immunoassay kit (the cutoff values were 1.5 ng/mL). At this time, no patient showed clinical evidence of infection or any other inflammatory conditions, such as pneumonia and ulcerative colitis. GPS was constructed as previously described.17 Briefly, patients with both an elevated C-reactive protein (>10 mg/L) and hypoalbuminaemia (<35 g/L) were allocated a score of 2. Patients in whom only 1 of these biochemical abnormalities was present were allocated a score of 1. Patients in whom neither of these abnormalities was present were allocated a score of 0. The study was approved by the Research Ethics Committee of Showa General Hospital. Neoadjuvant chemoradiotherapy. nCRT regimen consisted of both fluorouracil, 600 mg/m2 per day delivered by continuous intravenous infusion on days 1 to 5, and cisplatin, 10 mg/body per day on days 1–5 and 5 mg/body per day on days 8–12 and 15–19, respectively, delivered by intravenous infusion in combination with concomitant radiotherapy (30 Gy over 3 weeks). Histological criteria for response to CRT were as follows:18 grade 0, neither necrosis nor cellular or structural changes seen throughout the lesion; grade 1, necrosis or disappearance of tumor in <2/3 of the whole lesion; grade 2, necrosis or disappearance of tumor in $2/3 of the whole lesion, but viable tumor cells still remain; and grade 3, whole lesion is necrotic and/or replaced by fibrosis, with or without granulomatous changes, and no viable tumor cells are observed. CRT was considered effective in patients with histological response of grade 2 or 3. Conversely, CRT was judged ineffective in patients with histological response of grade 0 or 1. The extent of tumor spread was recorded using the TNM classification. Endoscopy, computed tomography were performed again weeks after nCRT in order to determine resectability. As to the indication for operation in our hospital, radical esophageal resection is indicated for clinical stages I, II, and III cancer. If they detect any remote metastasis, radical esophageal resection is not performed. Surgical technique. Surgical resection consisted of radical en-bloc esophagectomy with an extended en bloc mediastinal and abdominal lymphadenectomy 3–4 weeks after nCRT. Cervical lymphadenectomy was not undertaken routinely. Intrathoracic esophagogastric anastomosis for reconstruction using a circular stapler was performed after esophagectomy. Statistical analysis. Data are presented as mean and range (95% confidence interval [CI]).
Kobayashi et al 731
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Table I. Clinical characteristics in patients with esophageal squamous cell carcinoma Patients (n = 48) Age (yr) < 70 $70 Sex Male Female GPS 0 1 2 Tumor site Ut Mt Lt SCC <1.5 ng/ml $1.5 ng/ml cTNM classification IIA IIB III Grade of response to nCRT 1 2 3
Table II. Clinical characteristics and cancerspecific survival in patients with esophageal squamous cell carcinoma: univariate analysis Survival Survival P Patients (months) (months) (n = 48) mean (95% CI) value
36 12 39 9 27 16 5 5 26 17 26 14 13 7 28 29 16 3
GPS, Glasgow Prognostic Score; nCRT, neoadjuvant chemoradiotherapy.
Univariate survival analysis was performed using the Kaplan-Meier method with the log-rank test. Multivariate survival analysis and calculation of odds ratios with 95% CI was performed Cox proportional hazard regression model, including all covariates that were significant on univariate analysis. Correlation between GPS classification and age, sex, tumor site, SCC, grade of response to nCRT, number of lymph nodes metastasis, lymphatic invasion, venous invasion, and pTNM classification were analyzed by v2 test or Fisher exact test as appropriate. Analysis was performed using software package Stat View version 5.0 for Windows (SAS Institute Inc., Cary, NC). RESULTS The classified background characteristics of the 48 patients who under went nCRT followed by surgery for ESCC are shown in Table I. There were 39 men and 9 women. Twenty-nine patients were categorized into grade 1 of response to nCRT, 16 into grade 2, and 3 into grade 3. Results of univariate analysis of cancer-specific survival are shown in Table II. The present study showed that mean survival times in all 48 patients
Overall Age(yr) < 70 $70 Sex Male Female GPS 0 1 and 2 Tumor site Ut Mt Lt SCC <1.5 ng/ml $1.5 ng/ml Grade of response to nCRT 1 2, 3 Number of lymph nodes metastasis 5$ $6 Lymphatic invasion negative positive Venous invasion negative positive pTNM classification 0+I II+III
48
24.6
19.1–30.0
36 12
21.6 33.3
16.0–27.3 18.8–47.9 .4961
39 9
24.3 25.8
18.3–30.3 9.6–42.0 .3652
27 21
31.3 16.0
23.4–39.1 9.8–22.1 <.0001
5 26 17
15.2 20.7 33.3
6.2–24.2 14.0–27.3 22.2–44.4 .0589
26 14
24.5 21.8
16.8–32.1 12.4–31.2 .4812
29 19
19.7 32.1
12.6–26.8 23.9–40.2 .004
39 9
27.7 11.1
21.4–34.0 6.5–15.7 .0065
24 24
30.3 18.8
11.0–26.7 22.9–37.7 .0002
23 25
31.0 18.6
23.5–38.6 11.0–26.2 .0001
9 39
36.4 21.8
23.2–49.7 15.9–27.8 .0150
GPS, Glasgow Prognostic Score; nCRT, neoadjuvant chemoradiotherapy; Ut, upper thoracic; Mt, middle thoracic; Lt, lower thoracic.
were 24.6 months (95% CI, 19.1–30.0 months), with 3- and 5-year survival rates of 36.4 % and 29.1%, respectively. There were no significant differences in overall survival in terms of age (<70/$70), sex, tumor site, or SCC. On the other hand, significant differences were observed in relation to grade of response to nCRT (1/2 and 3), number of lymph node metastasis (5$/$6), lymphatic invasion, venous invasion, pTNM (0+I/II+III) classification, and GPS (0/1 and 2). Table III shows the relationships between GPS and clinicopathological characteristics. Age, sex,
732 Kobayashi et al
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Table III. Relationships between clinicopathological characteristics and GPS in patients with esophageal squamous cell carcinoma GPS 0 GPS 1 GPS 2 P (n = 27) (n = 16) (n = 5) value 21 6
11 5
4 1
21 6
15 1
3 2
3 13 11
2 9 5
0 4 1
.7285
18 6
6 5
2 3
.2280
.7745
.1886
P Grade of nCRT response (1/2 and 3) Lymphatic invasion (negative/positive) Venous invasion (negative/positive) Number of lymph nodes metastasis (5$/$6) pTNM (stage 0+I/II+III) GPS (0/1 and 2)
Odds Ratio 95% CI
.6711
1.340
0.34–5.27
.2828
0.540
0.18–1.66
.4743
0.640
0.19–2.18
.0778
0.263
0.06–1.16
.6476 .0019
0.685 0.170
0.14–3.46 0.06–0.52
GPS, Glasgow Prognostic Score; nCRT, neoadjuvant chemoradiotherapy.
(%)
23 4
14 2
2 3
GPS 0
100
.0485
15 12
9 7
5 0
17 10
7 9
0 5
.0292
16 11
7 9
0 5
.0473
7 20
2 14
0 5
.1605
Cancer-specific survival rate
Age (yr) <70 $70 Sex Male Female Tumor site Ut Mt Lt SCC <1.5 ng/ml $1.5 ng/ml Number of lymph nodes metastasis 5$ $6 Grade of response to nCRT 1 2 and 3 Lymphatic invasion Negative Positive Venous invasion Negative Positive pTNM classification 0+I II+III
Table IV. Multivariate logistic regression analysis in relation to survival in patients with esophageal squamous cell carcinoma
GPS 1
80 GPS 2
60
40
20
0 0
10
20
30
40
50
60
70
80
Months after surgery
.2899
GPS, Glasgow Prognostic Score; nCRT, neoadjuvant chemoradiotherapy; Ut, upper thoracic; Mt, middle thoracic; Lt, lower thoracic.
tumor site, SCC, pTNM, and grade of response to CRT showed no significant relationship with GPS classification. On the other hand, lymphatic invasion, venous invasion, and number of lymph node metastasis showed a close relationship with GPS classification. Multivariate analyses using the same factors as those in Table III revealed that GPS was associated with postoperative mortality (odds ratio, 0.17; 95% CI, 0.06–0.52; P = .0019) (Table IV). Kaplan-Meier analysis demonstrated significant differences among the 3 groups: GPS 0 (mean survival, 31.3 months; 95% CI, 23.4--39.1 months), GPS 1 (mean survival, 19.1 months; 95% CI, 11.7-26.6 months), and GPS 2 (mean survival, 5.8 months; 95% CI, 3.8--7.8 months). Thus the use of the GPS classification was able to clearly divide patients with SCCE into 3 independent groups (Figure). As to the mortality and morbidity after
Figure. Cancer-specific survival curves according to Glasgow prognostic score (GPS) 0–2. There were significant differences between GPS 0 and GPS 1 (P < .0001), and between GPS 1 and 2 (P = .0006). 5-year survival rates were 62.0% in patients with GPS 0, 7.8% in those with GPS 1, and 0% in those with GPS 2.
surgery, there was no mortality. There were complications in 10 patients (20.8%) as follows: anastomotic leakage in 3 patients, hematoma in 2, vocal cord palsy in 3, pneumonia in 1, chyrothorax in 1, and sepsis in 1. As to the morbidity in each group, postoperative complications were observed in 6 out of 27 patients of GPS 0, 1 out of 16 patients in GPS 1, and 3 out of 5 patients in GPS 2. Just for reference, we present our data on the 23 patients with stage II/III, who were excluded from this study and received surgery alone without nCRT. Eleven patients were graded into GPS 0 (mean survival, 26.0 months; 95% CI, 12.9--39.1 months), 7 patients into GPS 1 (mean survival, 16.1 months; 95% CI, 10.4--21.9 months), and 5
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patients into GPS 2 (mean survival, 12.2 months; 95% CI, 3.6--20.8 months). Especially, postoperative prognosis of GPS 2 group of this study (mean survival, 5.8 months) was worse than that of GPS 2 group without nCRT (mean survival, 12.2 months), albeit statistically not significant. As to the mortality and morbidity after surgery, there was no mortality. There were complications in 5 patients (21.7%) as follows: anastomotic leakage in 3 patients, vocal cord palsy in 2, and chyrothorax in 1. DISCUSSION This study was undertaken to see whether GPS, measured prior to nCRT, is useful in predicting postoperative outcome in patients with advanced ESCC. Despite the retrospective nature of the study and relatively small patient numbers in a single center, a homogeneous patient population and prospective data collection were sufficient to indicate the significance of GPS as postoperative prognostication of patients with advanced ESCC. The prognosis for patients undergoing radical resection is influenced by various pathological characteristics of the resected tumor specimen. Especially in patients receiving nCRT, the grade of response to CRT based on histopathological examinations is well known to be associated with prognosis.18 Generally, pathological TNM classification is the current gold standard for predicting outcome, and venous/lymphatic involvement, nodal metastases, response to nCRT, and depth of penetration have been accepted as parameters predicting postoperative outcome in the field of esophageal surgery.19,20 Indeed, the univariate analysis in this study showed the similar prognostic values for these conventional parameters. However, these parameters are evaluated only after surgery. Of interest, multivariate analyses revealed that GPS was associated with postoperative mortality, indicating that GPS, measured at admission prior to treatment, might become the useful predictor of postoperative outcome; although, we should be careful in drawing this conclusion on the basis of small number of patients. The presence of an ongoing systemic inflammatory response is caused by infiltration of proinflammatory lymphocytes,21 and is associated with poor outcome in patients with advanced cancer.15,22,23 Recently, several papers have reported that the presence of a systemic inflammatory response appears to be a useful indicator of outcome among patients with esophageal cancer.14,24 However, few studies have investigated whether GPS is useful for predicting postoperative outcome in patients with advanced ESCC. In this point, this study is the first
Kobayashi et al 733
report that revealed the efficacy of GPS as a prognostic variable even in such cases. The cause-effect relationship between a systemic inflammatory response and cancer survival is questionable. However, it may be that the presence of a systemic inflammatory response and the associated nutritional decline25,26 influences tolerance and compliance with active treatment.17,27 An alternative explanation is that an elevated C-reactive protein concentration may identify those patients with a proangiogenic environment, as angiogenesis is associated with poor outcome in patients with gastrointestinal tumors,28,29 and circulating concentrations of vascular endothelial growth factor are directly associated with C-reactive protein.30 Results of the present study showing that GPS had close correlation with venous/lymphatic invasion, as well as lymph node status, may be explained by functional deterioration and/or resistance to nCRT caused by a systemic inflammatory response. Serum albumin is related to the systemic inflammatory response,16 and serum albumin level > 35 g/L is independent predictive factor of complete response to CRT in patients with advanced esophageal cancer treated with definitive CRT.31 It is clinically obvious that patients with elevated C-reactive protein and low albumin correspond to patients with much more advanced stages of the disease. On the contrary, patients with advanced carcinoma with multiple metastatic lymph nodes vascular and lymphatic invasion will have a much worst nutritional status. GPS may thus reflect both the presence of an ongoing systemic inflammatory response (C-reactive protein) and the progressive nutritional decline (albumin) of the patient with advanced cancer. Therefore, systemic inflammatory response reflected by the GPS may lead to malnutrition and functional deterioration, ultimately resulting in increased mortality. The prognosis of patients who showed complete response to nCRT followed by surgery is obviously favorable with 5-year survival rates of 62%.10 Our results also showed that cancer-specific survivals of patients with grades 2 and 3 in terms of response to nCRT were 51.6%, which was significantly better than those with grade 1. However, the precise assessment of response to nCRT has been made by histopathological examination only after a major operation so far. In contrast, mean survival in GPS 2 group was so poor compared with that in GPS 0 and GPS 1 groups. Pathological examination revealed that 3 out of 5 patients in GPS 2 group had many lymph node metastases (more than 6), and all patients in GPS 2 group had both massive lymphatic and venous
734 Kobayashi et al
involvement. Recurrent diseases progressed so rapidly that they could not receive sufficient postoperative treatments. As a result, they died of multiple lymph node metastasis, as well as liver and lung metastasis. In addition, postoperative prognosis of GPS 2 group in this study was worse than that of GPS 2 group without nCRT, although there was insignificant difference. These findings strongly suggested that nCRT to GPS 2 group might do more harm than good. It is noteworthy that GPS measured prior to nCRT was associated with cancer-specific survival, indicating that in a selected case, GPS measured at admission could avoid surgery with little hope beforehand, and it may be useful for making an alternative decision toward treatment strategy. Although this is a relatively small study in a single center and requires verification in large cohorts in other centers, GPS, measured prior to nCRT, may be used as a novel predictor of postoperative outcome in patients with advanced ESCC, and it may be useful in selecting patients suitable for nCRT followed by radical surgery. REFERENCES 1. Lerut T, Coosemans W, De Leyn P, Van Raemdonck D, Deneffe G, Decker G. Treatment of esophageal carcinoma. Chest 1999;116(Suppl):463S-5S. 2. Nygaard K, Hagen S, Hansen HS, Hatlevoll R, Hultborn R, Jakobsen A, et al. Pre-operative radiotherapy prolongs survival in operable esophageal carcinoma: a randomized, multicenter study of pre-operative radiotherapy and chemotherapy. The second Scandinavian trial in esophageal cancer. World J Surg 1992;16:1104-9. 3. Apinop C, Puttisak P, Preecha N. A prospective study of combined therapy in esophageal cancer. Hepatogastroenterology 1994;41:391-3. 4. Le Prise E, Etienne PL, Meunier B, Maddern G, Ben Hassel M, Gedouin D, et al. A randomized study of chemotherapy, radiation therapy, and surgery versus surgery for localized squamous cell carcinoma of the esophagus. Cancer 1994;73: 1779-84. 5. Bosset JF, Gignoux M, Triboulet JP, Tiret E, Mantion G, Elias D, et al. Chemoradiotherapy followed by surgery compared with surgery alone in squamous-cell cancer of the esophagus. N Engl J Med 1997;337:161-7. 6. Urba SG, Orringer MB, Turrisi A, Iannettoni M, Forastiere A, Strawderman M. Randomized trial of preoperative chemoradiation versus surgery alone in patients with locoregional esophageal carcinoma. J Clin Oncol 2001;19:305-13. 7. Burmeister BH, Smithers BM, Gebski V, Fitzgerald L, Simes RJ, Devitt P, et al. Surgery alone versus chemoradiotherapy followed by surgery for resectable cancer of the oesophagus: a randomised controlled phase III trial. Lancet Oncol 2005;6: 659-68. 8. Walsh TN, Noonan N, Hollywood D, Kelly A, Keeling N, Hennessy TP. A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med 1996; 335:462-7.
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9. Mariette C, Piessen G, Triboulet JP. Therapeutic strategies in oesophageal carcinoma: role of surgery and other modalities. Lancet Oncol 2007;8:545-53. 10. Mariette C, Piessen G, Lamblin A, Mirabel X, Adenis A, Triboulet JP. Impact of preoperative radiochemotherapy on postoperative course and survival in patients with locally advanced squamous cell oesophageal carcinoma. Br J Surg 2006;93:1077-83. 11. Gardner-Thorpe J, Hardwick RH, Dwerryhouse SJ. Salvage oesophagectomy after local failure of definitive chemoradiotherapy. Br J Surg 2007;94:1059-66. 12. Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet 2001;357:539-45. 13. Coussens LM, Werb Z. Inflammation and cancer. Nature 2002;420:860-7. 14. Crumley AB, McMillan DC, McKernan M, McDonald AC, Stuart RC. Evaluation of an inflammation-based prognostic score in patients with inoperable gastro-oesophageal cancer. Br J Cancer 2006;94:637-41. 15. McMillan DC, Canna K, McArdle CS. Systemic inflammatory response predicts survival following curative resection of colorectal cancer. Br J Surg 2003;90:215-9. 16. McMillan DC, Elahi MM, Sattar N, Angerson WJ, Johnstone J, McArdle CS. Measurement of the systemic inflammatory response predicts cancer-specific and non-cancer survival in patients with cancer. Nutr Cancer 2001;41:64-9. 17. Forrest LM, McMillan DC, McArdle CS, Angerson WJ, Dunlop DJ. Comparison of an inflammation-based prognostic score (GPS) with performance status (ECOG) in patients receiving platinum-based chemotherapy for inoperable non-small-cell lung cancer. Br J Cancer 2004;90:1704-6. 18. Esophageal Disease Research Society. Guidelines for the Clinical and Pathologic Studies on Carcinoma of the Esophagus. 9th ed. Tokyo: Kanehara; 1999. 19. Roder JD, Busch R, Stein HJ, Fink U, Siewert JR. Ratio of invaded to removed lymph nodes as a predictor of survival in squamous cell carcinoma of the oesophagus. Br J Surg 1994; 81:410-3. 20. Siewert JR, Bottcher K, Stein HJ, Roder JD. Relevant prognostic factors in gastric cancer: ten-year results of the German Gastric Cancer Study. Ann Surg 1998;228:449-61. 21. Canna K, McArdle PA, McMillan DC, McNicol AM, Smith GW, McKee RF, et al. The relationship between tumour Tlymphocyte infiltration, the systemic inflammatory response and survival in patients undergoing curative resection for colorectal cancer. Br J Cancer 2005;92:651-4. 22. Hilmy M, Bartlett JM, Underwood MA, McMillan DC. The relationship between the systemic inflammatory response and survival in patients with transitional cell carcinoma of the urinary bladder. Br J Cancer 2005;92:625-7. 23. Jamieson NB, Glen P, McMillan DC, McKay CJ, Foulis AK, Carter R, et al. Systemic inflammatory response predicts outcome in patients undergoing resection for ductal adenocarcinoma head of pancreas. Br J Cancer 2005;92:21-3. 24. Crumley AB, McMillan DC, McKernan M, Going JJ, Shearer CJ, Stuart RC. An elevated C-reactive protein concentration, prior to surgery, predicts poor cancer-specific survival in patients undergoing resection for gastro-oesophageal cancer. Br J Cancer 2006;94:1568-71. 25. Scott HR, McMillan DC, Forrest LM, Brown DJ, McArdle CS, Milroy R. The systemic inflammatory response, weight loss, performance status and survival in patients with inoperable non-small cell lung cancer. Br J Cancer 2002;87:264-7. 26. McMillan DC, Scott HR, Watson WS, Preston T, Milroy R, McArdle CS. Longitudinal study of body cell mass depletion
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and the inflammatory response in cancer patients. Nutr Cancer 1998;31:101-5. 27. Bromwich E, McMillan DC, Lamb GW, Vasey PA, Aitchison M. The systemic inflammatory response, performance status and survival in patients undergoing alpha-interferon treatment for advanced renal cancer. Br J Cancer 2004;91:1236-8. 28. Tanigawa N, Amaya H, Matsumura M, Shimomatsuya T. Correlation between expression of vascular endothelial growth factor and tumor vascularity, and patient outcome in human gastric carcinoma. J Clin Oncol 1997;15:826-32. 29. Fondevila C, Metges JP, Fuster J, Grau JJ, Palacin A, Castells A, et al. p53 and VEGF expression are independent
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predictors of tumour recurrence and survival following curative resection of gastric cancer. Br J Cancer 2004;90: 206-15. 30. Xavier P, Belo L, Beires J, Rebelo I, Martinez-de-Oliveira J, Lunet N, et al. Serum levels of VEGF and TNF-alpha and their association with C-reactive protein in patients with endometriosis. Arch Gynecol Obstet 2006;273:227-31. 31. Di Fiore F, Lecleire S, Pop D, Rigal O, Hamidou H, Paillot B, et al. Baseline nutritional status is predictive of response to treatment and survival in patients treated by definitive chemoradiotherapy for a locally advanced esophageal cancer. Am J Gastroenterol 2007;102:2557-63.