World J Surg DOI 10.1007/s00268-014-2486-2
Hemoglobin Level Influences Tumor Response and Survival After Neoadjuvant Chemoradiotherapy for Esophageal Squamous Cell Carcinoma Yoichi Hamai • Jun Hihara • Junya Taomoto • Ichiko Yamakita • Yuta Ibuki • Morihito Okada
Ó Socie´te´ Internationale de Chirurgie 2014
Abstract Background Neoadjuvant chemoradiotherapy (nCRT) followed by esophagectomy confers a survival benefit on patients with esophageal cancer. However, nCRT might be less meaningful for poor responders. Thus, being able to predict responses would help ensure the selection of optimal therapy. Methods We reviewed data from 123 patients with esophageal squamous cell carcinoma (ESCC) who underwent nCRT that comprised concurrent radiation (40 Gy) and chemotherapy followed by esophagectomy. We assessed associations between clinical and blood data obtained before starting nCRT and the pathologic response. Results We compared good (Japan Esophageal Society response evaluation criteria grades 3/2; n = 89, 72.4 %) and poor (grades 1/0; n = 34, 27.6 %) responders. Performance status (p = 0.02), hemoglobin level (p = 0.005), and platelet counts (p = 0.03) were statistically significant pretherapeutic factors for a response to nCRT. Multivariable analysis subsequently selected the hemoglobin level (odds ratio 1.52; 95 % confidence interval 1.08–2.15; p = 0.02) as the sole independent predictor. Receiver operating characteristic curves showed that the optimal cutoff for pretherapeutic hemoglobin was 13 g/dl for predicting a response. We found that 48.8 and 17.1 % of patients with hemoglobin level B13 and [13 g/dl,
Y. Hamai (&) J. Hihara J. Taomoto I. Yamakita Y. Ibuki M. Okada Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-Ku, Hiroshima 734-8551, Japan e-mail: [email protected] J. Hihara e-mail: [email protected]
respectively, were poor responders (p = 0.0002), with 5-year overall survival rates of 40.9 and 58.9 %, respectively (p = 0.048). Conclusions Pretherapeutic hemoglobin levels can influence responses and survival after nCRT for ESCC. Thus, hemoglobin levels can serve as a useful marker for tailoring optimal therapies for individual patients with advanced ESCC.
Abbreviations ESCC Esophageal squamous cell carcinoma Hb Hemoglobin nCRT Neoadjuvant chemoradiotherapy pCR Pathological complete response ROC Receiver operating characteristics SUVmax Maximum standardized uptake value
Introduction A multidisciplinary approach comprising surgery, radiotherapy, and chemotherapy is needed for local control and to improve survival in patients with esophageal cancer [1– 4]. Therefore, many institutions with substantial experience of treating esophageal cancer currently apply this trimodal strategy for resectable advanced esophageal cancer. Although the effect of neoadjuvant chemoradiotherapy (nCRT) is associated with improved survival, the prognosis is worse for poor responders than for good responders to nCRT [5–8]. Thus, poor responders might be exposed to toxicity and potential complications without obvious advantage. If the effects of CRT could be predicted from the patient’s pretherapeutic data, optimal therapy could be selected for these patients.
123
World J Surg
Some studies have attempted to predict the effects of neoadjuvant therapy based on assessments of biopsy samples [9–11]. However, the findings still could not clinically distinguish good from poor responders. Other studies of various cancers have also found that clinical blood parameters including hemoglobin (Hb) [12], albumin [13], lymphocytes [13, 14], platelets [13], neutrophil-to-lymphocyte ratio [15], C-reactive protein [13] and tumor markers [12] have a major impact on tumor responses to chemotherapy and/or radiation therapy. However, few studies have evaluated pretherapeutic clinical blood data from the viewpoint of identifying factors that could predict responses of esophageal squamous cell carcinoma (ESCC) to nCRT. The present study investigated associations between clinical and blood data obtained before starting treatment and the pathologic responses in patients with ESCC who underwent nCRT followed by esophagectomy.
Patients and methods Patients The institutional review board of Hiroshima University approved this retrospective review of 123 patients who underwent nCRT followed by esophagectomy at our institution between July 2003 and January 2013. Information about these patients was collected from chart reviews and a database. Clinical and blood data were collected immediately before starting nCRT. Pretreatment workups included a physical examination, standard laboratory tests, chest radiography, upper gastrointestinal endoscopy, esophagography, and computed tomography (CT) imaging of the neck, chest, and abdomen. A total of 94 patients have been examined by systematic positron emission tomography (PET)/CT imaging since 2006. Radiologists, surgeons, and oncologists at our hospital collectively evaluated pretreatment clinical tumor stages in all patients. Resectable cancer in the esophagus or gastroesophageal junction, where tumors are more invasive than in the muscularis propria (clinical T2–T3), lymph node metastasis (clinical N1), or resectable supraclavicular or celiac lymph node metastasis (clinical M1 LYM) were treated with nCRT and surgery. Some patients with clinical T4 primary tumors that had been reduced and thus rendered potentially resectable after nCRT underwent esophagectomy. Table 1 shows the pretherapeutic clinical and blood data for the patients (106 men and 17 women with a mean age of 63.1 ± 8.0 years) enrolled in our study. Their clinicopathologic profiles were based on the TNM classification of malignant tumors 6th edition [16]. Tumors were located in
123
Table 1 Pretherapeutic data of the study patients (n = 123) Factor
Data
Age (years)
63.1 ± 8.0
Sex (male/female)
106 (86.2 %)/17 (13.8 %)
Performance statusa (0/1/2–4)
105 (85.4 %)/18 (14.6 %)/0
Smoking (pack-years)
34.7 ± 31.0
Chronic alcohol consumption (;)
30 (24.4 %)/93 (75.6 %)
Primary tumor location (C/U/M/L/EG)
2 (1.6 %)/23 (18.7 %)/60 (48.8 %)/31 (25.2 %)/7 (5.7 %)
Histologic type by biopsy specimen [Well (G1)/Mod (G2)/Poor (G3)/ not assessed (GX)]
14 (11.4 %)/43 (35.0 %)/47 (38.2 %)/19(15.4 %)
Primary tumor depthb (cT 1/2/3/4)
3 (2.4 %)/15 (12.2 %)/99 (80.4 %)/6 (4.9 %)
Lymph node metastasisb (cN 0/1)
30 (24.4 %)/93 (75.6 %)
cStageb (II/III/IV)
31 (25.2 %)/67 (54.5 %)/25 (20.3 %)
SUVmax of primary tumor (n = 94)
11.3 ± 5.7
WBC count (/ll)
6823 ± 1855
Neutrophil/lymphocyte ratio
3.1 ± 1.8
Hemoglobin (g/dl)
13.5 ± 1.7
3
Platelets (9 10 /ll)
253 ± 84.3
Albumin (g/dl)
4.2 ± 0.4
Prognostic nutritional index CEA (ng/ml)
50.2 ± 5.5 3.6 ± 4.2
SCC antigen (ng/ml)
2.0 ± 2.1
Results are expressed as the number and percent or the mean ± SD C cervical, CEA carcinoembryonic antigen, EG esophagogastric junction, L lower thoracic, M middle thoracic, Mod moderately differentiated, Poor poorly-differentiated, SCC squamous cell carcinoma, SUVmax maximum standardized uptake value, U upper thoracic WBC white blood cell, Well well-differentiated a
Eastern Cooperative Oncology Group (ECOG) performance status
b
TNM grades according to the criteria of the TNM classification of malignant tumors, 6th Edition
the cervical esophagus; upper, middle, and lower thirds of the thoracic esophagus; and esophagogastric junction in 2 (1.6 %), 23 (18.7 %), 60 (48.8 %), 31 (25.2 %), and 7 (5.7 %) patients, respectively. All histologic tumor types were diagnosed as squamous cell carcinoma (SCC) in biopsy samples before treatment. Their SCC differentiation statuses were as follows: Well (G1), moderately (G2), poorly (G3), and not assessed (GX) differentiation were diagnosed in 14 (11.4 %), 43 (35.0 %), 47 (38.2 %), and 19 (15.4 %) patients, respectively. The depths of the primary tumors were judged to be T1, T2, T3, or T4 in 3 (2.4 %), 15 (12.2 %), 99 (80.4 %), and 6 (4.9 %) patients, respectively. Regional lymph node metastasis (N1) was identified in 93 (75.6 %) patients and M1 lymph node metastasis in 25 (20.3 %) patients. The clinical stages of cancer were, accordingly, II, III, and IV in 31 (25.2 %), 67 (54.5 %), and 25 (20.3 %) patients, respectively.
World J Surg Table 2 Comparison of variables for pathologic effects (grades 1/0 vs. 3/2) Factor
Poor responders, grades 1/0 (n = 34)
Good responders, grades 3/2 (n = 89)
p
Age (years)
61.5 ± 9.6
63.7 ± 7.3
0.19
Sex (male/female)
31 (91.2 %)/3 (8.8 %)
75 (84.3 %)/14 (15.7 %)
0.32
Performance statusa (0/1)
25 (73.5 %)/9 (26.5 %)
80 (89.9 %)/9 (10.1 %)
0.02 0.87
Smoking, pack-years
35.5 ± 36.7
34.4 ± 28.7
Chronic alcohol consumption (;)
7 (20.6 %)/27 (79.4 %)
23 (25.8 %)/66 (74.2 %)
0.54
Histologic type, grade (G1/G2/G3) (n = 104)
3 (10.0 %)/11 (36.7 %)/16 (53.3 %)
11 (14.9 %)/32 (43.2 %)/31 (41.9 %)
0.54
Primary tumor location (C, U/M/L, EG)
6 (17.6 %)/15 (44.1 %)/13 (38.2 %)
19 (21.3 %)/45 (50.6 %)/25 (28.1 %)
0.55
Primary tumor depthb (cT 1, 2/3, 4)
2 (5.8 %)/32 (94.1 %)
16 (18.0 %)/73 (82.0 %)
0.09
Lymph node metastasisb (cN 0/1)
6 (17.6 %)/28 (82.3 %)
24 (27.0 %)/65 (73.0 %)
0.28
cStageb (II/III/IV)
6 (17.6 %)/24 (70.6 %)/4 (11.8 %)
25 (28.1 %)/43 (48.3 %)/21 (23.6 %)
0.08
SUVmax primary tumor (n = 94) WBC count (/ll)
11.9 ± 3.6 7227 ± 2342
11.1 ± 6.2 6669 ± 1620
0.56 0.14
Neutrophil/lymphocyte ratio
3.6 ± 2.1
2.9 ± 1.7
0.07
Hemoglobin (g/dl)
12.7 ± 2.1
13.8 ± 1.4
0.005
3
Platelet count (9 10 /ll)
283 ± 92
246 ± 79
0.03
Albumin (g/dl)
4.1 ± 0.5
4.2 ± 0.4
0.16
Prognostic nutritional index
48.8 ± 6.3
50.7 ± 5.2
0.09
CEA (ng/mL)
4.8 ± 7.1
3.1 ± 2.3
0.05
SCC antigen (ng/ml)
2.4 ± 2.4
1.8 ± 2.0
0.20
Results are expressed as the number and percent or the mean ± SD a
ECOG performance status
b
TNM grades according to the criteria of the TNM classification of malignant tumors, 6th Edition
We also analyzed performance status, history of smoking, alcohol consumption, and maximum standardized uptake values (SUVmax) on pretherapeutic PET/CT images of the primary tumors. Additional pretherapeutic assessments included white blood cell counts, neutrophil/ lymphocyte ratios, platelet counts, hemoglogin and serum albumin levels, prognostic nutritional index [17, 18], and carcinoembryonic antigen and SCC antigen levels. Neoadjuvant chemoradiotherapy Neoadjuvant chemoradiotherapy comprised concurrent (40 Gy) radiotherapy and chemotherapy with 5-fluorouracil (5-FU) plus either docetaxel, or cisplatin or a combination of the two. The chemotherapy regimen between 2003 and 2007 consisted of docetaxel plus 5-FU [19]. The regimen from 2008 comprised standard doses of cisplatin (70 mg/m2/day) on days 1 and 29 and of 5-FU (700 mg/ m2/day) on days 1–4 and 29–32). Patients with elevated serum creatinine were treated with nedaplatin instead of cisplatin, and others in a clinical trial from 2009 received docetaxel, cisplatin and 5-FU [20]. The chemotherapy regimens were docetaxel/5-FU, cisplatin/5-FU, docetaxel/cisplatin/5-FU, and nedaplatin/5-FU in 39 (31.7 %), 62 (50.4 %), 18 (14.6 %), and 4 (3.3 %)
patients, respectively. Surgery for all patients proceeded 4–6 weeks after completing nCRT. Pathological evaluation of primary tumors The pathological effects of nCRT on primary tumors were graded from 0 to 3 according to response evaluation criteria regarding the effects of irradiation and/or chemotherapy published by the Japan Esophageal Society [21]: 0, ineffective with no recognizable cytologic or histologic therapeutic effect; 1, slightly effective with apparently viable cancer cells accounting for one-third or more of the tumor tissue; 2, moderately effective with viable cancer cells accounting for less than one-third of the tumor tissue; 3, markedly effective, with no evident viable cancer cells (pathologic complete response, or pCR). Statistical analysis Patient survival was calculated from the first day of nCRT until the date of death or the most recent follow-up. Survival data were analyzed using Kaplan–Meier curves and compared using the log-rank test. Categoric variables were analyzed using the v2 test, and continuous variables were analyzed using an unpaired t test. Potential independent
123
World J Surg Table 3 Multivariate analysis of pathologic response predictors Variable
OR
95 % CI
p
Performance statusa
0.51
0.16–1.63
0.25
Primary tumor depth
0.24
0.04–1.38
0.11
cStage
1.28
0.61– 0.67
0.51
Table 4 Prediction of pathologic responses based on pretherapeutic hemoglobin level Hemoglobin (g/dl)
No. of patients
Poor responders, grades 1/0 (n = 34)
Good responders, grades 3/2 (n = 89)
p
0.0002
Neutrophil/lymphocyte ratio
0.83
0.63–1.08
0.16
B13.0
41
20 (48.8 %)
21 (51.2 %)
Hemoglobin
1.52
1.08–2.15
0.02
[13.0
82
14 (17.1 %)
68 (82.9 %)
Platelet count
1.00
0.99–1.00
0.33
Prognostic nutritional index
0.97
0.87–1.08
0.57
CEA
0.90
0.80–0.02
0.11
Multivariate analysis was performed using a logistic regression model CI confidence interval, OR odds ratio a
ECOG performance status
pretherapeutic parameters with p \ 0.1 selected by univariate analyses were entered into a backward stepwise multiple logistic regression analysis. In addition, Hb cutoffs for predicting a pathological response were determined using receiver operating characteristic (ROC) curves. All data were statistically analyzed using SPSS software (version 20.0; IBM, New York, NY, USA).
Results Relation between pathological response and survival The pathological responses of primary tumors to nCRT in 42 (34.1 %), 47 (38.2 %), 33 (26.8 %), and 1 (0.8 %) patients were graded as 3, 2, 1 and 0, respectively, according to the Japan Esophageal Society criteria. At the time of the outcome analysis, 75 patients remained alive and the survivors were followed up for a median of 37.5 (range 6.0–102.6) months. The 1-, 3- and 5-year survival rates were 92.5, 75.6, and 75.6 %, respectively, in patients with grade 3 responses, 84.1, 69.1, and 57.2 %, respectively, in those with grade 2 and 73.0, 31.8, and 25.2 %, respectively, in those with grades 1/0. Survival rates significantly differed between grades 3 and 1/0 (p = 0.0002) and between grades 2 and 1/0 (p = 0.003) but not between grades 3 and 2 (p = 0.27).
whereas other factors including pre-therapeutic SUVmax of primary tumor (p = 0.56), primary tumor depth (p = 0.09), lymph node metastasis (p = 0.28), prognostic nutritional index (p = 0.09), and clinical tumor stage (p = 0.08) were not. Pre-therapeutic parameters with p \ 0.1 in univariate analysis was subsequently entered into a multivariable analysis. Of the eight variables that were significant or borderline significant on univariate analysis, Hb (OR, 1.52; 95 %CI, 1.08–2.15; p = 0.02) emerged as the sole independent covariate for a response to nCRT (Table 3). Response and survival based on hemoglobin level We plotted the sensitivity and specificity of pathologic responses at the indicated Hb levels to prepare curves from which we derived an optimal pretherapeutic Hb cutoff value of 13 g/dl for predicting a response (area under the curve, 0.68; 95 % confidence interval, 0.57–0.80; p = 0.002). Table 4 shows the results of the pathologic responses according to the Hb cutoff of 13 g/dl. Pretherapeutic Hb was a significant predictive marker of a pathologic response, and 48.8 and 17.1 % of patients with Hb B13 or [13 g/dl, respectively, were poor responders (p = 0.0002). The sensitivity, specificity, and accuracy for predicting poor responders based on Hb B13 g/dl were 58.8, 76.4, and 71.5 %, respectively. The 1-, 3-, and 5-year survival rates were 85.2, 45.4, and 40.9 %, respectively, in patients with Hb B13 g/dl. They were 83.2, 67.7, and 58.9 %, respectively, in those with Hb [13 g/dl. Overall survival differed significantly between these two patient groups (p = 0.048).
Comparison of pathological good and poor responders
Discussion
We defined grades 3/2 as good responses (n = 89, 72.4 %) and grades 1/0 as poor responses (n = 34, 27.6 %) based on our survival data and then compared pre-therapeutic parameters between patients with good and poor responses (Table 2). Performance status (p = 0.02), Hb level (p = 0.005), and platelet number (p = 0.03) were statistically significant,
Neoadjuvant chemoradiotherapy followed by esophagectomy generally confers a survival benefit on patients with esophageal cancer [1–4]. However, the benefit is highly dependent on the tumor response to nCRT [5–8]. We found that nCRT elicited a good response for a large portion of patients (grades 3/2, n = 89, 72.4 %), and their prognosis was extremely favorable. In contrast, survival was significantly poorer for patients with a
123
World J Surg
poor response (grades 1/0, n = 34, 27.6 %) than for those with a good response (grades 3/2). Therefore, nCRT might not confer a survival benefit on some poor responders. The present study aimed to identify pretherapeutic clinical and blood parameters that could predict the pathologic responses of advanced ESCC to nCRT. We identified the pretherapeutic Hb level as an independent useful marker for predicting pathologic tumor response. Many patients with pretherapeutic Hb[13 g/dl had good pathologic responses. Conversely, nCRT did not confer any such a benefit on patients with Hb B13 g/dl. The Hb level was more significantly predictive of a tumor response than any other pretherapeutic parameters, including performance status, primary tumor depth, lymph node metastasis, tumor stage, SUVmax of the primary tumor, and other blood data. The effects of nCRT were inevitably influenced by compliance with nCRT, and the Hb level might be related to such compliance. We reduced the doses of chemotherapeutic agents for 17 (20.7 %) of our patients with Hb [13.0 g/dl (n = 82) and for 6 (14.6 %) with Hb B13.0 g/dl (n = 41). The frequency of decreasing the doses of chemotherapeutic agents did not differ significantly between these Hb levels (p = 0.41). Furthermore, the chemotherapy regimens in the present study mainly comprised docetaxel/5-FU, cisplatin/5-FU, and docetaxel/cisplatin/5-FU. Therefore, we investigated tumor response rates based on Hb B13 or [13 g/dl in the three groups. Although the cisplatin/5-FU regimen reached statistical significance, the other two did not because of a very small sample size. However, the tendencies of the responses to nCRT under these regimens were also similar between these Hb levels. The optimal cutoff value for Hb might vary somewhat among CRT regimens. The pretherapeutic Hb level and response to nCRT were significantly associated with the prognosis after nCRT and esophagectomy in the present study. However, the survival of ESCC patients might be also influenced by preoperative co-morbidities and postoperative complications. Therefore, we evaluated the frequency of these factors between the groups with Hb B13 and[13 g/dl. In all, 21 (51.2 %) of 41 patients with Hb B13.0 and 46 (56.1 %) of 82 patients with Hb [13.0 g/dl had preoperative co-morbidities (p = 0.61). Also, 24 (58.5 %) and 49 (59.8 %) with Hb B and[13.0 g/dl, respectively, developed postoperative complications (p = 0.90). The frequencies of co-morbidities and complications did not significantly differ between these Hb levels. The Hb level is associated with sensitivity [12], locoregional control [22, 23], and survival [24, 25] after radiation therapy for esophageal cancer regardless of chemotherapy. Several findings for other types of cancer also suggest that the Hb level is an important determinant of treatment outcomes [26–28]. However, the Hb level has never been evaluated as a predictor of pathologic tumor response to neoadjuvant therapy. The present study
correlated tumor responses with Hb levels in surgically resected specimens and showed that pretherapeutic Hb levels can also predict pathologic responses and the survival of patients with advanced ESCC treated by nCRT. The pretherapeutic Hb level was B13 g/dl in 41 (33.3 %) of 123 patients in our study, and the response to nCRT was significantly poorer for many of them than for the patients with Hb[13 g/dl. Anemia in patients with malignant tumors is generally caused by tumor-related bleeding, nutritional deficiencies, and tumor infiltration of bone marrow. In addition, malignant tumors are often associated with inflammatory cytokines such as tumor necrosis factor and interleukin-1, which are both associated with inhibiting the proliferation of erythrocytic progenitors [29, 30]. Therefore, anemia is a frequent complication of malignant tumors. Tumor-associated anemia is a major pathogenetic mechanism that is involved in the development of tumor hypoxia, which deprives tumor cells of the oxygen essential for the cytotoxic activities of irradiation and chemotherapy. Thus, tumor-associated anemia is a direct cause of tumor resistance to these treatment strategies [31, 32]. Moreover, anemia and hypoxia indirectly reduce tumor sensitivity through mechanisms that include proteomic and genomic changes. These changes can lead to increased invasiveness and metastatic potential, loss of apoptosis, and chaotic angiogenesis, further increasing treatment resistance [32]. Therefore, the Hb level is an extremely important factor associated with both the therapeutic effect and the prognosis of patients with cancer. Although the specificity and accuracy of the pretherapeutic Hb value were high in the present study, the sensitivity was comparatively low for diagnosing poor responders. Therefore, good and poor responders cannot be precisely distinguished based on Hb levels alone. The Hb level is clinically useful, however, because it is uniformly available, recursive, inexpensive, and minimally invasive. Combining Hb levels with other biomarkers using a molecular biologic approach can contribute to more precise predictions of ESCC responses to nCRT.
Conclusions We discovered that the pretherapeutic Hb level could influence the pathologic responses of tumors and survival of the patient after nCRT for ESCC. It can serve as a potential predictor of tumor responses. Although large and prospective randomized studies are required to confirm this finding, evaluations based on Hb levels could easily be incorporated into routine clinical practice as one of the useful markers for determining optimal therapeutic strategies for individual patients with advanced ESCC.
123
World J Surg Conflict of interest The authors have no disclosures regarding commercial support or conflicts of interest. 16.
References
17.
1. Sjoquist KM, Burmeister BH, Smithers BM et al (2011) Survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal carcinoma: an updated meta-analysis. Lancet Oncol 12:681–692 2. Van Hagen P, Hulshof MC, van Lanschot JJ et al (2012) Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med 366:2074–2084 3. Tepper J, Krasna MJ, Niedzwiecki D et al (2008) Phase III trial of trimodality therapy with cisplatin, fluorouracil, radiotherapy, and surgery compared with surgery alone for esophageal cancer: CALGB 9781. J Clin Oncol 26:1086–1092 4. Walsh TN, Noonan N, Hollywood D et al (1996) A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med 335:462–467 5. Berger AC, Farma J, Scott WJ et al (2005) Complete response to neoadjuvant chemoradiotherapy in esophageal carcinoma is associated with significantly improved survival. J Clin Oncol 23:4330–4337 6. Bru¨cher BL, Stein HJ, Zimmermann F et al (2004) Responders benefit from neoadjuvant radiochemotherapy in esophageal squamous cell carcinoma: results of a prospective phase-II trial. Eur J Surg Oncol 30:963–971 7. Reynolds JV, Muldoon C, Hollywood D et al (2007) Long-term outcomes following neoadjuvant chemoradiotherapy for esophageal cancer. Ann Surg 245:707–716 8. Dittrick GW, Weber JM, Shridhar R et al (2012) Pathologic nonresponders after neoadjuvant chemoradiation for esophageal cancer demonstrate no survival benefit compared with patients treated with primary esophagectomy. Ann Surg Oncol 19: 1678–1684 9. Li SH, Huang EY, Lu HI et al (2012) Phosphorylated mammalian target of rapamycin expression is associated with the response to chemoradiotherapy in patients with esophageal squamous cell carcinoma. J Thorac Cardiovasc Surg 144:1352–1359 10. Duong C, Greenawalt DM, Kowalczyk A et al (2007) Pretreatment gene expression profiles can be used to predict response to neoadjuvant chemoradiotherapy in esophageal cancer. Ann Surg Oncol 14:3602–3609 11. Maher SG, Gillham CM, Duggan SP et al (2009) Gene expression analysis of diagnostic biopsies predicts pathological response to neoadjuvant chemoradiotherapy of esophageal cancer. Ann Surg 250:729–737 12. Yi Y, Li B, Sun H et al (2010) Predictors of sensitivity to chemoradiotherapy of esophageal squamous cell carcinoma. Tumour Biol 31:333–340 13. Yasuda K, Sunami E, Kawai K et al (2012) Laboratory blood data have a significant impact on tumor response and outcome in preoperative chemoradiotherapy for advanced rectal cancer. J Gastrointest Cancer 43:236–243 14. Kitayama J, Yasuda K, Kawai K et al (2010) Circulating lymphocyte number has a positive association with tumor response in neoadjuvant chemoradiotherapy for advanced rectal cancer. Radiat Oncol 5:47 15. Sato H, Tsubosa Y, Kawano T (2012) Correlation between the pretherapeutic neutrophil to lymphocyte ratio and the pathologic
18.
123
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29. 30. 31.
32.
response to neoadjuvant chemotherapy in patients with advanced esophageal cancer. World J Surg 36:617–622 Sobin LH, Wittekind C (2002) TNM classification of malignant tumours, 6th edn. John & Sons, New York Nozoe T, Kohno M, Iguchi T et al (2012) The prognostic nutritional index can be a prognostic indicator in colorectal carcinoma. Surg Today 42:532–535 Onodera T, Goseki N, Kosaki G (1984) Prognostic nutritional index in gastrointestinal surgery of malnourished cancer patients. Nippon Geka Gakkai Zasshi 85:1001–1005 (in Japanese; English abstract) Hihara J, Yoshida K, Hamai Y et al (2007) Phase I study of docetaxel (TXT) and 5-fluorouracil (5-FU) with concurrent radiotherapy in patients with advanced esophageal cancer. Anticancer Res 27:2597–2603 Emi M, Hihara J, Hamai Y et al (2012) Neoadjuvant chemoradiotherapy with docetaxel, cisplatin, and 5-fluorouracil for esophageal cancer. Cancer Chemother Pharmacol 69:1499–1505 Japan Esophageal Society (2009) Japanese classification of esophageal cancer, tenth edition: parts II and III. Esophagus 6:71–94 Zhao KL, Liu G, Jiang GL et al (2006) Association of haemoglobin level with morbidity and mortality of patients with locally advanced oesophageal carcinoma undergoing radiotherapy: a secondary analysis of three consecutive clinical phase III trials. Clin Oncol 18:621–627 Rades D, Golke H, Schild SE et al (2008) The impact of tumor expression of erythropoietin receptors and erythropoietin on clinical outcome of esophageal cancer patients treated with chemoradiation. Int J Radiat Oncol Biol Phys 71:152–159 Zenda S, Hironaka S, Boku N et al (2008) Impact of hemoglobin level on survival in definitive chemoradiotherapy for T4/M1 lymph node esophageal cancer. Dis Esophagus 21:195–200 Valencia Julve J, Alonso Ordun˜a V, Esco´ Baro´n R et al (2006) Influence of hemoglobin levels on survival after radical treatment of esophageal carcinoma with radiotherapy. Clin Transl Oncol 8:22–30 Langendijk H, de Jong J, Wanders R et al (2003) The importance of pre-treatment haemoglobin level in inoperable non-small cell lung carcinoma treated with radical radiotherapy. Radiother Oncol 67:321–325 Dunst J, Kuhnt T, Strauss HG et al (2003) Anemia in cervical cancers: impact on survival, patterns of relapse, and association with hypoxia and angiogenesis. Int J Radiat Oncol Biol Phys 56:778–787 Kim JH, Lee JM, Ryu KS et al (2011) The prognostic impact of duration of anemia during chemotherapy in advanced epithelial ovarian cancer. Oncologist 16:1154–1161 Varlotto J, Stevenson MA (2005) Anemia, tumor hypoxemia, and the cancer patient. Int J Radiat Oncol Biol Phys 63:25–36 Adamson JW (2008) The anemia of inflammation/malignancy: mechanisms and management. Hematology 2008:159–165 Vaupel P, Thews O, Hoeckel M (2001) Treatment resistance of solid tumors: role of hypoxia and anemia. Med Oncol 18: 243–259 Harrison L, Blackwell K (2004) Hypoxia and anemia: factors in decreased sensitivity to radiation therapy and chemotherapy? Oncologist 9:31–40
Hemoglobin Level Influences Tumor Response and Survival After Neoadjuvant Chemoradiotherapy for Esophageal Squamous Cell Carcinoma Yoichi Hamai • Jun Hihara • Junya Taomoto • Ichiko Yamakita • Yuta Ibuki • Morihito Okada
Ó Socie´te´ Internationale de Chirurgie 2014
Abstract Background Neoadjuvant chemoradiotherapy (nCRT) followed by esophagectomy confers a survival benefit on patients with esophageal cancer. However, nCRT might be less meaningful for poor responders. Thus, being able to predict responses would help ensure the selection of optimal therapy. Methods We reviewed data from 123 patients with esophageal squamous cell carcinoma (ESCC) who underwent nCRT that comprised concurrent radiation (40 Gy) and chemotherapy followed by esophagectomy. We assessed associations between clinical and blood data obtained before starting nCRT and the pathologic response. Results We compared good (Japan Esophageal Society response evaluation criteria grades 3/2; n = 89, 72.4 %) and poor (grades 1/0; n = 34, 27.6 %) responders. Performance status (p = 0.02), hemoglobin level (p = 0.005), and platelet counts (p = 0.03) were statistically significant pretherapeutic factors for a response to nCRT. Multivariable analysis subsequently selected the hemoglobin level (odds ratio 1.52; 95 % confidence interval 1.08–2.15; p = 0.02) as the sole independent predictor. Receiver operating characteristic curves showed that the optimal cutoff for pretherapeutic hemoglobin was 13 g/dl for predicting a response. We found that 48.8 and 17.1 % of patients with hemoglobin level B13 and [13 g/dl,
Y. Hamai (&) J. Hihara J. Taomoto I. Yamakita Y. Ibuki M. Okada Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-Ku, Hiroshima 734-8551, Japan e-mail: [email protected] J. Hihara e-mail: [email protected]
respectively, were poor responders (p = 0.0002), with 5-year overall survival rates of 40.9 and 58.9 %, respectively (p = 0.048). Conclusions Pretherapeutic hemoglobin levels can influence responses and survival after nCRT for ESCC. Thus, hemoglobin levels can serve as a useful marker for tailoring optimal therapies for individual patients with advanced ESCC.
Abbreviations ESCC Esophageal squamous cell carcinoma Hb Hemoglobin nCRT Neoadjuvant chemoradiotherapy pCR Pathological complete response ROC Receiver operating characteristics SUVmax Maximum standardized uptake value
Introduction A multidisciplinary approach comprising surgery, radiotherapy, and chemotherapy is needed for local control and to improve survival in patients with esophageal cancer [1– 4]. Therefore, many institutions with substantial experience of treating esophageal cancer currently apply this trimodal strategy for resectable advanced esophageal cancer. Although the effect of neoadjuvant chemoradiotherapy (nCRT) is associated with improved survival, the prognosis is worse for poor responders than for good responders to nCRT [5–8]. Thus, poor responders might be exposed to toxicity and potential complications without obvious advantage. If the effects of CRT could be predicted from the patient’s pretherapeutic data, optimal therapy could be selected for these patients.
123
World J Surg
Some studies have attempted to predict the effects of neoadjuvant therapy based on assessments of biopsy samples [9–11]. However, the findings still could not clinically distinguish good from poor responders. Other studies of various cancers have also found that clinical blood parameters including hemoglobin (Hb) [12], albumin [13], lymphocytes [13, 14], platelets [13], neutrophil-to-lymphocyte ratio [15], C-reactive protein [13] and tumor markers [12] have a major impact on tumor responses to chemotherapy and/or radiation therapy. However, few studies have evaluated pretherapeutic clinical blood data from the viewpoint of identifying factors that could predict responses of esophageal squamous cell carcinoma (ESCC) to nCRT. The present study investigated associations between clinical and blood data obtained before starting treatment and the pathologic responses in patients with ESCC who underwent nCRT followed by esophagectomy.
Patients and methods Patients The institutional review board of Hiroshima University approved this retrospective review of 123 patients who underwent nCRT followed by esophagectomy at our institution between July 2003 and January 2013. Information about these patients was collected from chart reviews and a database. Clinical and blood data were collected immediately before starting nCRT. Pretreatment workups included a physical examination, standard laboratory tests, chest radiography, upper gastrointestinal endoscopy, esophagography, and computed tomography (CT) imaging of the neck, chest, and abdomen. A total of 94 patients have been examined by systematic positron emission tomography (PET)/CT imaging since 2006. Radiologists, surgeons, and oncologists at our hospital collectively evaluated pretreatment clinical tumor stages in all patients. Resectable cancer in the esophagus or gastroesophageal junction, where tumors are more invasive than in the muscularis propria (clinical T2–T3), lymph node metastasis (clinical N1), or resectable supraclavicular or celiac lymph node metastasis (clinical M1 LYM) were treated with nCRT and surgery. Some patients with clinical T4 primary tumors that had been reduced and thus rendered potentially resectable after nCRT underwent esophagectomy. Table 1 shows the pretherapeutic clinical and blood data for the patients (106 men and 17 women with a mean age of 63.1 ± 8.0 years) enrolled in our study. Their clinicopathologic profiles were based on the TNM classification of malignant tumors 6th edition [16]. Tumors were located in
123
Table 1 Pretherapeutic data of the study patients (n = 123) Factor
Data
Age (years)
63.1 ± 8.0
Sex (male/female)
106 (86.2 %)/17 (13.8 %)
Performance statusa (0/1/2–4)
105 (85.4 %)/18 (14.6 %)/0
Smoking (pack-years)
34.7 ± 31.0
Chronic alcohol consumption (;)
30 (24.4 %)/93 (75.6 %)
Primary tumor location (C/U/M/L/EG)
2 (1.6 %)/23 (18.7 %)/60 (48.8 %)/31 (25.2 %)/7 (5.7 %)
Histologic type by biopsy specimen [Well (G1)/Mod (G2)/Poor (G3)/ not assessed (GX)]
14 (11.4 %)/43 (35.0 %)/47 (38.2 %)/19(15.4 %)
Primary tumor depthb (cT 1/2/3/4)
3 (2.4 %)/15 (12.2 %)/99 (80.4 %)/6 (4.9 %)
Lymph node metastasisb (cN 0/1)
30 (24.4 %)/93 (75.6 %)
cStageb (II/III/IV)
31 (25.2 %)/67 (54.5 %)/25 (20.3 %)
SUVmax of primary tumor (n = 94)
11.3 ± 5.7
WBC count (/ll)
6823 ± 1855
Neutrophil/lymphocyte ratio
3.1 ± 1.8
Hemoglobin (g/dl)
13.5 ± 1.7
3
Platelets (9 10 /ll)
253 ± 84.3
Albumin (g/dl)
4.2 ± 0.4
Prognostic nutritional index CEA (ng/ml)
50.2 ± 5.5 3.6 ± 4.2
SCC antigen (ng/ml)
2.0 ± 2.1
Results are expressed as the number and percent or the mean ± SD C cervical, CEA carcinoembryonic antigen, EG esophagogastric junction, L lower thoracic, M middle thoracic, Mod moderately differentiated, Poor poorly-differentiated, SCC squamous cell carcinoma, SUVmax maximum standardized uptake value, U upper thoracic WBC white blood cell, Well well-differentiated a
Eastern Cooperative Oncology Group (ECOG) performance status
b
TNM grades according to the criteria of the TNM classification of malignant tumors, 6th Edition
the cervical esophagus; upper, middle, and lower thirds of the thoracic esophagus; and esophagogastric junction in 2 (1.6 %), 23 (18.7 %), 60 (48.8 %), 31 (25.2 %), and 7 (5.7 %) patients, respectively. All histologic tumor types were diagnosed as squamous cell carcinoma (SCC) in biopsy samples before treatment. Their SCC differentiation statuses were as follows: Well (G1), moderately (G2), poorly (G3), and not assessed (GX) differentiation were diagnosed in 14 (11.4 %), 43 (35.0 %), 47 (38.2 %), and 19 (15.4 %) patients, respectively. The depths of the primary tumors were judged to be T1, T2, T3, or T4 in 3 (2.4 %), 15 (12.2 %), 99 (80.4 %), and 6 (4.9 %) patients, respectively. Regional lymph node metastasis (N1) was identified in 93 (75.6 %) patients and M1 lymph node metastasis in 25 (20.3 %) patients. The clinical stages of cancer were, accordingly, II, III, and IV in 31 (25.2 %), 67 (54.5 %), and 25 (20.3 %) patients, respectively.
World J Surg Table 2 Comparison of variables for pathologic effects (grades 1/0 vs. 3/2) Factor
Poor responders, grades 1/0 (n = 34)
Good responders, grades 3/2 (n = 89)
p
Age (years)
61.5 ± 9.6
63.7 ± 7.3
0.19
Sex (male/female)
31 (91.2 %)/3 (8.8 %)
75 (84.3 %)/14 (15.7 %)
0.32
Performance statusa (0/1)
25 (73.5 %)/9 (26.5 %)
80 (89.9 %)/9 (10.1 %)
0.02 0.87
Smoking, pack-years
35.5 ± 36.7
34.4 ± 28.7
Chronic alcohol consumption (;)
7 (20.6 %)/27 (79.4 %)
23 (25.8 %)/66 (74.2 %)
0.54
Histologic type, grade (G1/G2/G3) (n = 104)
3 (10.0 %)/11 (36.7 %)/16 (53.3 %)
11 (14.9 %)/32 (43.2 %)/31 (41.9 %)
0.54
Primary tumor location (C, U/M/L, EG)
6 (17.6 %)/15 (44.1 %)/13 (38.2 %)
19 (21.3 %)/45 (50.6 %)/25 (28.1 %)
0.55
Primary tumor depthb (cT 1, 2/3, 4)
2 (5.8 %)/32 (94.1 %)
16 (18.0 %)/73 (82.0 %)
0.09
Lymph node metastasisb (cN 0/1)
6 (17.6 %)/28 (82.3 %)
24 (27.0 %)/65 (73.0 %)
0.28
cStageb (II/III/IV)
6 (17.6 %)/24 (70.6 %)/4 (11.8 %)
25 (28.1 %)/43 (48.3 %)/21 (23.6 %)
0.08
SUVmax primary tumor (n = 94) WBC count (/ll)
11.9 ± 3.6 7227 ± 2342
11.1 ± 6.2 6669 ± 1620
0.56 0.14
Neutrophil/lymphocyte ratio
3.6 ± 2.1
2.9 ± 1.7
0.07
Hemoglobin (g/dl)
12.7 ± 2.1
13.8 ± 1.4
0.005
3
Platelet count (9 10 /ll)
283 ± 92
246 ± 79
0.03
Albumin (g/dl)
4.1 ± 0.5
4.2 ± 0.4
0.16
Prognostic nutritional index
48.8 ± 6.3
50.7 ± 5.2
0.09
CEA (ng/mL)
4.8 ± 7.1
3.1 ± 2.3
0.05
SCC antigen (ng/ml)
2.4 ± 2.4
1.8 ± 2.0
0.20
Results are expressed as the number and percent or the mean ± SD a
ECOG performance status
b
TNM grades according to the criteria of the TNM classification of malignant tumors, 6th Edition
We also analyzed performance status, history of smoking, alcohol consumption, and maximum standardized uptake values (SUVmax) on pretherapeutic PET/CT images of the primary tumors. Additional pretherapeutic assessments included white blood cell counts, neutrophil/ lymphocyte ratios, platelet counts, hemoglogin and serum albumin levels, prognostic nutritional index [17, 18], and carcinoembryonic antigen and SCC antigen levels. Neoadjuvant chemoradiotherapy Neoadjuvant chemoradiotherapy comprised concurrent (40 Gy) radiotherapy and chemotherapy with 5-fluorouracil (5-FU) plus either docetaxel, or cisplatin or a combination of the two. The chemotherapy regimen between 2003 and 2007 consisted of docetaxel plus 5-FU [19]. The regimen from 2008 comprised standard doses of cisplatin (70 mg/m2/day) on days 1 and 29 and of 5-FU (700 mg/ m2/day) on days 1–4 and 29–32). Patients with elevated serum creatinine were treated with nedaplatin instead of cisplatin, and others in a clinical trial from 2009 received docetaxel, cisplatin and 5-FU [20]. The chemotherapy regimens were docetaxel/5-FU, cisplatin/5-FU, docetaxel/cisplatin/5-FU, and nedaplatin/5-FU in 39 (31.7 %), 62 (50.4 %), 18 (14.6 %), and 4 (3.3 %)
patients, respectively. Surgery for all patients proceeded 4–6 weeks after completing nCRT. Pathological evaluation of primary tumors The pathological effects of nCRT on primary tumors were graded from 0 to 3 according to response evaluation criteria regarding the effects of irradiation and/or chemotherapy published by the Japan Esophageal Society [21]: 0, ineffective with no recognizable cytologic or histologic therapeutic effect; 1, slightly effective with apparently viable cancer cells accounting for one-third or more of the tumor tissue; 2, moderately effective with viable cancer cells accounting for less than one-third of the tumor tissue; 3, markedly effective, with no evident viable cancer cells (pathologic complete response, or pCR). Statistical analysis Patient survival was calculated from the first day of nCRT until the date of death or the most recent follow-up. Survival data were analyzed using Kaplan–Meier curves and compared using the log-rank test. Categoric variables were analyzed using the v2 test, and continuous variables were analyzed using an unpaired t test. Potential independent
123
World J Surg Table 3 Multivariate analysis of pathologic response predictors Variable
OR
95 % CI
p
Performance statusa
0.51
0.16–1.63
0.25
Primary tumor depth
0.24
0.04–1.38
0.11
cStage
1.28
0.61– 0.67
0.51
Table 4 Prediction of pathologic responses based on pretherapeutic hemoglobin level Hemoglobin (g/dl)
No. of patients
Poor responders, grades 1/0 (n = 34)
Good responders, grades 3/2 (n = 89)
p
0.0002
Neutrophil/lymphocyte ratio
0.83
0.63–1.08
0.16
B13.0
41
20 (48.8 %)
21 (51.2 %)
Hemoglobin
1.52
1.08–2.15
0.02
[13.0
82
14 (17.1 %)
68 (82.9 %)
Platelet count
1.00
0.99–1.00
0.33
Prognostic nutritional index
0.97
0.87–1.08
0.57
CEA
0.90
0.80–0.02
0.11
Multivariate analysis was performed using a logistic regression model CI confidence interval, OR odds ratio a
ECOG performance status
pretherapeutic parameters with p \ 0.1 selected by univariate analyses were entered into a backward stepwise multiple logistic regression analysis. In addition, Hb cutoffs for predicting a pathological response were determined using receiver operating characteristic (ROC) curves. All data were statistically analyzed using SPSS software (version 20.0; IBM, New York, NY, USA).
Results Relation between pathological response and survival The pathological responses of primary tumors to nCRT in 42 (34.1 %), 47 (38.2 %), 33 (26.8 %), and 1 (0.8 %) patients were graded as 3, 2, 1 and 0, respectively, according to the Japan Esophageal Society criteria. At the time of the outcome analysis, 75 patients remained alive and the survivors were followed up for a median of 37.5 (range 6.0–102.6) months. The 1-, 3- and 5-year survival rates were 92.5, 75.6, and 75.6 %, respectively, in patients with grade 3 responses, 84.1, 69.1, and 57.2 %, respectively, in those with grade 2 and 73.0, 31.8, and 25.2 %, respectively, in those with grades 1/0. Survival rates significantly differed between grades 3 and 1/0 (p = 0.0002) and between grades 2 and 1/0 (p = 0.003) but not between grades 3 and 2 (p = 0.27).
whereas other factors including pre-therapeutic SUVmax of primary tumor (p = 0.56), primary tumor depth (p = 0.09), lymph node metastasis (p = 0.28), prognostic nutritional index (p = 0.09), and clinical tumor stage (p = 0.08) were not. Pre-therapeutic parameters with p \ 0.1 in univariate analysis was subsequently entered into a multivariable analysis. Of the eight variables that were significant or borderline significant on univariate analysis, Hb (OR, 1.52; 95 %CI, 1.08–2.15; p = 0.02) emerged as the sole independent covariate for a response to nCRT (Table 3). Response and survival based on hemoglobin level We plotted the sensitivity and specificity of pathologic responses at the indicated Hb levels to prepare curves from which we derived an optimal pretherapeutic Hb cutoff value of 13 g/dl for predicting a response (area under the curve, 0.68; 95 % confidence interval, 0.57–0.80; p = 0.002). Table 4 shows the results of the pathologic responses according to the Hb cutoff of 13 g/dl. Pretherapeutic Hb was a significant predictive marker of a pathologic response, and 48.8 and 17.1 % of patients with Hb B13 or [13 g/dl, respectively, were poor responders (p = 0.0002). The sensitivity, specificity, and accuracy for predicting poor responders based on Hb B13 g/dl were 58.8, 76.4, and 71.5 %, respectively. The 1-, 3-, and 5-year survival rates were 85.2, 45.4, and 40.9 %, respectively, in patients with Hb B13 g/dl. They were 83.2, 67.7, and 58.9 %, respectively, in those with Hb [13 g/dl. Overall survival differed significantly between these two patient groups (p = 0.048).
Comparison of pathological good and poor responders
Discussion
We defined grades 3/2 as good responses (n = 89, 72.4 %) and grades 1/0 as poor responses (n = 34, 27.6 %) based on our survival data and then compared pre-therapeutic parameters between patients with good and poor responses (Table 2). Performance status (p = 0.02), Hb level (p = 0.005), and platelet number (p = 0.03) were statistically significant,
Neoadjuvant chemoradiotherapy followed by esophagectomy generally confers a survival benefit on patients with esophageal cancer [1–4]. However, the benefit is highly dependent on the tumor response to nCRT [5–8]. We found that nCRT elicited a good response for a large portion of patients (grades 3/2, n = 89, 72.4 %), and their prognosis was extremely favorable. In contrast, survival was significantly poorer for patients with a
123
World J Surg
poor response (grades 1/0, n = 34, 27.6 %) than for those with a good response (grades 3/2). Therefore, nCRT might not confer a survival benefit on some poor responders. The present study aimed to identify pretherapeutic clinical and blood parameters that could predict the pathologic responses of advanced ESCC to nCRT. We identified the pretherapeutic Hb level as an independent useful marker for predicting pathologic tumor response. Many patients with pretherapeutic Hb[13 g/dl had good pathologic responses. Conversely, nCRT did not confer any such a benefit on patients with Hb B13 g/dl. The Hb level was more significantly predictive of a tumor response than any other pretherapeutic parameters, including performance status, primary tumor depth, lymph node metastasis, tumor stage, SUVmax of the primary tumor, and other blood data. The effects of nCRT were inevitably influenced by compliance with nCRT, and the Hb level might be related to such compliance. We reduced the doses of chemotherapeutic agents for 17 (20.7 %) of our patients with Hb [13.0 g/dl (n = 82) and for 6 (14.6 %) with Hb B13.0 g/dl (n = 41). The frequency of decreasing the doses of chemotherapeutic agents did not differ significantly between these Hb levels (p = 0.41). Furthermore, the chemotherapy regimens in the present study mainly comprised docetaxel/5-FU, cisplatin/5-FU, and docetaxel/cisplatin/5-FU. Therefore, we investigated tumor response rates based on Hb B13 or [13 g/dl in the three groups. Although the cisplatin/5-FU regimen reached statistical significance, the other two did not because of a very small sample size. However, the tendencies of the responses to nCRT under these regimens were also similar between these Hb levels. The optimal cutoff value for Hb might vary somewhat among CRT regimens. The pretherapeutic Hb level and response to nCRT were significantly associated with the prognosis after nCRT and esophagectomy in the present study. However, the survival of ESCC patients might be also influenced by preoperative co-morbidities and postoperative complications. Therefore, we evaluated the frequency of these factors between the groups with Hb B13 and[13 g/dl. In all, 21 (51.2 %) of 41 patients with Hb B13.0 and 46 (56.1 %) of 82 patients with Hb [13.0 g/dl had preoperative co-morbidities (p = 0.61). Also, 24 (58.5 %) and 49 (59.8 %) with Hb B and[13.0 g/dl, respectively, developed postoperative complications (p = 0.90). The frequencies of co-morbidities and complications did not significantly differ between these Hb levels. The Hb level is associated with sensitivity [12], locoregional control [22, 23], and survival [24, 25] after radiation therapy for esophageal cancer regardless of chemotherapy. Several findings for other types of cancer also suggest that the Hb level is an important determinant of treatment outcomes [26–28]. However, the Hb level has never been evaluated as a predictor of pathologic tumor response to neoadjuvant therapy. The present study
correlated tumor responses with Hb levels in surgically resected specimens and showed that pretherapeutic Hb levels can also predict pathologic responses and the survival of patients with advanced ESCC treated by nCRT. The pretherapeutic Hb level was B13 g/dl in 41 (33.3 %) of 123 patients in our study, and the response to nCRT was significantly poorer for many of them than for the patients with Hb[13 g/dl. Anemia in patients with malignant tumors is generally caused by tumor-related bleeding, nutritional deficiencies, and tumor infiltration of bone marrow. In addition, malignant tumors are often associated with inflammatory cytokines such as tumor necrosis factor and interleukin-1, which are both associated with inhibiting the proliferation of erythrocytic progenitors [29, 30]. Therefore, anemia is a frequent complication of malignant tumors. Tumor-associated anemia is a major pathogenetic mechanism that is involved in the development of tumor hypoxia, which deprives tumor cells of the oxygen essential for the cytotoxic activities of irradiation and chemotherapy. Thus, tumor-associated anemia is a direct cause of tumor resistance to these treatment strategies [31, 32]. Moreover, anemia and hypoxia indirectly reduce tumor sensitivity through mechanisms that include proteomic and genomic changes. These changes can lead to increased invasiveness and metastatic potential, loss of apoptosis, and chaotic angiogenesis, further increasing treatment resistance [32]. Therefore, the Hb level is an extremely important factor associated with both the therapeutic effect and the prognosis of patients with cancer. Although the specificity and accuracy of the pretherapeutic Hb value were high in the present study, the sensitivity was comparatively low for diagnosing poor responders. Therefore, good and poor responders cannot be precisely distinguished based on Hb levels alone. The Hb level is clinically useful, however, because it is uniformly available, recursive, inexpensive, and minimally invasive. Combining Hb levels with other biomarkers using a molecular biologic approach can contribute to more precise predictions of ESCC responses to nCRT.
Conclusions We discovered that the pretherapeutic Hb level could influence the pathologic responses of tumors and survival of the patient after nCRT for ESCC. It can serve as a potential predictor of tumor responses. Although large and prospective randomized studies are required to confirm this finding, evaluations based on Hb levels could easily be incorporated into routine clinical practice as one of the useful markers for determining optimal therapeutic strategies for individual patients with advanced ESCC.
123
World J Surg Conflict of interest The authors have no disclosures regarding commercial support or conflicts of interest. 16.
References
17.
1. Sjoquist KM, Burmeister BH, Smithers BM et al (2011) Survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal carcinoma: an updated meta-analysis. Lancet Oncol 12:681–692 2. Van Hagen P, Hulshof MC, van Lanschot JJ et al (2012) Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med 366:2074–2084 3. Tepper J, Krasna MJ, Niedzwiecki D et al (2008) Phase III trial of trimodality therapy with cisplatin, fluorouracil, radiotherapy, and surgery compared with surgery alone for esophageal cancer: CALGB 9781. J Clin Oncol 26:1086–1092 4. Walsh TN, Noonan N, Hollywood D et al (1996) A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med 335:462–467 5. Berger AC, Farma J, Scott WJ et al (2005) Complete response to neoadjuvant chemoradiotherapy in esophageal carcinoma is associated with significantly improved survival. J Clin Oncol 23:4330–4337 6. Bru¨cher BL, Stein HJ, Zimmermann F et al (2004) Responders benefit from neoadjuvant radiochemotherapy in esophageal squamous cell carcinoma: results of a prospective phase-II trial. Eur J Surg Oncol 30:963–971 7. Reynolds JV, Muldoon C, Hollywood D et al (2007) Long-term outcomes following neoadjuvant chemoradiotherapy for esophageal cancer. Ann Surg 245:707–716 8. Dittrick GW, Weber JM, Shridhar R et al (2012) Pathologic nonresponders after neoadjuvant chemoradiation for esophageal cancer demonstrate no survival benefit compared with patients treated with primary esophagectomy. Ann Surg Oncol 19: 1678–1684 9. Li SH, Huang EY, Lu HI et al (2012) Phosphorylated mammalian target of rapamycin expression is associated with the response to chemoradiotherapy in patients with esophageal squamous cell carcinoma. J Thorac Cardiovasc Surg 144:1352–1359 10. Duong C, Greenawalt DM, Kowalczyk A et al (2007) Pretreatment gene expression profiles can be used to predict response to neoadjuvant chemoradiotherapy in esophageal cancer. Ann Surg Oncol 14:3602–3609 11. Maher SG, Gillham CM, Duggan SP et al (2009) Gene expression analysis of diagnostic biopsies predicts pathological response to neoadjuvant chemoradiotherapy of esophageal cancer. Ann Surg 250:729–737 12. Yi Y, Li B, Sun H et al (2010) Predictors of sensitivity to chemoradiotherapy of esophageal squamous cell carcinoma. Tumour Biol 31:333–340 13. Yasuda K, Sunami E, Kawai K et al (2012) Laboratory blood data have a significant impact on tumor response and outcome in preoperative chemoradiotherapy for advanced rectal cancer. J Gastrointest Cancer 43:236–243 14. Kitayama J, Yasuda K, Kawai K et al (2010) Circulating lymphocyte number has a positive association with tumor response in neoadjuvant chemoradiotherapy for advanced rectal cancer. Radiat Oncol 5:47 15. Sato H, Tsubosa Y, Kawano T (2012) Correlation between the pretherapeutic neutrophil to lymphocyte ratio and the pathologic
18.
123
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29. 30. 31.
32.
response to neoadjuvant chemotherapy in patients with advanced esophageal cancer. World J Surg 36:617–622 Sobin LH, Wittekind C (2002) TNM classification of malignant tumours, 6th edn. John & Sons, New York Nozoe T, Kohno M, Iguchi T et al (2012) The prognostic nutritional index can be a prognostic indicator in colorectal carcinoma. Surg Today 42:532–535 Onodera T, Goseki N, Kosaki G (1984) Prognostic nutritional index in gastrointestinal surgery of malnourished cancer patients. Nippon Geka Gakkai Zasshi 85:1001–1005 (in Japanese; English abstract) Hihara J, Yoshida K, Hamai Y et al (2007) Phase I study of docetaxel (TXT) and 5-fluorouracil (5-FU) with concurrent radiotherapy in patients with advanced esophageal cancer. Anticancer Res 27:2597–2603 Emi M, Hihara J, Hamai Y et al (2012) Neoadjuvant chemoradiotherapy with docetaxel, cisplatin, and 5-fluorouracil for esophageal cancer. Cancer Chemother Pharmacol 69:1499–1505 Japan Esophageal Society (2009) Japanese classification of esophageal cancer, tenth edition: parts II and III. Esophagus 6:71–94 Zhao KL, Liu G, Jiang GL et al (2006) Association of haemoglobin level with morbidity and mortality of patients with locally advanced oesophageal carcinoma undergoing radiotherapy: a secondary analysis of three consecutive clinical phase III trials. Clin Oncol 18:621–627 Rades D, Golke H, Schild SE et al (2008) The impact of tumor expression of erythropoietin receptors and erythropoietin on clinical outcome of esophageal cancer patients treated with chemoradiation. Int J Radiat Oncol Biol Phys 71:152–159 Zenda S, Hironaka S, Boku N et al (2008) Impact of hemoglobin level on survival in definitive chemoradiotherapy for T4/M1 lymph node esophageal cancer. Dis Esophagus 21:195–200 Valencia Julve J, Alonso Ordun˜a V, Esco´ Baro´n R et al (2006) Influence of hemoglobin levels on survival after radical treatment of esophageal carcinoma with radiotherapy. Clin Transl Oncol 8:22–30 Langendijk H, de Jong J, Wanders R et al (2003) The importance of pre-treatment haemoglobin level in inoperable non-small cell lung carcinoma treated with radical radiotherapy. Radiother Oncol 67:321–325 Dunst J, Kuhnt T, Strauss HG et al (2003) Anemia in cervical cancers: impact on survival, patterns of relapse, and association with hypoxia and angiogenesis. Int J Radiat Oncol Biol Phys 56:778–787 Kim JH, Lee JM, Ryu KS et al (2011) The prognostic impact of duration of anemia during chemotherapy in advanced epithelial ovarian cancer. Oncologist 16:1154–1161 Varlotto J, Stevenson MA (2005) Anemia, tumor hypoxemia, and the cancer patient. Int J Radiat Oncol Biol Phys 63:25–36 Adamson JW (2008) The anemia of inflammation/malignancy: mechanisms and management. Hematology 2008:159–165 Vaupel P, Thews O, Hoeckel M (2001) Treatment resistance of solid tumors: role of hypoxia and anemia. Med Oncol 18: 243–259 Harrison L, Blackwell K (2004) Hypoxia and anemia: factors in decreased sensitivity to radiation therapy and chemotherapy? Oncologist 9:31–40
