Evaluation of a prognostic scoring system based on the systemic inflammatory and nutritional status of patients with locally advanced non-small-cell lung cancer treated with chemoradiotherapy

Evaluation of a prognostic scoring system based on the systemic inflammatory and nutritional... Journal of Radiation Research, Vol. 59, No. 1, 2018, pp. 50–57 doi: 10.1093/jrr/rrx060 Advance Access Publication: 22 November 2017 Evaluation of a prognostic scoring system based on the systemic inflammatory and nutritional status of patients with locally advanced non-small-cell lung cancer treated with chemoradiotherapy 1 1, 2 1 Takamasa Mitsuyoshi , Yukinori Matsuo , Hitoshi Itou , Takashi Shintani , 1 3 1 Yusuke Iizuka , Young Hak Kim and Takashi Mizowaki Department of Radiation Oncology and Image-applied Therapy, Graduate School of Medicine, Kyoto University, Kyoto, Japan Department of Radiation Oncology, Kyoto-Katsura Hospital, Kyoto, Japan Department of Respiratory Medicine, Kyoto University, Kyoto, Japan *Corresponding author. Department of Radiation Oncology and Image-applied Therapy, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawaharacho, Sakyo-ku, Kyoto, 606-8507, Japan. Tel: +81-75-751-3762; Fax: +81-75-771-9749; Email: ymatsuo@kuhp.kyoto-u.ac.jp (Received 16 May 2017; revised 28 July 2017; editorial decision 26 September 2017) ABSTRACT Systemic inflammation and poor nutritional status have a negative effect on the outcomes of cancer. Here, we analyzed the effects of the pretreatment inflammatory and nutritional status on clinical outcomes of locally advanced non-small-cell lung cancer (NSCLC) patients treated with chemoradiotherapy. We retrospectively reviewed 89 patients with locally advanced NSCLC treated with chemoradiotherapy between July 2006 and June 2013. Serum C-reactive protein (CRP) was assessed as an inflammatory marker, and serum albumin, body mass index (BMI) and skeletal mass index were assessed as nutritional status markers. The relationships between these markers and overall survival (OS) were assessed. The median OS was 24.6 months [95% confidence inter- val (CI): 19.4–39.3 months]. During follow-up, 58 patients (65%) had disease recurrence and 52 patients (58%) died. In multivariate Cox hazard analysis, CRP levels and BMI approached but did not achieve a signifi- cant association with OS (P = 0.062 and 0.094, respectively). Recursive partitioning analysis identified three prognostic groups based on hazard similarity (CRP-BMI scores): 0 = CRP < 0.3 mg/dl, 1 = CRP ≥ 0.3 mg/dl 2 2 and BMI ≥ 18.5 kg/m , and 2 = CRP ≥ 0.3 mg/dl and BMI < 18.5 kg/m . The CRP-BMI score was signifi- cantly associated with OS (P = 0.023). Patients with scores of 0, 1 and 2 had median OS of 39.3, 24.5 and 14.5 months, respectively, and the scores also predicted the probability of receiving salvage treatment after recur- rence. The CRP-BMI score is thus a simple and useful prognostic marker of clinical outcome for patients with locally advanced NSCLC treated with chemoradiotherapy. Keywords: systemic inflammatory response; nutritional status; non-small-cell lung cancer; chemoradiotherapy; recursive partitioning analysis INTRODUCTION an estimated 5-year overall survival (OS) rate of <20% (range Lung cancer is the most common cause of cancer-related death 15–40%) [3]. Treatment of patients with NSCLC is mainly based worldwide [1] . Non-small-cell lung cancer (NSCLC) accounts for on the TNM staging system [2]. However, this system provides lim- at least 80% of all lung cancer cases and presents as locally advanced ited information on the best treatment option, and, in some disease in 25–30% of cases. Chemoradiotherapy or radiotherapy is a patients, the disease progresses within a few months. Thus, identifi- standard regimen for treatment of inoperable locally advanced cation of more sensitive prognostic factors would help to optimize NSCLC [2]; however, the prognosis for these patients is poor, with the therapeutic approach for patients with NSCLC. © The Author 2017. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/ by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re- use, please contact journals.permissions@oup.com � 50 Downloaded from https://academic.oup.com/jrr/article-abstract/59/1/50/4647146 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Prognostic score for NSCLC � 51 Systemic inflammation, poor nutritional status, and sarcopenia nodal regions. A shrinking field technique was used, with opposed are increasingly recognized to be associated with low survival rates anterior/posterior fields covering the primary tumor and elective medi- in various malignancies [4–7]. The effect of systemic inflammation astinal nodes, followed by cone-down fields angled off the spinal cord. on OS has been examined in early stage NSCLC patients treated Patients were followed up at an outpatient clinic every 3 months for with surgery or radiotherapy and in advanced stage NSCLC patients the first year and every 6 months thereafter. Telephone interviews treated with chemotherapy [8–10]. A few studies have also evalu- were carried out for patients who failed to attend the outpatient clinic. ated the influence of poor nutritional status and sarcopenia on OS in NSCLC patients treated with surgery or chemotherapy [11, 12]. However, the effect of the pretreatment systemic inflammatory and Data collection nutritional status on clinical outcomes of locally advanced NSCLC OS was defined as the time from the date of first treatment to the patients treated with chemoradiotherapy has not been examined. date of death or date of last contact if the exact date of death was unavailable. Progression-free survival (PFS) was defined as the time A combination of factors reflecting systemic inflammatory and nutritional statusiswidelyusedasaprognostic factor andiscon- from the date of first treatment to the date of disease progression or sidered to have greater sensitivity and precision than single prognostic death from any cause. factors [4, 6, 9]. However, the specific parameters used to generate the Age, gender, height, weight, clinical stage, tumor histology, per- combination score differ with the type of cancer and treatment [13, formance status (Eastern Cooperative Oncology Group, ECOG-PS), 14], and methods for calculating combination scores also differ [15]. history, laboratory data, and clinical outcome data were retrospectively obtained from hospital-based registries and medical records. Blood Thus,there is aneedtoidentifythe most appropriate combination score to predict prognosis in specific cancers [14, 16]. Although serum samples were also obtained before treatment for measurement of ser- C-reactive protein (CRP) is widely used as a systemic inflammatory um CRP and Alb. The cut-offs for abnormal elevation of serum CRP response index, the optimal nutritional index to create combination and Alb were 0.3 mg/dl and 3.5 g/dl, respectively, based on the scores has yet to be identified; those used to date include serum reagent instruction manual or past studies [18]. BMI was calculated 2 2 albumin (Alb), body mass index (BMI) and skeletal mass index as: weight (kg)/height (m ). Patients were classified according to the World Health Organization system as underweight at BMI < (SMI). Accordingly, the nutritional index that best predicts outcomes for locally advanced lung cancer after chemoradiotherapy is unclear 18.5 kg/m [19]. [10, 13, 17]. Here, we tested CRP and the nutritional indexes Alb, BMI and SMI to determine the optimal combination for predicting Table 1. Clinicopathological patient characteristics the prognosis of patients with locally advanced NSCLC treated with Characteristic n (%) chemoradiotherapy. Median age (years) 66 (42–81) MATERIALS AND METHODS Gender Patients Male 67 (75) Patients who were treated with definitive chemoradiotherapy for locally advanced NSCLC were eligible for this retrospective review. Female 22 (25) Exclusion criteria included: treatment with radiotherapy alone, treatment with surgery after chemoradiotherapy, history of other PS malignancies within 5 years, or patients that we couldn’tfollowup 0 50 (56) due to them not being available. The diagnosis of NSCLC was con- firmed by histological evaluation. All patients were staged with 1 36 (41) thoracoabdominal computed tomography (CT) and magnetic reson- 2 3 (3) ance imaging or CT of the brain. The clinical stage at presentation was subsequently categorized according to the TNM classification of Histology malignant tumors (7th edition). SqCC 40 (45) Medical records and clinical laboratory data for the patients were retrospectively collected and anonymized to exclude personal Adenocarcinoma 36 (40) information. The study protocol was approved by the Institutional Review Board of R0718. Others 13 (15) cStage Treatments and outcomes IIIA 34 (38) Patients received radical radiotherapy and chemotherapy consisting of vinorelbine plus cisplatin or paclitaxel plus carboplatin with each com- IIIB 55 (62) bination being administered either concurrently or sequentially. The Age is presented as years (range); all other data are presented as the number prescribed radiation dose was 50–66 Gy delivered in 2.0 Gy daily frac- (and %) of patients (n = 89). PS = performance status, ECOG-PS = Eastern tions, five times a week. Patients were treated with elective nodal irradi- Cooperative Oncology Group PS, SqCC = squamous cell carcinoma, cStage = ation therapy, which prophylactically targeted uninvolved mediastinal clinical stage. Downloaded from https://academic.oup.com/jrr/article-abstract/59/1/50/4647146 by Ed 'DeepDyve' Gillespie user on 16 March 2018 52 � T. Mitsuyoshi et al. Sarcopenia (loss of skeletal muscle mass) was assessed by meas- RESULTS uring the total psoas muscle area at the L3 level on the pretreatment Eighty-nine patients received definitive chemoradiotherapy and CT, which is significantly related to whole-body tissue mass in follow-up after initial treatments for locally advanced NSCLC at our healthy adults and cancer patients [20–22]. Measurements were institution between July 2006 and June 2013. Characteristics of the performed with manual outlining of the psoas muscle border and 89 included patients are shown in Table 1. Chemotherapy and setting the density threshold at between −30 and 110 Hounsfield radiotherapy were given concurrently to 85 patients (96%), of units. This value was normalized to the square of body height to whom 46 (52%) received cisplatin-based chemotherapy and 39 provide the skeletal mass index (SMI), calculated as: total psoas (44%) received carboplatin-based chemotherapy. The 4 patients 2 2 2 muscle area at L3 (cm )/height (m )[22, 23]. When stratified by (4%) received carboplatin-based chemotherapy sequentially. Most gender, the mean adjusted SMI was significantly lower for women patients (n = 84; 94%) received a total radiation dose of at least than for men. The thresholds were set at the lowest quartile SMI 60 Gy (range 50–66 Gy) in 2.0 Gy daily fractions. for men and women [24]. The median follow-up period was 21 months (range 2–103 months). In total, 58 (65%) had disease recurrence and 52 patients (58%) died during follow-up. The median OS and PFS were 24.6 Statistical analysis months [95% confidence interval (CI): 19.4–39.3] and 12.1 months For univariate analysis, relationships between systemic inflammatory (95% CI: 9.0–16.3), respectively. In univariate analysis, there was a or nutritional status and OS were assessed using the Kaplan–Meier significant association between OS and gender (P = 0.02). method and a log-rank test. Multivariate survival analysis and calcu- The relationships between pretreatment systemic inflammatory lation of hazard ratios (HR) was performed using Cox regression and nutritional status and OS are shown in Table 2. The thresholds analysis. Fisher’s exact test, the Chi-square test, and the log-rank 2 2 2 2 of SMI were set at 3.73 cm /m for men and 2.45 cm /m for trend test were used to assess the association between scores and women. On univariate analysis, CRP was significantly associated clinical characteristics. For regression tree growing during recursive with OS (P = 0.046). On multivariate analysis, elevated CRP partitioning analysis, the log rank test was used as the splitting cri- (≥0.3 mg/dl) and low BMI (<18.5 kg/m ) were correlated with terion [25, 26]. The dichotomous prognostic parameter that shorter OS. Alb and SMI were not correlated with OS. resulted in the largest separation of survival at each node with P < 0.05 was selected as the criterion for that node. All analyses were carried out with EZR ver. 2.2-3 (Saitama Medical Center, Jichi Recursive partitioning analysis Medical University, Saitama, Japan) [27], with P < 0.05 (two-tailed) Recursive partitioning analysis for OS was performed with stepwise considered significant. variable selection of inflammatory and nutritional status factors: Table 2. Univariate and multivariate analysis of the association between overall survival and systemic inflammatory and nutritional status Characteristic Number of Univariate survival analysis Multivariate survival analysis patients n (%) HR (95% CI) P value HR (95% CI) P value CRP (mg/dl) 0.046 0.062 <0.3 36 (40) ≥0.3 53 (60) 1.85 (1.01–3.37) 1.74 (0.97–3.12) Alb (g/dl) 0.491 <3.5 16 (18) ≥3.5 73 (82) 1.34 (0.57–3.16) BMI (kg/m ) 0.223 0.094 <18.5 24 (27) ≥18.5 65 (73) 0.65 (0.33–1.29) 0.60 (0.33–1.09) 2 2 SMI (cm /m ) 0.873 <threshold 22 (25) ≥threshold 67 (75) 0.94 (0.45–1.94) HR = hazard ratio, CI = confidence interval, CRP = C-reactive protein, Alb = albumin, BMI = body mass index, SMI = skeletal muscle index. SMI thresholds were 2 2 2 2 3.73 cm /m for men and 2.45 cm /m for women. Downloaded from https://academic.oup.com/jrr/article-abstract/59/1/50/4647146 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Prognostic score for NSCLC � 53 CRP (<0.3 or ≥0.3 mg/dl), Alb (<3.5 or ≥3.5 g/dl), BMI (<18.5 24.5 months, and 26.9% and 14.5 months, respectively. Correlations or ≥18.5 kg/m ) and SMI (<threshold or ≥threshold). The regres- between the CRP-BMI score and clinical characteristics are shown sion tree obtained is shown in Fig. 1. The top node contained CRP in Table 3. Only gender significantly correlated with the CRP-BMI as the predictor variable. For patients with elevated CRP, BMI score (P = 0.001). We assessed CRP-BMI score separately in each became the prognostic factor. The CRP-BMI scores were defined gender group. The higher CRP-BMI tended to be associated with as: 0 = CRP < 0.3 mg/dl, 1 = CRP ≥ 0.3 mg/dl and BMI ≥ worse OS for each gender. The Kaplan–Meier curves for OS strati- 2 2 18.5 kg/m , and 2 = CRP ≥ 0.3 mg/dl and BMI < 18.5 kg/m . fied by the CRP-BMI scores are shown in Fig. 3a for men and Figure 2 shows the Kaplan–Meier curves for OS stratified by the Fig. 3b for women. The higher CRP-BMI tended to be associated CRP-BMI scores. There was a significant trend between the CRP- with worse OS for each gender (P = 0.070 for men and 0.191 for BMI score and OS rate using the log-rank trend test (P = 0.023). female). The 2-year OS rates and median OS times for patients with CRP- BMI scores of 0, 1 and 2 were 63.7% and 39.3 months, 50.1% and Recurrence Of the 58 patients with recurrent disease, 27 (30.3%) developed local recurrence, 16 (18.0%) developed regional recurrence (defined as lymph node recurrence in the mediastinum) and 41 (46.1%) developed distant metastasis, including overlapping recurrence (Table 4). After disease recurrence, salvage treatment was prescribed Table 3. Relationships between C-reactive protein–body mass index score and clinical characteristics Characteristic CRP-BMI score 0 1 2 P value n (%) n (%) n (%) (n = 36) (n = 39) (n = 14) Figure 1. Regression tree diagram from the Age (years) 0.469 recursive partitioning analysis of overall survival. Each terminal node shows the CRP-BMI score, the ≥70 16 (43) 12 (33) 9 (24) median overall survival time, and the number of <70 20 (38) 27 (52) 5 (10) events and patients in the node. Gender 0.001 Male 20 (30) 33 (49) 14 (21) Female 16 (73) 6 (27) 0 (0) PS 0.362 0 24 (48) 20 (40) 6 (12) 1 12 (33) 17 (52) 7 (19) 2 0 (0) 2 (67) 1 (33) Histology 0.753 SqCC 15 (38) 20 (50) 5 (12) Adenocarcinoma 15 (42) 14 (39) 7 (19) Others 6 (46) 5 (38) 2 (15) cStage 0.371 IIIA 15 (44) 16 (47) 3 (9) IIIB 21 (38) 23 (42) 11 (20) CRP-BMI = C-reactive protein–body mass index score, PS = performance status, Figure 2. Kaplan–Meier curves of overall survival stratified ECOG-PS = Eastern Cooperative Oncology Group PS, SqCC = squamous cell by C-reactive protein–body mass index score. carcinoma, cStage = clinical stage. Downloaded from https://academic.oup.com/jrr/article-abstract/59/1/50/4647146 by Ed 'DeepDyve' Gillespie user on 16 March 2018 54 � T. Mitsuyoshi et al. Figure 3. Kaplan–Meier curves of overall survival stratified by C-reactive protein–body mass index score for male (a) and for female (b). Table 4. Associations between C-reactive protein–body mass index score, disease recurrence, and median survival time after recurrence Total CRP-BMI score n = 89 (%) 0 1 2 n = 36 (%) n = 39 (%) n = 14 (%) Total recurrence 58 (65) 24 (67) 25 (64) 9 (64) Local recurrence 27 (30) 10 (28) 12 (31) 5 (36) Regional recurrence 16 (18) 8 (22) 6 (15) 2 (14) Metastasis 41 (46) 16 (44) 18 (46) 7 (50) Salvage treatment for recurrence 46 (79) 23 (96) 20 (80) 3 (33) Median survival time after recurrence (months) 10.3 12.3 10.2 5.2 CRP-BMI = C-reactive protein–body mass index. for 46 patients (79.3%). Significantly more patients who received sal- practice to determine treatment for lung cancer patients [2, 28, 29]. vage treatment had CRP-BMI scores of 0 or 1 than a score of 2 However, this staging system sometimes fails to predict patient (P < 0.01). Of the 9 patients who developed recurrence and had a prognosis and may not offer appropriate clinical practice guidance. CRP-BMI score 2, 6 could not receive salvage treatments because of Indeed, patients at the same TNM stage may have other conditions their medical condition or history, such as interstitial pneumonia or that influence treatment outcomes. Thus, there is a need to identify renal failure. The median survival time after recurrence was longer more sensitive and convenient pretreatment prognostic factors to for patients with CRP-BMI scores of 0 or 1 than for those with a enable more personalized treatment. Many studies have examined score of 2. the relationships between pretreatment systemic inflammatory sta- tus, nutritional status, and skeletal muscle mass and the outcomes of treatment for cancer [18, 30]. Although this has also been examined DISCUSSION in NSCLC, most studies have involved surgical treatments [8, 11, 31]. The TNM staging system, which classifies cancer mainly according In this study, we evaluated these relationships in patients with locally to the size and extension of the primary tumor, its lymphatic advanced NSCLC treated with chemoradiotherapy. involvement, and the presence of metastases, is used in clinical Downloaded from https://academic.oup.com/jrr/article-abstract/59/1/50/4647146 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Prognostic score for NSCLC � 55 Several serum markers have been investigated as predictors of however, there was a trend that high CRP-BMI score tended to show systemic inflammatory status and prognosis of patients with a worse OS rate, regardless of gender. To our knowledge, this is the NSCLC, but none are available for use in daily practice. Serum first study to identify the CRP-BMI score as a prognostic factor in CRP level is widely used in the diagnosis of acute and chronic sys- patients with advanced NSCLC. The CRP-BMI score was significantly correlated with gender. temic inflammation and is a prognostic factor for patients with malignant tumors such as hepatocellular carcinoma, esophageal can- Considering this correlation, we analyzed OS rates separately for cer, and colon cancer [32–34] . Some studies of NSCLC patients each gender with CRP-BMI score. Even though they were analyzed treated with surgery or chemotherapy have also assessed CRP as an separately, the higher CRP-BMI tended to be associated with worse independent risk factor [35–37]. In the present study, elevated pre- OS for each gender. We concluded that the CRP-BMI score may be treatment serum CRP tended to correlate with poor OS, consistent a prognostic factor in patients with advanced NSCLC regardless of with previous studies. Thus, CRP may be a prognostic factor for gender, though it was not proved in this study. locally advanced NSCLC patients treated with chemoradiotherapy. Some limitations of this study should be acknowledged. First, the Serum Alb is commonly used to assess nutritional status. study was performed retrospectively in a small population of 89 Hypoalbuminemia (Alb < 3.5 g/dl) often reflects malnutrition and patients. We think that a further study on a large number of patients may be a predictor of survival in patients with NSCLC after curative is needed to clarify the issues. Second, there was some heterogeneity pulmonary resection [38]. However, in our study, hypoalbuminemia in the patient treatments, which may have led to different clinical was not a prognostic factor in univariate analysis. Recovery of Alb prognoses. Thus, further studies are needed to examine the relation- level is important after surgery [39], but radical chemoradiotherapy ship between pretreatment systemic inflammatory and nutritional sta- is a less invasive treatment than surgery. This may explain why tus and the prognosis of patients with locally advanced NSCLC hypoalbuminemia was not associated with a risk of complication and treated with chemoradiotherapy. thus did not affect the post-chemoradiotherapy outcome. In conclusion, the results of this study indicate that the CRP- BMI is also widely used to evaluate nutritional status [40]. A BMI score that is based on pretreatment systemic inflammatory and Phase III trial of first line systemic chemotherapy for advanced nutritional status is associated with clinical outcome of NSCLC NSCLC in 2684 patients showed that BMI ≥ 18.5 kg/m indicated patients treated with chemoradiotherapy and the probability of a better prognosis than BMI < 18.5 kg/m [41]. This may be receiving salvage treatment after recurrence. We think that further related to the difference in rates of treatment discontinuation due to large-scale prospective studies are required in order to establish the disease progression or death in that study, which were 52.3% for CRP-BMI score as a guide for selection of patients for treatment. the underweight patients and 42.3% for the obese patients. In our study, a similar trend was found for the relationship between BMI ACKNOWLEDGEMENTS and discontinuation of treatment at the time of recurrence. The OS Results from this study were presented at the 73rd Annual Meeting for patients with BMI < 18.5 kg/m was also worse than for those of the Japan Radiological Society. with BMI ≥ 18.5 kg/m . Sarcopenia, which reflects degenerative loss of skeletal muscle CONFLICT OF INTEREST mass, is an objective indicator of cancer cachexia and a predictor of The authors declare no conflicts of interest with regard to the work worse clinical outcomes in several studies of malignancy [42, 43]. in the manuscript. This condition may reflect increased metabolic activity of more aggressive tumors, leading to systemic inflammation and muscle FUNDING wasting [44]. However, in our study, SMI was not a significant This work was supported by JSPS KAKENHI Grant Number (C) prognostic factor for OS. The reason for this result is unclear, but 15K09992. The study sponsor had no involvement in the study most studies have examined SMI in the context of postoperative design; collection, analysis, and interpretation of data; or the deci- complications in abdominal surgery, and SMI obtained by measur- sion to submit the manuscript for publication. ing the total psoas muscle area at L3 may have little relationship to outcomes of thoracic cancer treated with chemoradiotherapy. One merit of the CRP-BMI score is that it is easy to acquire in REFERENCES clinical practice. Another merit is that it can be used to predict 1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA whether salvage treatment can be received at the time of recurrence. Cancer J Clin 2015;65:5–29. Although the recurrence rate for each CRP-BMI score group was 2. McCloskey P, Balduyck B, Van Schil PE et al. Radical treatment almost the same, the rate of administration of salvage treatment for of non-small cell lung cancer during the last 5 years. 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Low perioperative serum prealbumin predicts early recurrence after curative pulmonary resection for non- of postoperative respiratory complications in patients with small-cell lung cancer. World J Surg 2012;36:2853–7. esophageal cancer. Ann Surg Oncol 2015;22:4432–7. 39. Matsuoka K, Misaki N, Sumitomo S. Preoperative hypoalbumi- 43. Fukushima H, Yokoyama M, Nakanishi Y et al. Sarcopenia as a nemia is a risk factor for late bronchopleural fistula after pneu- prognostic biomarker of advanced urothelial carcinoma. PLoS monectomy. Ann Thorac Cardiovasc Surg 2010;16:401–5. One 2015;10:e0115895. 40. Ryan AM, Power DG, Daly L et al. Cancer-associated malnutri- 44. Dodson S, Baracos VE, Jatoi A et al. Muscle wasting in cancer tion, cachexia and sarcopenia: the skeleton in the hospital closet cachexia: clinical implications, diagnosis, and emerging treat- 40 years later. Proc Nutr Soc 2016;75:199–211. ment strategies. Annu Rev Med 2011;62:265–79. 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Evaluation of a prognostic scoring system based on the systemic inflammatory and nutritional status of patients with locally advanced non-small-cell lung cancer treated with chemoradiotherapy

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Journal of Radiation Research, Vol. 59, No. 1, 2018, pp. 50–57 doi: 10.1093/jrr/rrx060 Advance Access Publication: 22 November 2017 Evaluation of a prognostic scoring system based on the systemic inflammatory and nutritional status of patients with locally advanced non-small-cell lung cancer treated with chemoradiotherapy 1 1, 2 1 Takamasa Mitsuyoshi , Yukinori Matsuo , Hitoshi Itou , Takashi Shintani , 1 3 1 Yusuke Iizuka , Young Hak Kim and Takashi Mizowaki Department of Radiation Oncology and Image-applied Therapy, Graduate School of Medicine, Kyoto University, Kyoto, Japan Department of Radiation Oncology, Kyoto-Katsura Hospital, Kyoto, Japan Department of Respiratory Medicine, Kyoto University, Kyoto, Japan *Corresponding author. Department of Radiation Oncology and Image-applied Therapy, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawaharacho, Sakyo-ku, Kyoto, 606-8507, Japan. Tel: +81-75-751-3762; Fax: +81-75-771-9749; Email: ymatsuo@kuhp.kyoto-u.ac.jp (Received 16 May 2017; revised 28 July 2017; editorial decision 26 September 2017) ABSTRACT Systemic inflammation and poor nutritional status have a negative effect on the outcomes of cancer. Here, we analyzed the effects of the pretreatment inflammatory and nutritional status on clinical outcomes of locally advanced non-small-cell lung cancer (NSCLC) patients treated with chemoradiotherapy. We retrospectively reviewed 89 patients with locally advanced NSCLC treated with chemoradiotherapy between July 2006 and June 2013. Serum C-reactive protein (CRP) was assessed as an inflammatory marker, and serum albumin, body mass index (BMI) and skeletal mass index were assessed as nutritional status markers. The relationships between these markers and overall survival (OS) were assessed. The median OS was 24.6 months [95% confidence inter- val (CI): 19.4–39.3 months]. During follow-up, 58 patients (65%) had disease recurrence and 52 patients (58%) died. In multivariate Cox hazard analysis, CRP levels and BMI approached but did not achieve a signifi- cant association with OS (P = 0.062 and 0.094, respectively). Recursive partitioning analysis identified three prognostic groups based on hazard similarity (CRP-BMI scores): 0 = CRP < 0.3 mg/dl, 1 = CRP ≥ 0.3 mg/dl 2 2 and BMI ≥ 18.5 kg/m , and 2 = CRP ≥ 0.3 mg/dl and BMI < 18.5 kg/m . The CRP-BMI score was signifi- cantly associated with OS (P = 0.023). Patients with scores of 0, 1 and 2 had median OS of 39.3, 24.5 and 14.5 months, respectively, and the scores also predicted the probability of receiving salvage treatment after recur- rence. The CRP-BMI score is thus a simple and useful prognostic marker of clinical outcome for patients with locally advanced NSCLC treated with chemoradiotherapy. Keywords: systemic inflammatory response; nutritional status; non-small-cell lung cancer; chemoradiotherapy; recursive partitioning analysis INTRODUCTION an estimated 5-year overall survival (OS) rate of <20% (range Lung cancer is the most common cause of cancer-related death 15–40%) [3]. Treatment of patients with NSCLC is mainly based worldwide [1] . Non-small-cell lung cancer (NSCLC) accounts for on the TNM staging system [2]. However, this system provides lim- at least 80% of all lung cancer cases and presents as locally advanced ited information on the best treatment option, and, in some disease in 25–30% of cases. Chemoradiotherapy or radiotherapy is a patients, the disease progresses within a few months. Thus, identifi- standard regimen for treatment of inoperable locally advanced cation of more sensitive prognostic factors would help to optimize NSCLC [2]; however, the prognosis for these patients is poor, with the therapeutic approach for patients with NSCLC. © The Author 2017. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/ by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re- use, please contact journals.permissions@oup.com � 50 Downloaded from https://academic.oup.com/jrr/article-abstract/59/1/50/4647146 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Prognostic score for NSCLC � 51 Systemic inflammation, poor nutritional status, and sarcopenia nodal regions. A shrinking field technique was used, with opposed are increasingly recognized to be associated with low survival rates anterior/posterior fields covering the primary tumor and elective medi- in various malignancies [4–7]. The effect of systemic inflammation astinal nodes, followed by cone-down fields angled off the spinal cord. on OS has been examined in early stage NSCLC patients treated Patients were followed up at an outpatient clinic every 3 months for with surgery or radiotherapy and in advanced stage NSCLC patients the first year and every 6 months thereafter. Telephone interviews treated with chemotherapy [8–10]. A few studies have also evalu- were carried out for patients who failed to attend the outpatient clinic. ated the influence of poor nutritional status and sarcopenia on OS in NSCLC patients treated with surgery or chemotherapy [11, 12]. However, the effect of the pretreatment systemic inflammatory and Data collection nutritional status on clinical outcomes of locally advanced NSCLC OS was defined as the time from the date of first treatment to the patients treated with chemoradiotherapy has not been examined. date of death or date of last contact if the exact date of death was unavailable. Progression-free survival (PFS) was defined as the time A combination of factors reflecting systemic inflammatory and nutritional statusiswidelyusedasaprognostic factor andiscon- from the date of first treatment to the date of disease progression or sidered to have greater sensitivity and precision than single prognostic death from any cause. factors [4, 6, 9]. However, the specific parameters used to generate the Age, gender, height, weight, clinical stage, tumor histology, per- combination score differ with the type of cancer and treatment [13, formance status (Eastern Cooperative Oncology Group, ECOG-PS), 14], and methods for calculating combination scores also differ [15]. history, laboratory data, and clinical outcome data were retrospectively obtained from hospital-based registries and medical records. Blood Thus,there is aneedtoidentifythe most appropriate combination score to predict prognosis in specific cancers [14, 16]. Although serum samples were also obtained before treatment for measurement of ser- C-reactive protein (CRP) is widely used as a systemic inflammatory um CRP and Alb. The cut-offs for abnormal elevation of serum CRP response index, the optimal nutritional index to create combination and Alb were 0.3 mg/dl and 3.5 g/dl, respectively, based on the scores has yet to be identified; those used to date include serum reagent instruction manual or past studies [18]. BMI was calculated 2 2 albumin (Alb), body mass index (BMI) and skeletal mass index as: weight (kg)/height (m ). Patients were classified according to the World Health Organization system as underweight at BMI < (SMI). Accordingly, the nutritional index that best predicts outcomes for locally advanced lung cancer after chemoradiotherapy is unclear 18.5 kg/m [19]. [10, 13, 17]. Here, we tested CRP and the nutritional indexes Alb, BMI and SMI to determine the optimal combination for predicting Table 1. Clinicopathological patient characteristics the prognosis of patients with locally advanced NSCLC treated with Characteristic n (%) chemoradiotherapy. Median age (years) 66 (42–81) MATERIALS AND METHODS Gender Patients Male 67 (75) Patients who were treated with definitive chemoradiotherapy for locally advanced NSCLC were eligible for this retrospective review. Female 22 (25) Exclusion criteria included: treatment with radiotherapy alone, treatment with surgery after chemoradiotherapy, history of other PS malignancies within 5 years, or patients that we couldn’tfollowup 0 50 (56) due to them not being available. The diagnosis of NSCLC was con- firmed by histological evaluation. All patients were staged with 1 36 (41) thoracoabdominal computed tomography (CT) and magnetic reson- 2 3 (3) ance imaging or CT of the brain. The clinical stage at presentation was subsequently categorized according to the TNM classification of Histology malignant tumors (7th edition). SqCC 40 (45) Medical records and clinical laboratory data for the patients were retrospectively collected and anonymized to exclude personal Adenocarcinoma 36 (40) information. The study protocol was approved by the Institutional Review Board of R0718. Others 13 (15) cStage Treatments and outcomes IIIA 34 (38) Patients received radical radiotherapy and chemotherapy consisting of vinorelbine plus cisplatin or paclitaxel plus carboplatin with each com- IIIB 55 (62) bination being administered either concurrently or sequentially. The Age is presented as years (range); all other data are presented as the number prescribed radiation dose was 50–66 Gy delivered in 2.0 Gy daily frac- (and %) of patients (n = 89). PS = performance status, ECOG-PS = Eastern tions, five times a week. Patients were treated with elective nodal irradi- Cooperative Oncology Group PS, SqCC = squamous cell carcinoma, cStage = ation therapy, which prophylactically targeted uninvolved mediastinal clinical stage. Downloaded from https://academic.oup.com/jrr/article-abstract/59/1/50/4647146 by Ed 'DeepDyve' Gillespie user on 16 March 2018 52 � T. Mitsuyoshi et al. Sarcopenia (loss of skeletal muscle mass) was assessed by meas- RESULTS uring the total psoas muscle area at the L3 level on the pretreatment Eighty-nine patients received definitive chemoradiotherapy and CT, which is significantly related to whole-body tissue mass in follow-up after initial treatments for locally advanced NSCLC at our healthy adults and cancer patients [20–22]. Measurements were institution between July 2006 and June 2013. Characteristics of the performed with manual outlining of the psoas muscle border and 89 included patients are shown in Table 1. Chemotherapy and setting the density threshold at between −30 and 110 Hounsfield radiotherapy were given concurrently to 85 patients (96%), of units. This value was normalized to the square of body height to whom 46 (52%) received cisplatin-based chemotherapy and 39 provide the skeletal mass index (SMI), calculated as: total psoas (44%) received carboplatin-based chemotherapy. The 4 patients 2 2 2 muscle area at L3 (cm )/height (m )[22, 23]. When stratified by (4%) received carboplatin-based chemotherapy sequentially. Most gender, the mean adjusted SMI was significantly lower for women patients (n = 84; 94%) received a total radiation dose of at least than for men. The thresholds were set at the lowest quartile SMI 60 Gy (range 50–66 Gy) in 2.0 Gy daily fractions. for men and women [24]. The median follow-up period was 21 months (range 2–103 months). In total, 58 (65%) had disease recurrence and 52 patients (58%) died during follow-up. The median OS and PFS were 24.6 Statistical analysis months [95% confidence interval (CI): 19.4–39.3] and 12.1 months For univariate analysis, relationships between systemic inflammatory (95% CI: 9.0–16.3), respectively. In univariate analysis, there was a or nutritional status and OS were assessed using the Kaplan–Meier significant association between OS and gender (P = 0.02). method and a log-rank test. Multivariate survival analysis and calcu- The relationships between pretreatment systemic inflammatory lation of hazard ratios (HR) was performed using Cox regression and nutritional status and OS are shown in Table 2. The thresholds analysis. Fisher’s exact test, the Chi-square test, and the log-rank 2 2 2 2 of SMI were set at 3.73 cm /m for men and 2.45 cm /m for trend test were used to assess the association between scores and women. On univariate analysis, CRP was significantly associated clinical characteristics. For regression tree growing during recursive with OS (P = 0.046). On multivariate analysis, elevated CRP partitioning analysis, the log rank test was used as the splitting cri- (≥0.3 mg/dl) and low BMI (<18.5 kg/m ) were correlated with terion [25, 26]. The dichotomous prognostic parameter that shorter OS. Alb and SMI were not correlated with OS. resulted in the largest separation of survival at each node with P < 0.05 was selected as the criterion for that node. All analyses were carried out with EZR ver. 2.2-3 (Saitama Medical Center, Jichi Recursive partitioning analysis Medical University, Saitama, Japan) [27], with P < 0.05 (two-tailed) Recursive partitioning analysis for OS was performed with stepwise considered significant. variable selection of inflammatory and nutritional status factors: Table 2. Univariate and multivariate analysis of the association between overall survival and systemic inflammatory and nutritional status Characteristic Number of Univariate survival analysis Multivariate survival analysis patients n (%) HR (95% CI) P value HR (95% CI) P value CRP (mg/dl) 0.046 0.062 <0.3 36 (40) ≥0.3 53 (60) 1.85 (1.01–3.37) 1.74 (0.97–3.12) Alb (g/dl) 0.491 <3.5 16 (18) ≥3.5 73 (82) 1.34 (0.57–3.16) BMI (kg/m ) 0.223 0.094 <18.5 24 (27) ≥18.5 65 (73) 0.65 (0.33–1.29) 0.60 (0.33–1.09) 2 2 SMI (cm /m ) 0.873 <threshold 22 (25) ≥threshold 67 (75) 0.94 (0.45–1.94) HR = hazard ratio, CI = confidence interval, CRP = C-reactive protein, Alb = albumin, BMI = body mass index, SMI = skeletal muscle index. SMI thresholds were 2 2 2 2 3.73 cm /m for men and 2.45 cm /m for women. Downloaded from https://academic.oup.com/jrr/article-abstract/59/1/50/4647146 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Prognostic score for NSCLC � 53 CRP (<0.3 or ≥0.3 mg/dl), Alb (<3.5 or ≥3.5 g/dl), BMI (<18.5 24.5 months, and 26.9% and 14.5 months, respectively. Correlations or ≥18.5 kg/m ) and SMI (<threshold or ≥threshold). The regres- between the CRP-BMI score and clinical characteristics are shown sion tree obtained is shown in Fig. 1. The top node contained CRP in Table 3. Only gender significantly correlated with the CRP-BMI as the predictor variable. For patients with elevated CRP, BMI score (P = 0.001). We assessed CRP-BMI score separately in each became the prognostic factor. The CRP-BMI scores were defined gender group. The higher CRP-BMI tended to be associated with as: 0 = CRP < 0.3 mg/dl, 1 = CRP ≥ 0.3 mg/dl and BMI ≥ worse OS for each gender. The Kaplan–Meier curves for OS strati- 2 2 18.5 kg/m , and 2 = CRP ≥ 0.3 mg/dl and BMI < 18.5 kg/m . fied by the CRP-BMI scores are shown in Fig. 3a for men and Figure 2 shows the Kaplan–Meier curves for OS stratified by the Fig. 3b for women. The higher CRP-BMI tended to be associated CRP-BMI scores. There was a significant trend between the CRP- with worse OS for each gender (P = 0.070 for men and 0.191 for BMI score and OS rate using the log-rank trend test (P = 0.023). female). The 2-year OS rates and median OS times for patients with CRP- BMI scores of 0, 1 and 2 were 63.7% and 39.3 months, 50.1% and Recurrence Of the 58 patients with recurrent disease, 27 (30.3%) developed local recurrence, 16 (18.0%) developed regional recurrence (defined as lymph node recurrence in the mediastinum) and 41 (46.1%) developed distant metastasis, including overlapping recurrence (Table 4). After disease recurrence, salvage treatment was prescribed Table 3. Relationships between C-reactive protein–body mass index score and clinical characteristics Characteristic CRP-BMI score 0 1 2 P value n (%) n (%) n (%) (n = 36) (n = 39) (n = 14) Figure 1. Regression tree diagram from the Age (years) 0.469 recursive partitioning analysis of overall survival. Each terminal node shows the CRP-BMI score, the ≥70 16 (43) 12 (33) 9 (24) median overall survival time, and the number of <70 20 (38) 27 (52) 5 (10) events and patients in the node. Gender 0.001 Male 20 (30) 33 (49) 14 (21) Female 16 (73) 6 (27) 0 (0) PS 0.362 0 24 (48) 20 (40) 6 (12) 1 12 (33) 17 (52) 7 (19) 2 0 (0) 2 (67) 1 (33) Histology 0.753 SqCC 15 (38) 20 (50) 5 (12) Adenocarcinoma 15 (42) 14 (39) 7 (19) Others 6 (46) 5 (38) 2 (15) cStage 0.371 IIIA 15 (44) 16 (47) 3 (9) IIIB 21 (38) 23 (42) 11 (20) CRP-BMI = C-reactive protein–body mass index score, PS = performance status, Figure 2. Kaplan–Meier curves of overall survival stratified ECOG-PS = Eastern Cooperative Oncology Group PS, SqCC = squamous cell by C-reactive protein–body mass index score. carcinoma, cStage = clinical stage. Downloaded from https://academic.oup.com/jrr/article-abstract/59/1/50/4647146 by Ed 'DeepDyve' Gillespie user on 16 March 2018 54 � T. Mitsuyoshi et al. Figure 3. Kaplan–Meier curves of overall survival stratified by C-reactive protein–body mass index score for male (a) and for female (b). Table 4. Associations between C-reactive protein–body mass index score, disease recurrence, and median survival time after recurrence Total CRP-BMI score n = 89 (%) 0 1 2 n = 36 (%) n = 39 (%) n = 14 (%) Total recurrence 58 (65) 24 (67) 25 (64) 9 (64) Local recurrence 27 (30) 10 (28) 12 (31) 5 (36) Regional recurrence 16 (18) 8 (22) 6 (15) 2 (14) Metastasis 41 (46) 16 (44) 18 (46) 7 (50) Salvage treatment for recurrence 46 (79) 23 (96) 20 (80) 3 (33) Median survival time after recurrence (months) 10.3 12.3 10.2 5.2 CRP-BMI = C-reactive protein–body mass index. for 46 patients (79.3%). Significantly more patients who received sal- practice to determine treatment for lung cancer patients [2, 28, 29]. vage treatment had CRP-BMI scores of 0 or 1 than a score of 2 However, this staging system sometimes fails to predict patient (P < 0.01). Of the 9 patients who developed recurrence and had a prognosis and may not offer appropriate clinical practice guidance. CRP-BMI score 2, 6 could not receive salvage treatments because of Indeed, patients at the same TNM stage may have other conditions their medical condition or history, such as interstitial pneumonia or that influence treatment outcomes. Thus, there is a need to identify renal failure. The median survival time after recurrence was longer more sensitive and convenient pretreatment prognostic factors to for patients with CRP-BMI scores of 0 or 1 than for those with a enable more personalized treatment. Many studies have examined score of 2. the relationships between pretreatment systemic inflammatory sta- tus, nutritional status, and skeletal muscle mass and the outcomes of treatment for cancer [18, 30]. Although this has also been examined DISCUSSION in NSCLC, most studies have involved surgical treatments [8, 11, 31]. The TNM staging system, which classifies cancer mainly according In this study, we evaluated these relationships in patients with locally to the size and extension of the primary tumor, its lymphatic advanced NSCLC treated with chemoradiotherapy. involvement, and the presence of metastases, is used in clinical Downloaded from https://academic.oup.com/jrr/article-abstract/59/1/50/4647146 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Prognostic score for NSCLC � 55 Several serum markers have been investigated as predictors of however, there was a trend that high CRP-BMI score tended to show systemic inflammatory status and prognosis of patients with a worse OS rate, regardless of gender. To our knowledge, this is the NSCLC, but none are available for use in daily practice. Serum first study to identify the CRP-BMI score as a prognostic factor in CRP level is widely used in the diagnosis of acute and chronic sys- patients with advanced NSCLC. The CRP-BMI score was significantly correlated with gender. temic inflammation and is a prognostic factor for patients with malignant tumors such as hepatocellular carcinoma, esophageal can- Considering this correlation, we analyzed OS rates separately for cer, and colon cancer [32–34] . Some studies of NSCLC patients each gender with CRP-BMI score. Even though they were analyzed treated with surgery or chemotherapy have also assessed CRP as an separately, the higher CRP-BMI tended to be associated with worse independent risk factor [35–37]. In the present study, elevated pre- OS for each gender. We concluded that the CRP-BMI score may be treatment serum CRP tended to correlate with poor OS, consistent a prognostic factor in patients with advanced NSCLC regardless of with previous studies. Thus, CRP may be a prognostic factor for gender, though it was not proved in this study. locally advanced NSCLC patients treated with chemoradiotherapy. Some limitations of this study should be acknowledged. First, the Serum Alb is commonly used to assess nutritional status. study was performed retrospectively in a small population of 89 Hypoalbuminemia (Alb < 3.5 g/dl) often reflects malnutrition and patients. We think that a further study on a large number of patients may be a predictor of survival in patients with NSCLC after curative is needed to clarify the issues. Second, there was some heterogeneity pulmonary resection [38]. However, in our study, hypoalbuminemia in the patient treatments, which may have led to different clinical was not a prognostic factor in univariate analysis. Recovery of Alb prognoses. Thus, further studies are needed to examine the relation- level is important after surgery [39], but radical chemoradiotherapy ship between pretreatment systemic inflammatory and nutritional sta- is a less invasive treatment than surgery. This may explain why tus and the prognosis of patients with locally advanced NSCLC hypoalbuminemia was not associated with a risk of complication and treated with chemoradiotherapy. thus did not affect the post-chemoradiotherapy outcome. In conclusion, the results of this study indicate that the CRP- BMI is also widely used to evaluate nutritional status [40]. A BMI score that is based on pretreatment systemic inflammatory and Phase III trial of first line systemic chemotherapy for advanced nutritional status is associated with clinical outcome of NSCLC NSCLC in 2684 patients showed that BMI ≥ 18.5 kg/m indicated patients treated with chemoradiotherapy and the probability of a better prognosis than BMI < 18.5 kg/m [41]. This may be receiving salvage treatment after recurrence. We think that further related to the difference in rates of treatment discontinuation due to large-scale prospective studies are required in order to establish the disease progression or death in that study, which were 52.3% for CRP-BMI score as a guide for selection of patients for treatment. the underweight patients and 42.3% for the obese patients. In our study, a similar trend was found for the relationship between BMI ACKNOWLEDGEMENTS and discontinuation of treatment at the time of recurrence. The OS Results from this study were presented at the 73rd Annual Meeting for patients with BMI < 18.5 kg/m was also worse than for those of the Japan Radiological Society. with BMI ≥ 18.5 kg/m . Sarcopenia, which reflects degenerative loss of skeletal muscle CONFLICT OF INTEREST mass, is an objective indicator of cancer cachexia and a predictor of The authors declare no conflicts of interest with regard to the work worse clinical outcomes in several studies of malignancy [42, 43]. in the manuscript. This condition may reflect increased metabolic activity of more aggressive tumors, leading to systemic inflammation and muscle FUNDING wasting [44]. However, in our study, SMI was not a significant This work was supported by JSPS KAKENHI Grant Number (C) prognostic factor for OS. The reason for this result is unclear, but 15K09992. The study sponsor had no involvement in the study most studies have examined SMI in the context of postoperative design; collection, analysis, and interpretation of data; or the deci- complications in abdominal surgery, and SMI obtained by measur- sion to submit the manuscript for publication. ing the total psoas muscle area at L3 may have little relationship to outcomes of thoracic cancer treated with chemoradiotherapy. One merit of the CRP-BMI score is that it is easy to acquire in REFERENCES clinical practice. Another merit is that it can be used to predict 1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA whether salvage treatment can be received at the time of recurrence. Cancer J Clin 2015;65:5–29. Although the recurrence rate for each CRP-BMI score group was 2. McCloskey P, Balduyck B, Van Schil PE et al. Radical treatment almost the same, the rate of administration of salvage treatment for of non-small cell lung cancer during the last 5 years. 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Journal of Radiation ResearchOxford University Press

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