ONCOLOGY
The value of the high-sensitivity modified Glasgow prognostic score in predicting the survival of patients with a soft-tissue sarcoma T. Nakamura, A. Matsumine, K. Asanuma, T. Matsubara, A. Sudo From Mie University Graduate School of Medicine, Mie, Japan
The aim of this study was to determine whether the high-sensitivity modified Glasgow prognostic score (Hs-mGPS) could predict the disease-specific survival and oncological outcome in adult patients with non-metastatic soft-tissue sarcoma before treatment. A total of 139 patients treated between 2001 and 2012 were retrospectively reviewed. The HsmGPS varied between 0 and 2. Patients with a score of 2 had a poorer disease-specific survival than patients with a score of 0 (p < 0.001). The estimated five-year rate of diseasespecific survival for those with a score of 2 was 0%, compared with 85.4% (95% CI 77.3 to 93.5) for those with a score of 0. Those with a score of 2 also had a poorer disease-specific survival than those with a score of 1 (75.3%, 95% CI 55.8 to 94.8; p < 0.001). Patients with a score of 2 also had a poorer event-free rate than those with a score of 0 (p < 0.001). Those with a score of 2 also had a poorer event-free survival than did those with a score of 1 (p = 0.03). A multivariate analysis showed that the Hs-mGPS remained an independent predictor of survival and recurrence. The Hs-mGPS could be a useful prognostic marker in patients with a soft-tissue sarcoma. Cite this article: Bone Joint J 2015; 97-B:847–52.
T. Nakamura, MD, PhD, Orthopaedic Surgeon, Dept. of Orthopaedic Surgery A. Matsumine, MD, PhD, Orthopaedic Surgeon, Dept. of Orthopaedic Surgery K. Asanuma, MD, PhD, Orthopaedic Surgeon, Dept. of Orthopaedic Surgery T. Matsubara, MD, PhD, Orthopaedic Surgeon, Dept. of Orthopaedic Surgery A. Sudo, MD, PhD, Orthopaedic Surgeon, Professor, Dept. of Orthopaedic Surgery Mie University Graduate School of Medicine, 2-174, Edobashi, Tsu-city, Mie, Japan. Correspondence should be sent to Dr T. Nakamura; e-mail: [email protected] ©2015 The British Editorial Society of Bone & Joint Surgery doi:10.1302/0301-620X.97B6. 35098 $2.00 Bone Joint J 2015;97-B:847–52. Received 9 September 2014; Accepted after revision 4 February 2015
VOL. 97-B, No. 6, JUNE 2015
Inflammation plays a critical role in the development, progression, clinical presentation and diagnosis of tumours.1-4 It is therefore of interest that the combination of hypoalbuminaemia (< 3.5 g/dl) and an elevated C-reactive protein (CRP) (> 1.0 mg/dl) level, which are used in the Glasgow prognostic score (GPS)4-6 or the modified GPS (mGPS),4,5 has been shown to provide additional prognostic information in patients with a primary tumour which is resectable,5,6 as well as advanced (metastasised) cancer.4,6 It is, however, not clear whether the GPS is useful in patients with a soft-tissue sarcoma. Recently, some authors have suggested that a lower threshold for CRP (> 0.3 mg/dl) may enhance the prognostic value of the mGPS in patients with cancer, and a high-sensitivity modified GPS (HS-mGPS) has been proposed.6,7 The aim of this study was to determine whether the HS-mGPS could predict the disease-specific survival and oncological outcome in adult patients with a soft-tissue sarcoma before treatment, and also to examine whether there are links between an increased HS-mGPS and the clinical characteristics.
Patients and Methods Between January 2001 and December 2012, 139 adult patients with a primary soft-tissue
sarcoma were treated with resection. Patients presenting with recurrent disease, metastases, and those referred for additional resection after a previous inappropriate excision were excluded from this study. The mean age of the patients at the time of diagnosis was 60 years (20 to 89). There were 78 men and 61 women. The site of the tumour was the thigh (n = 57), leg (n = 14), buttock (n = 14), back (n = 10), upper arm (n = 9), chest wall (n = 8), forearm (n = 6), shoulder (n = 6) and other sites (n = 15), including two retroperitoneal lesions. The mean follow-up was 54 months (3 to 144). All patients underwent pre-treatment staging with CT scans of the lungs to exclude metastases. The histological diagnosis and grade of tumour was determined using the French Federation of Cancer Centers Sarcoma Group grading system.8 The serum albumin and CRP levels were obtained prior to treatment for all patients, and were measured using mainly a Denka Seiken X-2 autoanalyser (Denka Seiken Co., Ltd., Tokyo, Japan); at our institution the normal levels are > 3.5 g/dl and < 0.3 mg/dl, respectively. The HS-mGPS was constructed as described previously.7 Briefly, patients with both hypoalbuminaemia (< 3.5 g/ dl) and elevated CRP level (> 0.3 mg/dl) were allocated a score of 2. Those who had only an elevated CRP level were allocated a score of 1. 847
848
T. NAKAMURA, A. MATSUMINE, K. ASANUMA, T. MATSUBARA, A. SUDO
Table I. The relationship between HS-mGPS and clinical data
Variables
0
1
2
Mean age (yrs) Male gender Female gender Site Trunk Limbs Grade G1 G2 G3 Size (cm) Depth Superficial Deep
60 61 47
60 16 9
64 5 1
0.86* 0.11
24 84
4 21
1 5
0.76
51 19 38 9.4
4 5 16 12.5
0 1 5 13.2
0.007
24 84
1
HS-mGPS-0
p-value
4 21
0 6
Disease-specific survival
Hs-GPS
0.8 HS-mGPS-1 0.6 0.4
HS-mGPS-2
0.2
HS-mGPS-0 vs 1: p = 0.23 HS-mGPS-0 vs 2: p < 0.0001 HS-mGPS-1 vs 2: p = 0.0003
0 0.01* 0.36
0
30
60
90
120
150
Mths Fig. 1
HS-mGPS, high-sensitivity modified Glasgow prognostic score * The Kruskal-Wallis test was used; for the rest of the results, the Chi square test was used
Kaplan–Meier curve showing the disease-specific survival of the 139 patients with soft-tissue sarcomas.
The remaining patients were allocated a score of 0. A clinicopathological analysis was performed relating the HSmGPS to various factors, including age, gender, and the site, grade, size and depth of the tumour. The primary purpose of the study was to examine the prognostic factors, including the HS-mGPS, associated with patient survival using univariate and multivariate analyses. The following factors were studied: age (> 60 vs < 60 years), gender, the site (trunk vs limbs), grade (1/2 vs 3), size (> 10 cm vs < 10 cm) and depth of the tumour and the HS-mGPS (score 0/1 vs 2). Further aims were to examine the prognostic factors associated with the oncological outcome. Statistical analysis. The statistical associations of the clinicopathological factors were evaluated using the Mann– Whitney U test and the Kruskal–Wallis test for quantitative data, and the chi-squared test for qualitative data. Survival was taken as the time from the initial treatment for the tumour to the date when the patient was documented to be alive, or the date when the patient died from sarcoma. The survival and event-free curves were constructed using the Kaplan–Meier method, and the log rank test was used to compare survival and recurrences in the patients. A multivariate analysis was performed using Cox’s proportional hazards model. The variables included in the multivariate analysis were the significant factors identified in the univariate analysis. A p-value < 0.05 was considered to be significant in all statistical analyses.
undifferentiated pleomorphic sarcomas (UPS), 16 myxofibrosarcomas, 11 leiomyosarcomas, ten malignant peripheral nerve sheath tumours (MPNST), seven dermatofibrosarcoma protuberances (DFSP) and 19 other tumours. A total of 59 patients had grade 3 sarcomas, 25 had grade 2 and 55 had grade 1. The mean size of the tumours at diagnosis was 10.1 cm (2 to 30). In 28 patients the depth of the tumour was superficial and in 111 it was deep. A total of seven patients (5%) received radiotherapy (one brachytherapy, six post-operatively) and 20 (14%) received chemotherapy (four pre- and five post-operatively; 11 received pre- and post-operative chemotherapy). Radiotherapy was given to those patients with tumours in which an adequate margin could not be achieved and those in whom the margins contained tumour. The serum levels of albumin and CRP were measured before chemotherapy in these patients.
Results The characteristics of the patients, the tumours and the treatment. The tumours were classified histologically as
follows: 54 liposarcomas (37 well-differentiated type, 12 myxoid type, three de-differentiated type and two pleomorphic type), 22 malignant fibrous histiocytomas (MFH) or
The relationship between the Hs-GPS and clinical characteristics. The HS-mGPS varied from 0 to 2. A total of 108
patients (78%) had a score of 0, 25 (18%) had a score of 1 and six (4%) had a score of 2. The relationships between the clinicopathological features and the HS-mGPS are shown in Table I. The grade and size of the tumour were significantly associated with the Hs-GPS. Overall disease-specific survival and predictors of mortality. As of August 2014 most patients (111; 79%) were
alive, but 24 (17%) had died of disease and four (3%) had died of other causes. The disease-specific survival at five years was 79% (95% CI 71 to 87.1). When patients were divided into three groups according to the HS-mGPS, those with a score of 2 before treatment had a poorer disease-specific survival than those with a score of 0 (p < 0.001, log rank test) (Fig. 1). The three- and five-year disease-specific survival rates were respectively 16.7% (95% CI 0 to 46.5) and 0% for those with a score of THE BONE & JOINT JOURNAL
THE VALUE OF THE HIGH-SENSITIVITY MODIFIED GLASGOW PROGNOSTIC SCORE IN PREDICTING THE SURVIVAL OF PATIENTS
849
Table II. The prognostic factors for disease-specific survival in 139 patients Univariate analysis Variables Age (yrs)
> 60 < 60 Male Female Trunk Limbs Grade 3 Grade 2 Grade 1 > 10 < 10 Superficial Deep Score of 2 Score of 1 Score of 0
Gender Site Grade
Size (cm) Depth HS-mGPS
Multivariate analysis
N
3-Y DSS (%)
5-Y DSS (%)
p-value
79 60 78 61 29 110 59 25 55 67 72 28 111 6 25 108
82.7 89.4 89.8 80.7 75.2 88.6 70.3 91.8 100 81.4 89.7 88.5 85 16.7 82.2 91
76.8 81.8 85.4 70.4 75.2 80.1 60.4 77.7 100 73 84.7 88.5 76.4 0 75.3 85.4
0.26
HR (95% CI)
p-value
1 0.457 (0.154 to 1.358) 0.06 (0.008 to 0.458)
0.16 0.001
1 0.15 (0.044 to 0.508) 0.131 (0.048 to 0.362)
0.002 < 0.001
0.09 0.053 < 0.001
0.27 0.65 < 0.001
DSS, disease-specific survival; HR, hazard ratio; 95% CI, 95% confidence interval; HS-mGPS, high-sensitivity modified Glasgow prognostic score
1 Disease-specific survival
HS-mGPS-0 0.8 0.6
HS-mGPS-1 HS-mGPS-2
0.4 0.2
HS-mGPS-0 vs 1: p = 0.55 HS-mGPS-0 vs 2: p < 0.0001 HS-mGPS-1 vs 2: p = 0.001
0 0
30
60 Mths
90
120
Fig. 2 Kaplan–Meier curve showing the disease-specific survival of the 95 patients with soft-tissue sarcomas. Well-differentiated liposarcoma and dermatofibrosarcoma were excluded from this analysis.
2, compared with 91% (95% CI 85.3 to 96.6) and 85.4% (95% CI 77.3 to 93.5), respectively, for those with a score of 0. Those with a score of 2 also had a poorer disease-specific survival than those with a score of 1 (p < 0.001, log rank test; 82.2% (95% CI 66.2 to 98.1) and 75.3% (95% CI 55.8 to 94.8, respectively) (Fig. 1). There was no significant difference in the prognosis between patients with a score of 0 and those with a score of 1 (p = 0.23, log rank test) (Fig. 1). A univariate analysis of all possible prognostic factors confirmed the predictive value of the histological grade (p < 0.001) and HS-mGPS (p < 0.001). These factors maintained their prognostic significance in the multivariate analysis (Table II). Next, we excluded 44 patients with well-differentiated liposarcomas or DFSP from our cohort because of a low rate of relapse (including local recurrence and metastasis), VOL. 97-B, No. 6, JUNE 2015
and examined the relationship between the HS-mGPS and survival in the remaining 95 patients. Those with a score of 2 before treatment had a poorer disease-specific survival than those with a score of 0 (p < 0.001, log rank test). The three- and five-year disease-specific survival estimates were 16.7% (95% CI 0 to 46.5) and 0%, respectively, for those with a score of 2, versus 85.5% (95% CI 76.7 to 94.3) and 77.3% (95% CI 65.4 to 89.3), respectively, for those with a score of 0. The patients with a score of 2 also had a poorer disease-specific survival than those with a score of 1 (p = 0.001, log rank test; 79.3% (95% CI 61.1 to 97.6) and 70.5% (95% CI 47.5 to 93.5), respectively). There was no significant difference in the prognosis between the patients with a score of 0 and those with a score of 1 (p = 0.55, log rank test) (Fig. 2) (Table III). Event-free rate and predictors of local recurrence and metastasis. A total of 24 patients (17%) developed a local
recurrence, three of them after metastases. A total of 33 patients (24%) developed metastases. The five-year survival without event was 68.1% (95% CI 59.6 to 77.6). Patients with a score of 2 before treatment had a poorer event-free rate than those with a score of 0 (p < 0.001, log rank test) (Fig. 2). The estimated three- and five-year survival rates without event were 16.7% (95% CI 0 to 46.5) and 0%, respectively, for those with a score of 2, versus 79.2% (95% CI 71.2 to 87.2) and 77.2% (95% CI 68.4 to 85.9), respectively, for those with a score of 0. Patients with a score of 2 also had a poorer event-free survival than those with a score of 1 (p = 0.03, log rank test; 47.6% (95% CI 26.2 to 69) and 47.6% (95% CI 26.2 to 69), respectively) (Fig. 3). Furthermore, those with a score of 1 before treatment had a higher rate of event than those with a score of 0 (p < 0.001, log rank test) (Fig. 3). The univariate analysis also revealed significantly poorer outcomes for patients with truncal tumours (p = 0.01), older age
850
T. NAKAMURA, A. MATSUMINE, K. ASANUMA, T. MATSUBARA, A. SUDO
Table III. The prognostic factors for disease-specific survival in 95 patients Univariate analysis Variables Age (yrs)
> 60 < 60 Male Female Trunk Limbs Grade 3 Grade 2 Grade 1 > 10 < 10 Superficial Deep Score of 2 Score of 1 Score of 0
Gender Site Grade
Size (cm) Depth HS-mGPS
Multivariate analysis
N
3-Y DSS (%)
5-Y DSS (%) p-value
61 34 54 41 24 71 59 25 11 40 55 18 77 6 22 67
77.8 81.4 85.3 71.3 69.8 82.2 70.3 91.8 100 68.3 86.5 81.3 78.4 16.7 79.3 85.5
71.1 69.1 79.4 56.9 69.8 70.2 60.6 77.7 100 53.5 80.6 81.3 66.4 0 70.5 77.3
HR (95% CI)
p-value
1 0.636 (0.254 to 1.587)
0.33
1 0.15 (0.044 to 0.508) 0.131 (0.048 to 0.362)
0.002 < 0.001
0.77 0.06 0.17 0.1
0.04 0.73 < 0.001
DSS, disease-specific survival; HR, hazard ratio; 95% CI, 95% confidence interval; HS-mGPS, high-sensitivity modified Glasgow prognostic score
score of 1 (38.5%, 95% CI 15 to 62) and 38.5%, 95% CI 15 to 62), respectively) also had a poorer event-free rate than those with a score of 0 (p = 0.02, log rank test). There was no significant difference in the prognosis between the patients with a score of 1 and those with a score of 2 (p = 0.08, log rank test) (Fig. 4) (Table V).
1 HS-mGPS-0
Event-free survival
0.8 0.6
HS-mGPS-1
0.4 HS-mGPS-2 0.2
HS-mGPS-0 vs 1: p = 0.0003 HS-mGPS-0 vs 2: p < 0.0001 HS-mGPS-1 vs 2: p = 0.03
0 0
30
60
90
120
150
Mths Fig. 3 Kaplan–Meier curve showing the event-free rate of the 139 patients with soft-tissue sarcomas.
(p = 0.02) and high-grade tumours (p < 0.001). A multivariate analysis showed that the HS-mGPS, the site and grade of the tumour remained independent predictors of recurrence (Table IV). Next, we excluded 44 patients with well-differentiated liposarcomas or DFSP and examined the relationship between the HS-mGPS and event in the remaining 95 patients. The patients with a score of 2 before treatment had a poorer event-free survival than did those with a score of 0 (p < 0.001). The three- and five-year event-free rates of survival were 16.7% (95% CI 0 to 46.5) and 0%, respectively, for those with a score of 2, compared with 66.7% (95% CI 54.9 to 78.5) and 66.7% (95% CI 54.9 to 78.5), respectively, for those with a score of 0. The patients with a
Discussion The presence of an association between systemic inflammation and a poor prognosis has previously been reported in patients with a soft-tissue sarcoma.9-14 Our univariate and multivariate analyses showed that the HS-mGPS was associated with decreased disease-specific survival and eventfree rates in 139 adult patients with a soft-tissue sarcoma. Furthermore, we evaluated whether the HS-mGPS could predict survival and event-free survival in 95 patients with soft-tissue sarcoma that excluded well-differentiated liposarcoma and DFSP, which would not expect to be associated with a high rate of local recurrence and metastasis. Similarly, the HS-mGPS was associated with decreased survival and lower event-free rates. No studies have so far shown the relationship between the HS-mGPS and survival or oncological outcome in patients with a soft-tissue sarcoma based on a multivariate analysis, although previous studies have shown its impact on the survival of patients with several other forms of cancer.4-7 We also found that histological grade was a prognostic factor for survival and event. Truncal tumours did not have poorer disease-specific survival (p = 0.053) but had better eventfree survival, which may be because of the small number of patients with these tumours. We have previously reported that the combined use of the neutrophil:lymphocyte ratio (NLR) and CRP level THE BONE & JOINT JOURNAL
THE VALUE OF THE HIGH-SENSITIVITY MODIFIED GLASGOW PROGNOSTIC SCORE IN PREDICTING THE SURVIVAL OF PATIENTS
851
Table IV. The prognostic factors for event-free rate in 139 patients Univariate analysis Variables Age (yrs) Gender Site Grade
Size (cm) Depth HS-mGPS
> 60 < 60 Male Female Trunk Limbs Grade 3 Grade 2 Grade 1 > 10 < 10 Superficial Deep Score of 2 Score of 1 Score of 0
Multivariate analysis
N
3-Y EFR (%)
5-Y EFR (%)
p-value
HR (95% CI)
p-value
79 60 78 61 29 110 59 25 55 67 72 28 111 6 25 108
64 79.2 69.3 72.8 51.5 75.7 44.6 74.3 97.5 68.8 72.7 75 70 16.7 47.6 79.2
60 76.9 69.3 66.2 51.5 72.2 44.6 66.9 93.4 62.9 72.7 75 63.3 0 47.6 77.2
0.02
1 0.636 (0.316 to 1.28)
0.2
0.53 0.01 < 0.001
1 0.443 (0.224 to 0.879) 1 0.51 (0.23 to 1.135) 0.103 (0.031 to 0.349)
0.1 0.0003
1 0.445 (0.163 to 1.215) 0.167 (0.061 to 0.434)
0.11 < 0.001
0.02
0.28 0.36 < 0.001
EFR, event-free rate; HR, hazard ratio; 95% CI, 95% confidence interval; HS-mGPS, high-sensitivity modified Glasgow prognostic score
Event-free survival
1 0.8 HS-mGPS-0 0.6 0.4
HS-mGPS-1
0.2
HS-mGPS-0 vs 1: p=0.02 HS-mGPS-0 vs 2: p=0.0002 HS-mGPS-1 vs 2: p=0.08
HS-mGPS-2 0 0
30
60 Mths
90
120
Fig. 4 Kaplan–Meier curve showing the event-free rate of the 95 patients with soft-tissue sarcomas. Well-differentiated liposarcoma and dermatofibrosarcoma were excluded from this analysis.
could be useful as a prognostic predictor in these patients.9 However, there is no standard NLR, and therefore it may be difficult to confirm its validity in different cohorts.8-10 In contrast, the serum levels of albumin and CRP, as used in the GPS, mGPS or HS-mGPS, should be routinely available and standardised. They have been well validated in different cohorts. Therefore, it is likely that these scoring systems would be useful in patients with soft-tissue sarcomas, and could be useful for the stratification of patients entering randomised trials of intensive therapy – with, for instance, chemotherapy – in the future. These results are consistent with the possible mechanism whereby an ongoing systemic inflammatory response leads VOL. 97-B, No. 6, JUNE 2015
to increased protein breakdown and progressive nutritional decline.15,16 In this study, elevated HS-mGPS values were found in 22% of the 139 patients who did not have a metastasis, and the grade and size of the tumour in those with an elevated HS-mGPS were significantly higher than those in patients with a score of 0. An elevated HS-mGPS may therefore indicate a more aggressive tumour in these patients. We did not investigate the relationship between the HSGPS and survival in patients with metastatic disease at presentation, because only a small number of these patients had complete clinical data. It would therefore be of interest to determine whether the rate of elevated HS-mGPS values is
852
T. NAKAMURA, A. MATSUMINE, K. ASANUMA, T. MATSUBARA, A. SUDO
Table V. The prognostic factors for event-free rate in 95 patients Univariate analysis Variables Age (yrs) Gender Site Grade
Size (cm) Depth HS-mGPS
> 60 < 60 Male Female Trunk Limbs Grade 3 Grade 2 Grade 1 > 10 < 10 Superficial Deep Score of 2 Score of 1 Score of 0
Multivariate analysis
N
3-Y EFR (%)
5-Y EFR (%)
p-value
61 34 54 41 24 71 59 25 11 40 55 18 77 6 22 67
53.8 63.1 55.8 47.1 41.8 82.2 44.6 74.3 88.9 47.1 64.7 62.5 56.6 16.7 38.5 66.7
53.8 59.2 55.8 41.9 41.8 70.2 44.6 66.9 88.9 41.9 64.7 62.5 54.4 0 38.5 66.7
0.42
HR (95% CI)
p-value
0.47 0.054 0.006
0.03
1 0.474 (0.217 to 1.034) 0.06 0.142 (0.019 to 1.064) 0.06 1 0.72 (0.369 to 1.404) 0.33
0.48 < 0.001
1 0.522 (0.19 to 1.438) 0.2 0.287 (0.104 to 0.741) 0.01
EFR, event-free rate; HR, hazard ratio; 95% CI, 95% confidence interval; HS-mGPS, high-sensitivity modified Glasgow prognostic score
increased in patients with metastatic soft-tissue sarcomas, and moreover, whether the HS-mGPS can be used as a prognostic predictor in these patients. This study has some limitations. Although all patients had pretreatment staging with CT scans of the chest and routine blood tests to rule out the presence of metastases or inflammatory disease, other chronic conditions were not taken into consideration owing to the lack of information. Another limitation was the retrospective nature of the study. However, we believe that the HS-mGPS could be a useful prognostic marker in patients with soft-tissue sarcomas. Author contributions: T. Nakamura: Data collection, Analysis, Undertook the surgery, Writing the paper. A. Matsumine: Undertook the surgery, Reviewing the paper. K. Asanuma: Undertook the surgery T. Matsubara: Undertook the surgery A. Sudo: Reviewing the paper. This study was supported in part by the Health and Labour Sciences Research Expenses for Commission, Applied Research for Innovative Treatment of Cancer from the Ministry of Health, Labour and Welfare (H26-084). No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article. This article was primary edited by J. Scott and first proof edited by G. Scott.
References 1. Coussens LM, Werb Z. Inflammation and cancer. Nature 2002;420:860–867. 2. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature 2008;454:436–444. 3. Nakamura T, Grimer RJ, Gaston CL, et al. The prognostic value of the serum level of C-reactive protein for the survival of patients with a primary sarcoma of bone. Bone Joint J [Br] 2013;95-B:411–418.
4. Forrest LM, McMillan DC, McArdle CS, Angerson WJ, Dunlop DJ. Evaluation of cumulative prognostic scores based on the systemic inflammatory response in patients with inoperable non-small-cell lung cancer. Br J Cancer 2003;89:1028–1030. 5. McMillan DC, Crozier JE, Canna K, Angerson WJ, McArdle CS. Evaluation of an inflammation-based prognostic score (GPS) in patients undergoing resection for colon and rectal cancer. Int J Colorectal Dis 2007;22:881–886. 6. Proctor MJ, Horgan PG, Talwar D, et al. Optimization of the systemic inflammation-based Glasgow prognostic score: a Glasgow Inflammation Outcome Study. Cancer 2013;119:2325–2332. 7. Takeno S, Hashimoto T, Shibata R, et al. The high-sensitivity modified Glasgow prognostic score is superior to the modified Glasgow prognostic score as a prognostic predictor in patients with resectable gastric cancer. Oncology 2014;87:205–214. 8. Guillou L, Coindre JM, Bonichon F, et al. Comparative study of the National Cancer Institute and French Federation of Cancer Centers Sarcoma Group grading systems in a population of 410 adult patients with soft tissue sarcoma. J Clin Oncol 1997;15:350–362. 9. Nakamura T, Matsumine A, Matsubara T, et al. The combined use of the neutrophil-lymphocyte ratio and C-reactive protein level as prognostic predictors in adult patients with soft tissue sarcoma. J Surg Oncol 2013;108:481–485. 10. Idowu OK, Ding Q, Taktak AF, Chandrasekar CR, Yin Q. Clinical implication of pretreatment neutrophil to lymphocyte ratio in soft tissue sarcoma. Biomarkers 2012;17:539–544. 11. Choi ES, Kim HS, Han I. Elevated preoperative systemic inflammatory markers predict poor outcome in localized soft tissue sarcoma. Ann Surg Oncol 2014;21:778–785. 12. Nakamura T, Matsumine A, Matsubara T, et al. Clinical significance of pretreatment serum C-reactive protein level in soft tissue sarcoma. Cancer 2012;118:1055–1061. 13. Nakamura T, Grimer R, Gaston C, et al. The value of C-reactive protein and comorbidity in predicting survival of patients with high grade soft tissue sarcoma. Eur J Cancer 2013;49:377–385. 14. Szkandera J, Gerger A, Liegl-Atzwanger B, et al. Validation of the prognostic relevance of plasma C-reactive protein levels in soft-tissue sarcoma patients. Br J Cancer 2013;109:2316–2322. 15. McMillan DC, Scott HR, Watson WS, et al. Longitudinal study of body cell mass depletion and the inflammatory response in cancer patients. Nutr Cancer 1998;31:101–105. 16. McMillan DC, Watson WS, O’Gorman P, et al. Albumin concentrations are primarily determined by the body cell mass and the systemic inflammatory response in cancer patients with weight loss. Nutr Cancer 2001;39:210–213.
THE BONE & JOINT JOURNAL
The value of the high-sensitivity modified Glasgow prognostic score in predicting the survival of patients with a soft-tissue sarcoma T. Nakamura, A. Matsumine, K. Asanuma, T. Matsubara, A. Sudo From Mie University Graduate School of Medicine, Mie, Japan
The aim of this study was to determine whether the high-sensitivity modified Glasgow prognostic score (Hs-mGPS) could predict the disease-specific survival and oncological outcome in adult patients with non-metastatic soft-tissue sarcoma before treatment. A total of 139 patients treated between 2001 and 2012 were retrospectively reviewed. The HsmGPS varied between 0 and 2. Patients with a score of 2 had a poorer disease-specific survival than patients with a score of 0 (p < 0.001). The estimated five-year rate of diseasespecific survival for those with a score of 2 was 0%, compared with 85.4% (95% CI 77.3 to 93.5) for those with a score of 0. Those with a score of 2 also had a poorer disease-specific survival than those with a score of 1 (75.3%, 95% CI 55.8 to 94.8; p < 0.001). Patients with a score of 2 also had a poorer event-free rate than those with a score of 0 (p < 0.001). Those with a score of 2 also had a poorer event-free survival than did those with a score of 1 (p = 0.03). A multivariate analysis showed that the Hs-mGPS remained an independent predictor of survival and recurrence. The Hs-mGPS could be a useful prognostic marker in patients with a soft-tissue sarcoma. Cite this article: Bone Joint J 2015; 97-B:847–52.
T. Nakamura, MD, PhD, Orthopaedic Surgeon, Dept. of Orthopaedic Surgery A. Matsumine, MD, PhD, Orthopaedic Surgeon, Dept. of Orthopaedic Surgery K. Asanuma, MD, PhD, Orthopaedic Surgeon, Dept. of Orthopaedic Surgery T. Matsubara, MD, PhD, Orthopaedic Surgeon, Dept. of Orthopaedic Surgery A. Sudo, MD, PhD, Orthopaedic Surgeon, Professor, Dept. of Orthopaedic Surgery Mie University Graduate School of Medicine, 2-174, Edobashi, Tsu-city, Mie, Japan. Correspondence should be sent to Dr T. Nakamura; e-mail: [email protected] ©2015 The British Editorial Society of Bone & Joint Surgery doi:10.1302/0301-620X.97B6. 35098 $2.00 Bone Joint J 2015;97-B:847–52. Received 9 September 2014; Accepted after revision 4 February 2015
VOL. 97-B, No. 6, JUNE 2015
Inflammation plays a critical role in the development, progression, clinical presentation and diagnosis of tumours.1-4 It is therefore of interest that the combination of hypoalbuminaemia (< 3.5 g/dl) and an elevated C-reactive protein (CRP) (> 1.0 mg/dl) level, which are used in the Glasgow prognostic score (GPS)4-6 or the modified GPS (mGPS),4,5 has been shown to provide additional prognostic information in patients with a primary tumour which is resectable,5,6 as well as advanced (metastasised) cancer.4,6 It is, however, not clear whether the GPS is useful in patients with a soft-tissue sarcoma. Recently, some authors have suggested that a lower threshold for CRP (> 0.3 mg/dl) may enhance the prognostic value of the mGPS in patients with cancer, and a high-sensitivity modified GPS (HS-mGPS) has been proposed.6,7 The aim of this study was to determine whether the HS-mGPS could predict the disease-specific survival and oncological outcome in adult patients with a soft-tissue sarcoma before treatment, and also to examine whether there are links between an increased HS-mGPS and the clinical characteristics.
Patients and Methods Between January 2001 and December 2012, 139 adult patients with a primary soft-tissue
sarcoma were treated with resection. Patients presenting with recurrent disease, metastases, and those referred for additional resection after a previous inappropriate excision were excluded from this study. The mean age of the patients at the time of diagnosis was 60 years (20 to 89). There were 78 men and 61 women. The site of the tumour was the thigh (n = 57), leg (n = 14), buttock (n = 14), back (n = 10), upper arm (n = 9), chest wall (n = 8), forearm (n = 6), shoulder (n = 6) and other sites (n = 15), including two retroperitoneal lesions. The mean follow-up was 54 months (3 to 144). All patients underwent pre-treatment staging with CT scans of the lungs to exclude metastases. The histological diagnosis and grade of tumour was determined using the French Federation of Cancer Centers Sarcoma Group grading system.8 The serum albumin and CRP levels were obtained prior to treatment for all patients, and were measured using mainly a Denka Seiken X-2 autoanalyser (Denka Seiken Co., Ltd., Tokyo, Japan); at our institution the normal levels are > 3.5 g/dl and < 0.3 mg/dl, respectively. The HS-mGPS was constructed as described previously.7 Briefly, patients with both hypoalbuminaemia (< 3.5 g/ dl) and elevated CRP level (> 0.3 mg/dl) were allocated a score of 2. Those who had only an elevated CRP level were allocated a score of 1. 847
848
T. NAKAMURA, A. MATSUMINE, K. ASANUMA, T. MATSUBARA, A. SUDO
Table I. The relationship between HS-mGPS and clinical data
Variables
0
1
2
Mean age (yrs) Male gender Female gender Site Trunk Limbs Grade G1 G2 G3 Size (cm) Depth Superficial Deep
60 61 47
60 16 9
64 5 1
0.86* 0.11
24 84
4 21
1 5
0.76
51 19 38 9.4
4 5 16 12.5
0 1 5 13.2
0.007
24 84
1
HS-mGPS-0
p-value
4 21
0 6
Disease-specific survival
Hs-GPS
0.8 HS-mGPS-1 0.6 0.4
HS-mGPS-2
0.2
HS-mGPS-0 vs 1: p = 0.23 HS-mGPS-0 vs 2: p < 0.0001 HS-mGPS-1 vs 2: p = 0.0003
0 0.01* 0.36
0
30
60
90
120
150
Mths Fig. 1
HS-mGPS, high-sensitivity modified Glasgow prognostic score * The Kruskal-Wallis test was used; for the rest of the results, the Chi square test was used
Kaplan–Meier curve showing the disease-specific survival of the 139 patients with soft-tissue sarcomas.
The remaining patients were allocated a score of 0. A clinicopathological analysis was performed relating the HSmGPS to various factors, including age, gender, and the site, grade, size and depth of the tumour. The primary purpose of the study was to examine the prognostic factors, including the HS-mGPS, associated with patient survival using univariate and multivariate analyses. The following factors were studied: age (> 60 vs < 60 years), gender, the site (trunk vs limbs), grade (1/2 vs 3), size (> 10 cm vs < 10 cm) and depth of the tumour and the HS-mGPS (score 0/1 vs 2). Further aims were to examine the prognostic factors associated with the oncological outcome. Statistical analysis. The statistical associations of the clinicopathological factors were evaluated using the Mann– Whitney U test and the Kruskal–Wallis test for quantitative data, and the chi-squared test for qualitative data. Survival was taken as the time from the initial treatment for the tumour to the date when the patient was documented to be alive, or the date when the patient died from sarcoma. The survival and event-free curves were constructed using the Kaplan–Meier method, and the log rank test was used to compare survival and recurrences in the patients. A multivariate analysis was performed using Cox’s proportional hazards model. The variables included in the multivariate analysis were the significant factors identified in the univariate analysis. A p-value < 0.05 was considered to be significant in all statistical analyses.
undifferentiated pleomorphic sarcomas (UPS), 16 myxofibrosarcomas, 11 leiomyosarcomas, ten malignant peripheral nerve sheath tumours (MPNST), seven dermatofibrosarcoma protuberances (DFSP) and 19 other tumours. A total of 59 patients had grade 3 sarcomas, 25 had grade 2 and 55 had grade 1. The mean size of the tumours at diagnosis was 10.1 cm (2 to 30). In 28 patients the depth of the tumour was superficial and in 111 it was deep. A total of seven patients (5%) received radiotherapy (one brachytherapy, six post-operatively) and 20 (14%) received chemotherapy (four pre- and five post-operatively; 11 received pre- and post-operative chemotherapy). Radiotherapy was given to those patients with tumours in which an adequate margin could not be achieved and those in whom the margins contained tumour. The serum levels of albumin and CRP were measured before chemotherapy in these patients.
Results The characteristics of the patients, the tumours and the treatment. The tumours were classified histologically as
follows: 54 liposarcomas (37 well-differentiated type, 12 myxoid type, three de-differentiated type and two pleomorphic type), 22 malignant fibrous histiocytomas (MFH) or
The relationship between the Hs-GPS and clinical characteristics. The HS-mGPS varied from 0 to 2. A total of 108
patients (78%) had a score of 0, 25 (18%) had a score of 1 and six (4%) had a score of 2. The relationships between the clinicopathological features and the HS-mGPS are shown in Table I. The grade and size of the tumour were significantly associated with the Hs-GPS. Overall disease-specific survival and predictors of mortality. As of August 2014 most patients (111; 79%) were
alive, but 24 (17%) had died of disease and four (3%) had died of other causes. The disease-specific survival at five years was 79% (95% CI 71 to 87.1). When patients were divided into three groups according to the HS-mGPS, those with a score of 2 before treatment had a poorer disease-specific survival than those with a score of 0 (p < 0.001, log rank test) (Fig. 1). The three- and five-year disease-specific survival rates were respectively 16.7% (95% CI 0 to 46.5) and 0% for those with a score of THE BONE & JOINT JOURNAL
THE VALUE OF THE HIGH-SENSITIVITY MODIFIED GLASGOW PROGNOSTIC SCORE IN PREDICTING THE SURVIVAL OF PATIENTS
849
Table II. The prognostic factors for disease-specific survival in 139 patients Univariate analysis Variables Age (yrs)
> 60 < 60 Male Female Trunk Limbs Grade 3 Grade 2 Grade 1 > 10 < 10 Superficial Deep Score of 2 Score of 1 Score of 0
Gender Site Grade
Size (cm) Depth HS-mGPS
Multivariate analysis
N
3-Y DSS (%)
5-Y DSS (%)
p-value
79 60 78 61 29 110 59 25 55 67 72 28 111 6 25 108
82.7 89.4 89.8 80.7 75.2 88.6 70.3 91.8 100 81.4 89.7 88.5 85 16.7 82.2 91
76.8 81.8 85.4 70.4 75.2 80.1 60.4 77.7 100 73 84.7 88.5 76.4 0 75.3 85.4
0.26
HR (95% CI)
p-value
1 0.457 (0.154 to 1.358) 0.06 (0.008 to 0.458)
0.16 0.001
1 0.15 (0.044 to 0.508) 0.131 (0.048 to 0.362)
0.002 < 0.001
0.09 0.053 < 0.001
0.27 0.65 < 0.001
DSS, disease-specific survival; HR, hazard ratio; 95% CI, 95% confidence interval; HS-mGPS, high-sensitivity modified Glasgow prognostic score
1 Disease-specific survival
HS-mGPS-0 0.8 0.6
HS-mGPS-1 HS-mGPS-2
0.4 0.2
HS-mGPS-0 vs 1: p = 0.55 HS-mGPS-0 vs 2: p < 0.0001 HS-mGPS-1 vs 2: p = 0.001
0 0
30
60 Mths
90
120
Fig. 2 Kaplan–Meier curve showing the disease-specific survival of the 95 patients with soft-tissue sarcomas. Well-differentiated liposarcoma and dermatofibrosarcoma were excluded from this analysis.
2, compared with 91% (95% CI 85.3 to 96.6) and 85.4% (95% CI 77.3 to 93.5), respectively, for those with a score of 0. Those with a score of 2 also had a poorer disease-specific survival than those with a score of 1 (p < 0.001, log rank test; 82.2% (95% CI 66.2 to 98.1) and 75.3% (95% CI 55.8 to 94.8, respectively) (Fig. 1). There was no significant difference in the prognosis between patients with a score of 0 and those with a score of 1 (p = 0.23, log rank test) (Fig. 1). A univariate analysis of all possible prognostic factors confirmed the predictive value of the histological grade (p < 0.001) and HS-mGPS (p < 0.001). These factors maintained their prognostic significance in the multivariate analysis (Table II). Next, we excluded 44 patients with well-differentiated liposarcomas or DFSP from our cohort because of a low rate of relapse (including local recurrence and metastasis), VOL. 97-B, No. 6, JUNE 2015
and examined the relationship between the HS-mGPS and survival in the remaining 95 patients. Those with a score of 2 before treatment had a poorer disease-specific survival than those with a score of 0 (p < 0.001, log rank test). The three- and five-year disease-specific survival estimates were 16.7% (95% CI 0 to 46.5) and 0%, respectively, for those with a score of 2, versus 85.5% (95% CI 76.7 to 94.3) and 77.3% (95% CI 65.4 to 89.3), respectively, for those with a score of 0. The patients with a score of 2 also had a poorer disease-specific survival than those with a score of 1 (p = 0.001, log rank test; 79.3% (95% CI 61.1 to 97.6) and 70.5% (95% CI 47.5 to 93.5), respectively). There was no significant difference in the prognosis between the patients with a score of 0 and those with a score of 1 (p = 0.55, log rank test) (Fig. 2) (Table III). Event-free rate and predictors of local recurrence and metastasis. A total of 24 patients (17%) developed a local
recurrence, three of them after metastases. A total of 33 patients (24%) developed metastases. The five-year survival without event was 68.1% (95% CI 59.6 to 77.6). Patients with a score of 2 before treatment had a poorer event-free rate than those with a score of 0 (p < 0.001, log rank test) (Fig. 2). The estimated three- and five-year survival rates without event were 16.7% (95% CI 0 to 46.5) and 0%, respectively, for those with a score of 2, versus 79.2% (95% CI 71.2 to 87.2) and 77.2% (95% CI 68.4 to 85.9), respectively, for those with a score of 0. Patients with a score of 2 also had a poorer event-free survival than those with a score of 1 (p = 0.03, log rank test; 47.6% (95% CI 26.2 to 69) and 47.6% (95% CI 26.2 to 69), respectively) (Fig. 3). Furthermore, those with a score of 1 before treatment had a higher rate of event than those with a score of 0 (p < 0.001, log rank test) (Fig. 3). The univariate analysis also revealed significantly poorer outcomes for patients with truncal tumours (p = 0.01), older age
850
T. NAKAMURA, A. MATSUMINE, K. ASANUMA, T. MATSUBARA, A. SUDO
Table III. The prognostic factors for disease-specific survival in 95 patients Univariate analysis Variables Age (yrs)
> 60 < 60 Male Female Trunk Limbs Grade 3 Grade 2 Grade 1 > 10 < 10 Superficial Deep Score of 2 Score of 1 Score of 0
Gender Site Grade
Size (cm) Depth HS-mGPS
Multivariate analysis
N
3-Y DSS (%)
5-Y DSS (%) p-value
61 34 54 41 24 71 59 25 11 40 55 18 77 6 22 67
77.8 81.4 85.3 71.3 69.8 82.2 70.3 91.8 100 68.3 86.5 81.3 78.4 16.7 79.3 85.5
71.1 69.1 79.4 56.9 69.8 70.2 60.6 77.7 100 53.5 80.6 81.3 66.4 0 70.5 77.3
HR (95% CI)
p-value
1 0.636 (0.254 to 1.587)
0.33
1 0.15 (0.044 to 0.508) 0.131 (0.048 to 0.362)
0.002 < 0.001
0.77 0.06 0.17 0.1
0.04 0.73 < 0.001
DSS, disease-specific survival; HR, hazard ratio; 95% CI, 95% confidence interval; HS-mGPS, high-sensitivity modified Glasgow prognostic score
score of 1 (38.5%, 95% CI 15 to 62) and 38.5%, 95% CI 15 to 62), respectively) also had a poorer event-free rate than those with a score of 0 (p = 0.02, log rank test). There was no significant difference in the prognosis between the patients with a score of 1 and those with a score of 2 (p = 0.08, log rank test) (Fig. 4) (Table V).
1 HS-mGPS-0
Event-free survival
0.8 0.6
HS-mGPS-1
0.4 HS-mGPS-2 0.2
HS-mGPS-0 vs 1: p = 0.0003 HS-mGPS-0 vs 2: p < 0.0001 HS-mGPS-1 vs 2: p = 0.03
0 0
30
60
90
120
150
Mths Fig. 3 Kaplan–Meier curve showing the event-free rate of the 139 patients with soft-tissue sarcomas.
(p = 0.02) and high-grade tumours (p < 0.001). A multivariate analysis showed that the HS-mGPS, the site and grade of the tumour remained independent predictors of recurrence (Table IV). Next, we excluded 44 patients with well-differentiated liposarcomas or DFSP and examined the relationship between the HS-mGPS and event in the remaining 95 patients. The patients with a score of 2 before treatment had a poorer event-free survival than did those with a score of 0 (p < 0.001). The three- and five-year event-free rates of survival were 16.7% (95% CI 0 to 46.5) and 0%, respectively, for those with a score of 2, compared with 66.7% (95% CI 54.9 to 78.5) and 66.7% (95% CI 54.9 to 78.5), respectively, for those with a score of 0. The patients with a
Discussion The presence of an association between systemic inflammation and a poor prognosis has previously been reported in patients with a soft-tissue sarcoma.9-14 Our univariate and multivariate analyses showed that the HS-mGPS was associated with decreased disease-specific survival and eventfree rates in 139 adult patients with a soft-tissue sarcoma. Furthermore, we evaluated whether the HS-mGPS could predict survival and event-free survival in 95 patients with soft-tissue sarcoma that excluded well-differentiated liposarcoma and DFSP, which would not expect to be associated with a high rate of local recurrence and metastasis. Similarly, the HS-mGPS was associated with decreased survival and lower event-free rates. No studies have so far shown the relationship between the HS-mGPS and survival or oncological outcome in patients with a soft-tissue sarcoma based on a multivariate analysis, although previous studies have shown its impact on the survival of patients with several other forms of cancer.4-7 We also found that histological grade was a prognostic factor for survival and event. Truncal tumours did not have poorer disease-specific survival (p = 0.053) but had better eventfree survival, which may be because of the small number of patients with these tumours. We have previously reported that the combined use of the neutrophil:lymphocyte ratio (NLR) and CRP level THE BONE & JOINT JOURNAL
THE VALUE OF THE HIGH-SENSITIVITY MODIFIED GLASGOW PROGNOSTIC SCORE IN PREDICTING THE SURVIVAL OF PATIENTS
851
Table IV. The prognostic factors for event-free rate in 139 patients Univariate analysis Variables Age (yrs) Gender Site Grade
Size (cm) Depth HS-mGPS
> 60 < 60 Male Female Trunk Limbs Grade 3 Grade 2 Grade 1 > 10 < 10 Superficial Deep Score of 2 Score of 1 Score of 0
Multivariate analysis
N
3-Y EFR (%)
5-Y EFR (%)
p-value
HR (95% CI)
p-value
79 60 78 61 29 110 59 25 55 67 72 28 111 6 25 108
64 79.2 69.3 72.8 51.5 75.7 44.6 74.3 97.5 68.8 72.7 75 70 16.7 47.6 79.2
60 76.9 69.3 66.2 51.5 72.2 44.6 66.9 93.4 62.9 72.7 75 63.3 0 47.6 77.2
0.02
1 0.636 (0.316 to 1.28)
0.2
0.53 0.01 < 0.001
1 0.443 (0.224 to 0.879) 1 0.51 (0.23 to 1.135) 0.103 (0.031 to 0.349)
0.1 0.0003
1 0.445 (0.163 to 1.215) 0.167 (0.061 to 0.434)
0.11 < 0.001
0.02
0.28 0.36 < 0.001
EFR, event-free rate; HR, hazard ratio; 95% CI, 95% confidence interval; HS-mGPS, high-sensitivity modified Glasgow prognostic score
Event-free survival
1 0.8 HS-mGPS-0 0.6 0.4
HS-mGPS-1
0.2
HS-mGPS-0 vs 1: p=0.02 HS-mGPS-0 vs 2: p=0.0002 HS-mGPS-1 vs 2: p=0.08
HS-mGPS-2 0 0
30
60 Mths
90
120
Fig. 4 Kaplan–Meier curve showing the event-free rate of the 95 patients with soft-tissue sarcomas. Well-differentiated liposarcoma and dermatofibrosarcoma were excluded from this analysis.
could be useful as a prognostic predictor in these patients.9 However, there is no standard NLR, and therefore it may be difficult to confirm its validity in different cohorts.8-10 In contrast, the serum levels of albumin and CRP, as used in the GPS, mGPS or HS-mGPS, should be routinely available and standardised. They have been well validated in different cohorts. Therefore, it is likely that these scoring systems would be useful in patients with soft-tissue sarcomas, and could be useful for the stratification of patients entering randomised trials of intensive therapy – with, for instance, chemotherapy – in the future. These results are consistent with the possible mechanism whereby an ongoing systemic inflammatory response leads VOL. 97-B, No. 6, JUNE 2015
to increased protein breakdown and progressive nutritional decline.15,16 In this study, elevated HS-mGPS values were found in 22% of the 139 patients who did not have a metastasis, and the grade and size of the tumour in those with an elevated HS-mGPS were significantly higher than those in patients with a score of 0. An elevated HS-mGPS may therefore indicate a more aggressive tumour in these patients. We did not investigate the relationship between the HSGPS and survival in patients with metastatic disease at presentation, because only a small number of these patients had complete clinical data. It would therefore be of interest to determine whether the rate of elevated HS-mGPS values is
852
T. NAKAMURA, A. MATSUMINE, K. ASANUMA, T. MATSUBARA, A. SUDO
Table V. The prognostic factors for event-free rate in 95 patients Univariate analysis Variables Age (yrs) Gender Site Grade
Size (cm) Depth HS-mGPS
> 60 < 60 Male Female Trunk Limbs Grade 3 Grade 2 Grade 1 > 10 < 10 Superficial Deep Score of 2 Score of 1 Score of 0
Multivariate analysis
N
3-Y EFR (%)
5-Y EFR (%)
p-value
61 34 54 41 24 71 59 25 11 40 55 18 77 6 22 67
53.8 63.1 55.8 47.1 41.8 82.2 44.6 74.3 88.9 47.1 64.7 62.5 56.6 16.7 38.5 66.7
53.8 59.2 55.8 41.9 41.8 70.2 44.6 66.9 88.9 41.9 64.7 62.5 54.4 0 38.5 66.7
0.42
HR (95% CI)
p-value
0.47 0.054 0.006
0.03
1 0.474 (0.217 to 1.034) 0.06 0.142 (0.019 to 1.064) 0.06 1 0.72 (0.369 to 1.404) 0.33
0.48 < 0.001
1 0.522 (0.19 to 1.438) 0.2 0.287 (0.104 to 0.741) 0.01
EFR, event-free rate; HR, hazard ratio; 95% CI, 95% confidence interval; HS-mGPS, high-sensitivity modified Glasgow prognostic score
increased in patients with metastatic soft-tissue sarcomas, and moreover, whether the HS-mGPS can be used as a prognostic predictor in these patients. This study has some limitations. Although all patients had pretreatment staging with CT scans of the chest and routine blood tests to rule out the presence of metastases or inflammatory disease, other chronic conditions were not taken into consideration owing to the lack of information. Another limitation was the retrospective nature of the study. However, we believe that the HS-mGPS could be a useful prognostic marker in patients with soft-tissue sarcomas. Author contributions: T. Nakamura: Data collection, Analysis, Undertook the surgery, Writing the paper. A. Matsumine: Undertook the surgery, Reviewing the paper. K. Asanuma: Undertook the surgery T. Matsubara: Undertook the surgery A. Sudo: Reviewing the paper. This study was supported in part by the Health and Labour Sciences Research Expenses for Commission, Applied Research for Innovative Treatment of Cancer from the Ministry of Health, Labour and Welfare (H26-084). No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article. This article was primary edited by J. Scott and first proof edited by G. Scott.
References 1. Coussens LM, Werb Z. Inflammation and cancer. Nature 2002;420:860–867. 2. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature 2008;454:436–444. 3. Nakamura T, Grimer RJ, Gaston CL, et al. The prognostic value of the serum level of C-reactive protein for the survival of patients with a primary sarcoma of bone. Bone Joint J [Br] 2013;95-B:411–418.
4. Forrest LM, McMillan DC, McArdle CS, Angerson WJ, Dunlop DJ. Evaluation of cumulative prognostic scores based on the systemic inflammatory response in patients with inoperable non-small-cell lung cancer. Br J Cancer 2003;89:1028–1030. 5. McMillan DC, Crozier JE, Canna K, Angerson WJ, McArdle CS. Evaluation of an inflammation-based prognostic score (GPS) in patients undergoing resection for colon and rectal cancer. Int J Colorectal Dis 2007;22:881–886. 6. Proctor MJ, Horgan PG, Talwar D, et al. Optimization of the systemic inflammation-based Glasgow prognostic score: a Glasgow Inflammation Outcome Study. Cancer 2013;119:2325–2332. 7. Takeno S, Hashimoto T, Shibata R, et al. The high-sensitivity modified Glasgow prognostic score is superior to the modified Glasgow prognostic score as a prognostic predictor in patients with resectable gastric cancer. Oncology 2014;87:205–214. 8. Guillou L, Coindre JM, Bonichon F, et al. Comparative study of the National Cancer Institute and French Federation of Cancer Centers Sarcoma Group grading systems in a population of 410 adult patients with soft tissue sarcoma. J Clin Oncol 1997;15:350–362. 9. Nakamura T, Matsumine A, Matsubara T, et al. The combined use of the neutrophil-lymphocyte ratio and C-reactive protein level as prognostic predictors in adult patients with soft tissue sarcoma. J Surg Oncol 2013;108:481–485. 10. Idowu OK, Ding Q, Taktak AF, Chandrasekar CR, Yin Q. Clinical implication of pretreatment neutrophil to lymphocyte ratio in soft tissue sarcoma. Biomarkers 2012;17:539–544. 11. Choi ES, Kim HS, Han I. Elevated preoperative systemic inflammatory markers predict poor outcome in localized soft tissue sarcoma. Ann Surg Oncol 2014;21:778–785. 12. Nakamura T, Matsumine A, Matsubara T, et al. Clinical significance of pretreatment serum C-reactive protein level in soft tissue sarcoma. Cancer 2012;118:1055–1061. 13. Nakamura T, Grimer R, Gaston C, et al. The value of C-reactive protein and comorbidity in predicting survival of patients with high grade soft tissue sarcoma. Eur J Cancer 2013;49:377–385. 14. Szkandera J, Gerger A, Liegl-Atzwanger B, et al. Validation of the prognostic relevance of plasma C-reactive protein levels in soft-tissue sarcoma patients. Br J Cancer 2013;109:2316–2322. 15. McMillan DC, Scott HR, Watson WS, et al. Longitudinal study of body cell mass depletion and the inflammatory response in cancer patients. Nutr Cancer 1998;31:101–105. 16. McMillan DC, Watson WS, O’Gorman P, et al. Albumin concentrations are primarily determined by the body cell mass and the systemic inflammatory response in cancer patients with weight loss. Nutr Cancer 2001;39:210–213.
THE BONE & JOINT JOURNAL
