Abstract
Background/Objectives: To elucidate the role of the CALLY index in 172 adult patients with primary soft tissue sarcoma (STS) and to evaluate whether the CALLY index is superior to the modified Glasgow prognostic score (mGPS) and prognostic nutrition index (PNI). Methods: The study cohort included 100 men and 72 women with a mean age of 63 years. Receiver operating characteristic (ROC) curve analysis was performed to determine the threshold value of the CALLY index for identifying the risk of identifying oncological events at 2 years. Results: ROC analysis identified 2.07 as the threshold of the CALLY index for predicting the risk of identifying oncological events at 2 years. The 5-year disease-specific survival (DSS) rate was 50.9% in patients with a lower CALLY index compared to 84% in those with a higher CALLY index. All patients with mGPS scores of 1 or 2 had lower CALLY indices, whereas all patients with a higher CALLY index had an mGPS score of 0. Patients with a lower CALLY index and mGPS of 0 had better DSS than those with a lower CALLY index and mGPS of 1 or 2. No substantial differences in DSS and disease-free survival (DFS) were observed between patients with a higher CALLY index and those with a lower CALLY index and an mGPS of 0. Conclusions: The CALLY index is a useful marker for predicting oncological outcomes in patients with primary STS. In particular, the CALLY index was a statistically significant prognostic variable for survival in patients with UPS and DDLPS individually. However, we suggest that the mGPS remains a reliable system for identifying patients with primary STSs who are at a high risk of death and relapse because we showed the significant difference for survival and event-free survival between the patients with mGPS of 1 and 2.
Keywords: CALLY index, modified Glasgow prognostic score, prognostic nutrition index, nutrition, inflammation, soft tissue sarcoma
1. Introduction
Soft tissue sarcoma (STS) is a rare heterogeneous tumor. The incidence of STS is less than 6 per 100,000 cancer cases, accounting for 1–2% of all cancer cases in adults [1]. Although there are more than 50 histologic subtypes, the standard treatment in patients with primary non-metastatic STS remains wide local resection, except for round-cell sarcoma such as extra-skeletal Ewing sarcoma, and rhabdomyosarcoma. It must be carried out by a surgeon specifically trained in the treatment of this disease within a sarcoma-specific center. The standard surgical treatment is a complete tumor resection with R0 margin [2]. This implies removing the tumor in a single specimen with a rim of normal tissue around it. Neoadjuvant or adjuvant radiotherapy is typically added to surgery as part of the standard treatment of high-grade STS [2]. Radiotherapy is not commonly indicated in the case of a truly compartmental resection of a tumor entirely contained within the compartment. Also, radiotherapy may be omitted after multidisciplinary discussion, considering risk factors for local recurrence, including surgical margins, tumor size, depth, and histological type. Perioperative chemotherapy can be proposed for fit patients affected by disease at high risk of death [2]. Although complete local treatment is performed, lung metastasis develops in 20–50% of STS patients, and the subsequent prognosis is poor. Conventional prognostic factors such as age at diagnosis, tumor size, histological grade, and tumor depth are useful general risk assessment tools for determining the prognosis, surgical strategy, and adjuvant management of patients with STS [3,4]. In addition to conventional prognostic factors, non-invasive prognostic biomarkers identified using a range of standard test results have attracted attention because they are cost-effective, easy to measure, and familiar to physicians [5,6,7]. Immune system, nutritional condition, and inflammation should be deeply associated with cancer progression. Therefore, we noted the prognostic tools which reflect the nutritional status, inflammatory status, and immune-system status in patients with STS. The prognostic nutritional index (PNI), calculated based on a combination of serum albumin and absolute lymphocyte count, has been used as a prognostic tool for survival in cancer patients [8]. Inadequate nutritional conditions and immunosuppression, which are commonly found in patients with cancers, also adversely affect clinical outcome and are reflected in biochemical indicators of serum albumin and lymphocytes. Reduced levels of these indicators not only indicate malnutrition and reduced immunocompetence [8]. Recently, the relationship between the survival and PNI was reported in the patients with STS, especially for retroperitoneal STS [9,10,11]. The modified Glasgow Prognostic Score (mGPS) underscores the value of C-reactive protein (CRP) as a standalone prognostic factor and recognizes hypoalbuminaemia’s negative impact only when CRP is elevated. mGPS is now widely applied for the prognostic tool for the patients with many types of cancer including STS and is backed by substantial evidence of its prognostic value. Recently, a large international multicenter study validated mGPS as an independent prognostic indicator for disease-free survival (DFS) and overall survival (OS) in patients with a localized resectable STS [12,13,14,15]. Thus, the PNI is considered to reflect the immune, nutritional status of patients with cancer, and mGPS is considered to reflect the nutritional, and inflammatory status of patients with cancer. Recently, the CALLY index has been shown to have prognostic potential in oncology, which reflects the immune, nutritional, and inflammatory status of patients with cancer [16,17,18]. The CALLY index, based on CRP and albumin levels and absolute lymphocyte counts, has shown potential for predicting cancer prognosis and guiding treatment [16,17,18]. However, there are no reports on the relationship between the CALLY index and STS. Therefore, we investigated the role of the CALLY index in 172 adult patients with primary STS. Furthermore, we evaluated the superiority of the CALLY index over the modified Glasgow prognostic score (mGPS) and prognostic nutrition index (PNI), as these indicators include CRP, albumin, and lymphocyte levels. Multivariate analysis showed that the CALLY index remained a significant predictor of DSS.
2. Materials and Methods
This study was conducted in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. Patients who underwent surgical resection for primary STS between January 2004 and December 2023 were included in this study. We excluded patients with metastasis at the initial presentation and those who underwent unplanned excision. Patients with well-differentiated liposarcoma (LPS) and dermatofibrosarcoma protuberances were also excluded. This study was approved by the Clinical Research Ethics Review Committee of Mie University Hospital, Japan (H2020-224) on 18 November 2020, and conducted in accordance with the Declaration of Helsinki. The need for informed consent was waived owing to the retrospective study design. Instead, the patients were allowed to opt out. The study cohort included 100 men and 72 women with a mean age of 63 years (range, 21–89 years) at the time of primary STS surgery. The mean follow-up period was 78 months. The minimum follow-up duration was 2 years, except for patients who experienced oncological events within 2 years. Blood samples were collected before treatment. The CALLY index was calculated using the formula: (serum albumin level (g/dL) × absolute lymphocyte count (n/μL))/C-reactive level (mg/dL) × 10,000. The modified Glasgow prognostic score (mGPS) was calculated as follows: patients with both hypoalbuminemia (<3.5 g/dL) and an elevated CRP level (>1.0 mg/dL) were allocated a score of 2. Those with elevated CRP levels were assigned a score of 1. The remaining patients were assigned a score of 0. The prognostic nutritional index (PNI) was calculated from preoperative laboratory parameters using the formula: 10× serum albumin level (g/dL) + 0.005× lymphocyte count (n/μL) in the peripheral blood. Blood samples were obtained from all patients before treatment. The primary purpose of this study was to elucidate the relationship between the CALLY index and DSS in 172 patients with primary STS who underwent surgical resection. The secondary purpose of this study was to elucidate whether the CALLY index is the best tool for predicting survival compared to the mGPS and PNI.
Statistical Analysis
The clinicopathological factors were evaluated using the Mann–Whitney U-test and Kruskal–Wallis rank sum test (quantitative data), and chi square test (qualitative data). The correlations between quantitative data were tested using Spearman’s rank correlation analysis. DSS was defined as the time from the date of surgical resection for primary STS to the date of death or the last follow-up examination. Disease-free survival (DFS) was defined as the time from the date of surgical resection for primary STS to the date of local recurrence, distant metastasis, or last follow-up examination. Survival curves were constructed using the Kaplan–Meier method. Univariate analyses were conducted using the log-rank test for qualitative data or the Cox proportional hazards model (quantitative data) to compare survival rates. Multivariate analyses were performed using the Cox proportional hazards model. Values of p < 0.05 were included as variables in the multivariate analysis. Receiver operating characteristic (ROC) curve analysis was performed to determine the thresholds of the CALLY index and PNI for the risk of death at 2 years. All statistical analyses were performed using the EZR (version 1.70) graphical user interface (Saitama Medical Center, Jichi Medical University, Saitama, Japan) for R (version 4.20, R Foundation for Statistical Computing, Vienna, Austria), a modified version of R Commander designed to add statistical functions that are frequently used in biostatistics. p values < 0.05 were considered significant in all statistical analyses.
3. Results
3.1. Patient Characteristics
A total of 172 patients were included in this study (Table 1). The average tumor size was 8.5 cm (range, 2–30 cm). There were 39 and 133 patients of superficial and deep STS, respectively. The primary tumor sites were the thigh (n = 66), leg (n = 23), buttock (n = 15), chest wall (n = 15), upper arm (n = 12), back (n = 11), knee (n = 6), and others (n = 11). Three cases of retroperitoneal STS were included. Primary STS was histologically classified as follows: 39 undifferentiated pleomorphic sarcomas (UPS), 36 myxofibrosarcomas (MFS), 26 leiomyosarcomas (LMS), 17 myxoid liposarcomas (MLPS), 15 dedifferentiated liposarcomas (DDLPS), 9 malignant peripheral nerve sheath tumors (MPNST), 8 synovial sarcomas, and 22 tumors of other histological types. There were 23 and 149 patients of histologically low-grade and high-grade STS, respectively. All patients underwent surgical tumor resection for primary STS. Perioperative chemotherapy and radiotherapy were performed in 38 patients and 18 patients, respectively. Perioperative chemotherapy was given to those patients under 70 years with high-grade, deep and large (>5 cm) tumors. Radiotherapy was given to those patients with tumors in which an adequate margin could not be achieved and those in whom the margins contained tumor.
Table 1.
Patient’s characteristics.
| Variable | N | |
|---|---|---|
| Age (years) | Average | 63 |
| Range | 21–89 | |
| Sex | Male | 100 |
| Female | 72 | |
| Tumor size (cm) | Average | 8.5 |
| Range | 2–30 | |
| Depth | Superficial | 39 |
| Deep | 133 | |
| Grade | Low | 23 |
| High | 149 | |
| Tumor site | Thigh | 66 |
| Leg | 23 | |
| Buttock | 15 | |
| chest wall | 15 | |
| upper arm | 12 | |
| Back | 11 | |
| Knee | 6 | |
| Others | 24 | |
| Histology | UPS | 39 |
| myxofibrosarcoma | 36 | |
| leiomyosarcoma | 26 | |
| MLPS | 17 | |
| DDLPS | 15 | |
| MPNST | 9 | |
| synovial sarcoma | 8 | |
| Others | 22 | |
| Perioperative Cx | Yes | 38 |
| No | 134 | |
| Perioperative Rx | Yes | 18 |
| No | 154 |
Cx; chemotherapy, Rx: radiotherapy, UPS; Undifferentiated pleomorphic sarcoma, MLPS; myxoid liposarcoma, DDLPS; dedifferentiated liposarcoma, MPNST; malignant peripheral nerve sheath tumor.
3.1.1. Clinical Outcomes
At the final follow-up, 112 patients were alive with the disease, and 50 patients died from their disease. The remaining 10 patients died of other causes. Overall, the 5-year DSS rate was 73.8% (95% confidence interval (CI), 66–80.1%). The CALLY index varied from 0.01 to 117.39. The average CALLY index was 15.54 (95% CI, 11.97–19.11). The CALLY index consists of serum albumin level, absolute lymphocyte count, and CRP. The average levels of albumin, CRP were 4.3 g/dL (95% CI, 4.19–4.34) and 1.32 (95% CI, 0.79–1.86). The average absolute lymphocyte count was 1847/μL (95% CI, 1759.4–1934.7). CRP was strongly correlated with the CALLY index (Spearman’s rho = −0.984, p < 0.0001). Serum albumin level had a moderate correlation (Spearman’s rho = 0.437, p < 0.0001). Absolute lymphocyte count had a weak correlation (Spearman’s rho = 0.268, p < 0.000372). Age, sex, and tumor depths were not associated with the CALLY index. Tumor grade was associated with the CALLY index. The median CALLY index in patients with low-grade STS was 13.76, while it was 3.99 in those with high-grade STS (p = 0.0064. chi-square test). Tumor size was weakly correlated with the CALLY index (Spearman’s rho = −0.293, p < 0.0001). Figure 1 shows the ROC curve analysis of the CALLY threshold for identifying the risk of identifying oncological events at two years. The threshold was 2.07, and the area under the curve (AUC) was 0.704 (95% CI, 0.621–0.787) (Figure 1).
Figure 1.
Receiver operative characteristic (ROC) analysis shows the threshold (2.07) of the CALLY index at risk of identifying oncological events at 2 years.
The prognostic variables used to predict survival are shown in Table 2a,b. In the univariate analysis, age, tumor size, tumor site, tumor grade, perioperative Rx, and CALLY were prognostic variables. Multivariate analysis showed that tumor site, tumor size, and CALLY remained significant (Table 3).
Table 2.
(a) Prognostic variables for disease-specific survival (qualitative variables); (b) Prognostic variables for disease-specific survival (quantitative data).
| ( a ) | ||||
| Variables | N | 5Y-DSS (95% CI) | p Value | |
| Sex | Male | 100 | 75.8 (65.5–83.5) | 0.45 |
| Female | 72 | 70.7 (57.7–80.4) | ||
| Depth | Superficial | 39 | 69.9 (60.6–77.4) | 0.243 |
| Depth | 133 | 87.2 (71.9–94.5) | ||
| Tumor site | Extremities | 116 | 81.8 (72.9–88) | 0.00101 |
| Trunk | 58 | 56.4 (40.9–69.3) | ||
| Grade | Low | 23 | 94.1 (65–99.1) | 0.0452 |
| High | 149 | 70.8 (62.3–77.8) | ||
| CALLY | >2.07 | 118 | 84 (75.5–89.8) | <0.0001 |
| <2.07 | 54 | 50.9 (35.6–64.3) | ||
| Perioperative Rx | Yes | 18 | 61.1 (67.1–81.8) | 0.0298 |
| No | 154 | 75.3 (67.1–85.8) | ||
| Perioperative Cx | Yes | 38 | 66.7 (48.8–79.4) | 0.132 |
| No | 134 | 76.1 (67.3–82.9) | ||
| (b) | ||||
| Variables | HR | 95% CI | p Value | |
| Age | Years | 1.023 | 1.001–1.045 | 0.0378 |
| Size | Cm | 1.119 | 1.069–1.171 | <0.0001 |
Cx; chemotherapy, DSS; disease-specific survival, 95% CI; 95% confidential interval, HR: Hazard ratio.
Table 3.
Multivariate analysis for predicting disease-specific survival.
| Variables | HR | 95% CI | p-Value | |
|---|---|---|---|---|
| Age | Years | 1.019 | 0.997–1.041 | 0.0971 |
| CALLY index | >2.07 | 1 | ||
| <2.07 | 2.361 | 1.28–4.356 | 0.006 | |
| Grade | High | 1 | ||
| Low | 0.547 | 0.128–2.346 | 0.417 | |
| Tumor site | Extremities | 1 | ||
| Trunk | 2.05 | 1.154–3.643 | 0.0144 | |
| Perioperative Rx | No | 1 | ||
| Yes | 1.861 | 0.812–4.264 | 0.142 | |
| Tumor size | Cm | 1.095 | 1.038–1.154 | 0.0008 |
HR: Hazard ratio, 95% CI; 95% confidential interval, Rx; Radiotherapy.
When we divided the patients into two groups according to the CALLY index of 2.07, the 5-year DSS in patients with a lower CALLY index (n = 54) was 50.9% (35.6–64.3), compared to 84% (75.5–89.8) in those with a higher CALLY index (n = 118) (p < 0.0001, log-rank test) (Figure 2).
Figure 2.
Kaplan–Meier curve showing disease-specific survival depending on the CALLY index. (A: CALLY index > 2.07, B: CALLY index < 2.07).
Table 4 shows the relationship between the 5-years DSS and individual major histology according to the CALLY index. All 17 patients with MLPS had high CALLY indexes. Individually, CALLY index was a statistically significant prognostic variable for survival in UPS and DDLPS.
Table 4.
The relationship between individual histology and survival.
| Histology | CALLY Index | N | 5-Years DSS | p Value |
|---|---|---|---|---|
| UPS | >2.07 | 18 | 86.6% (55.2–96.6) | 0.0318 |
| <2.07 | 21 | 48.6% (25.2–68.5) | ||
| Myxofibrosarcoma | >2.07 | 28 | 92% (71.5–98) | 0.264 |
| <2.07 | 8 | 72.9% (27.6–92.5) | ||
| Leiomyosarcoma | >2.07 | 16 | 64% (32.8–83.6) | 0.95 |
| <2.07 | 10 | 70% (32.9–89.2) | ||
| Myxoid liposarcoma | >2.07 | 15 | 85.6% (53.3–96.2) | 0.642 |
| <2.07 | 2 | not reached | ||
| DDLPS | >2.07 | 9 | 88.9% (43.3–98.4) | 0.0062 |
| <2.07 | 6 | not reached |
UPS; undifferentiated pleomorphic sarcoma, DDLPS; dedifferentiated liposarcoma, DSS; disease-specific survival.
Local recurrence was observed as the initial event in 31 patients, and metastasis occurred in 52 patients. Local recurrence and metastasis were observed synchronously in 2 patients. The 5-year DFS rate was 55.5% (95% CI, 47.6–62.7) in all patients. Table 5 shows the prognostic variables for predicting DFS. In the univariate analysis, age, tumor size, tumor depth, tumor grade, and CALLY were prognostic variables. Multivariate analysis showed that age, tumor size, and CALLY remained significant (Table 6).
Table 5.
(a) Prognostic variables for disease-free survival (qualitative variables); (b) Prognostic variables for disease-specific survival (quantitative data).
| (a) | ||||
| Variables | N | 5Y-DFS (95% CI) | p Value | |
| Sex | Male | 100 | 53.9 (43.4–63.3) | 0.882 |
| Female | 72 | 57.5 (45.1–68.2) | ||
| Depth | superficial | 39 | 72.9 (55.3–84.5) | 0.0247 |
| Depth | 133 | 50.4 (41.5–58.7) | ||
| Tumor site | Extremities | 116 | 62.2 (52.5–70.4) | 0.0019 |
| Trunk | 56 | 41.5 (28.1–54.3) | ||
| Grade | Low | 23 | 89.3 (62.6–97.3) | 0.0012 |
| High | 149 | 50.3 (41.9–58.1) | ||
| CALLY index | >2.07 | 118 | 64.8 (55.2–72.9) | <0.0001 |
| <2.07 | 54 | 35.2 (22.8–47.8) | ||
| Perioperative Rx | Yes | 18 | 38.1 (0.166–59.5) | 0.0187 |
| No | 154 | 57.8 (49.4–65.2) | ||
| Perioperative Cx | Yes | 134 | 44.6 (28.5–59.4) | 0.196 |
| No | 38 | 58.7 (49.6–66.7) | ||
| (b) | ||||
| Variables | HR | 95% CI | p Value | |
| Age | Years | 1.024 | 1.008–1.041 | 0.00384 |
| Size | cm | 1.122 | 1.077–1.168 | <0.0001 |
Cx; chemotherapy, DFS; disease-free survival, 95% CI; 95% confidential interval, HR: Hazard ratio.
Table 6.
Multivariate analysis for predicting disease-free survival.
| Variables | HR | 95% CI | p Value | |
|---|---|---|---|---|
| Age | Years | 1.02 | 1.003–1.037 | 0.0182 |
| CALLY index | >2.07 | 1 | ||
| <2.07 | 1.903 | 1.197–3.028 | 0.0066 | |
| Grade | High | 1 | ||
| Low | 0.346 | 0.106–1.128 | 0.0785 | |
| Tumor site | Extremities | 1 | ||
| Trunk | 1.644 | 1.047–2.581 | 0.0308 | |
| Perioperative Rx | No | 1 | ||
| Yes | 1.521 | 0.801–2.891 | 0.2 | |
| Depth | Deep | 1 | ||
| Superficial | 0.858 | 0.462–1.593 | 0.627 | |
| Tumor size | Cm | 1.099 | 1.049–1.152 | <0.0001 |
HR: Hazard ratio, 95% CI; 95% confidential interval.
When we divided the patients into two groups according to the CALLY index of 2.07, the 5-year DFS in patients with a lower CALLY index (n = 54) was 35.2% (95% CI, 22.8–47.8), compared to 64.8% (95% CI, 55.2–72.9) in those with a higher CALLY index (n = 118) (p < 0.0001, log-rank test) (Figure 3).
Figure 3.
Kaplan–Meier curve showing the disease-free survival depending on CALLY index (A: CALLY index > 2.07, B: CALLY index < 2.07).
3.1.2. Relationship Between CALLY, PNI, and mGPS
PNI varied from 23.45 to 65.7, with an average of 51.91. ROC analysis at risk of identifying oncological events at 2 years showed that the CALLY index (AUC = 0.704) had a significantly higher AUC than the PNI (AUC = 0.577) (p = 0.0086).
The mGPS varied from 0 to 2. A total of 140 patients (81.4%) had a score of 0, 25 (14.5%) had a score of 1, and 7 (4.1%) had a score of 2. DSS and DFS improved in mGPS-dependent manner. The 5 years survival rate in patients with mGPS of 0, 1, and 2 was 82.2% (95% CI, 0.741–0.880), 40.4% (95% CI, 0.204–0.596), 28.6% (95% CI, 0.041–0.612), respectively. We compared ROC analysis between the CALLY index and CRP because mGPS consists of only three scores (0, 1, and 2). ROC analysis at risk of identifying oncological events at 2 years showed that there was no significant difference of AUC between CALLY index (AUC = 0.704) and CRP (AUC = 0.715).
The mGPS of all 118 patients with a higher CALLY index was 0 (Table 7). The patients with mGPS of 1 and 2 had a significantly lower CALLY index (p < 0.0001, Chi-square test). When the Kaplan–Meier curve was created based on the CALLY index and mGPS, patients with a lower CALLY index and mGPS of 0 had better DSS and DFS than those with a lower CALLY index and mGPS of 1 or 2 (Figure 4). There were no significant differences in DSS and DFS between patients with a higher CALLY index and those with a lower CALLY index and an mGPS of 0. The 5-year survival rates in 118 patients with higher CALLY index and mGPS of 0 was 84% (95% CI, 75.5–89.8). The 5 year’s survival rate in patients with lower CALLY index and mGPS of 0, 1, and 2 was 71.5% (95% CI, 0.435–0.87.4), 40.4% (95% CI, 0.204–0.596), 28.6% (95% CI, 0.041–0.612), respectively.
Table 7.
The relationship between mGPS and CALLY index.
| mGPS of 0 | mGPS of 1 | mGPS of 2 | p Value | |
|---|---|---|---|---|
| CALLY > 2.07 | 118 | 0 | 0 | <0.0001 |
| CALLY < 2.07 | 22 | 25 | 7 |
Figure 4.
Kaplan–Meier curve showing disease-specific survival depending on the CALLY index and modified Glasgow prognostic score (mGPS). (A; CALLY index > 2.07 and mGPS of 0, B; CALLY index < 2.07 and mGPS of 0, C; CALLY index < 2.07 and mGPS of 1, D; CALLY index < 2.07 and mGPS of 2).
The 5 years DFS rates in 118 patients with higher CALLY index and mGPS of 0 was 64.8% (95% CI, 0.552–0.729). The 5 years DFS rate in patients with lower CALLY index and mGPS of 0, 1, and 2 was 54.5% (95% CI, 32.1–72.4), 28% (95% CI, 0.124–0.460), 0%, respectively.
4. Discussion
The CALLY index, based on CRP, albumin, and lymphocyte levels, reflects the immune, nutritional, and inflammatory status of patients with cancer, which are crucial aspects in several types of cancer progression [16,17,18]. In the present study, tumor size and tumor grade were related to the CALLY index. Müller et al. developed CALLY in 2021 for patients with hepatocellular carcinoma (HCC) undergoing transarterial chemoembolization (TACE) [18]. They reported that the PNI was a favorable prognostic tool for survival stratification in patients with HCC that were undergoing TACE [19]. They hypothesized that CRP might play an additional component for prognostic score system in addition to PNI because it could reflect the inflammatory component of the tumor microenvironment and, thus, they developed the CALLY index, which combines the PNI with the CRP level [18]. Chen et al. pooled data from 18 studies which included a total of 7916 patients with digestive system cancers to comprehensively assess the impact of the CALLY index on the prognosis of patients with digestive system cancers [20]. They showed significant associations between the CALLY index and worse OS, DFS, relapse-free survival (RFS) and DFS in patients with digestive system cancers [20]. In this study, we demonstrated the usefulness of the CALLY index in predicting the survival of patients with primary STS. A lower CALLY index is significantly associated with poorer outcomes in several types of cancers. We showed that patients with a lower CALLY index had poor DDS and EFS. Additionally, we compared it with mGPS and PNI as the prognostic tools, including CRP, albumin, and lymphocyte counts. Interestingly, the mGPS was superior in predicting oncological outcomes because all patients with an mGPS of 1 or 2 had a lower CALLY index, and those with a higher CALLY index had an mGPS of 0. These results may be due to the significant role of CRP levels in the calculation of the CALLY index in primary STS. Actually, CRP was strong correlation with CALLY index using Spearman’s rank correlation analysis in this study. mGPS reflects the inflammatory condition, and CRP is a reliable marker for predicting oncological outcomes in STS [5,7,21,22]. Therefore, we suggested that mGPS may be more useful for predicting survival in patients with primary STS, compared to the CALLY index for predicting oncological events in patients with primary STS. The serum albumin level is a leading indicator of nutritional status and is likely to decrease secondary to a systemic inflammatory response [23,24]. In this study, serum albumin level was moderately correlated with the CALLY index. The utility of the CALLY index has been reported in digestive system cancers such as gastric, esophageal, and colorectal cancers [8,9,10,16,25,26,27]. Patients with these cancers are particularly affected by their nutritional status owing to their anatomical features. Malnutrition in patients with cancer is generally related to cancer-associated or cancer-induced weight reduction [28]. Cancer-associated weight reduction is caused by nutrient absorption disorders due to constriction or occlusion of the digestive tract, anorexia induced by anticancer drugs, or psychological stress [29]. The PNI is similar to the CALLY index [30,31]. Recent studies have demonstrated the high accuracy of the PNI in predicting treatment outcomes for various cancers, especially gastrointestinal cancer [30]. Immune system function plays a critical role in the efficacy of immune checkpoint inhibitors (ICIs), and serum albumin and lymphocyte levels are important indicators of immune system function. Therefore, the PNI has been reported to be a useful prognostic index for patients with gastrointestinal cancer who received ICI therapy [31]. Concerning STS, STS has often been regarded as an “immune cold” tumor category, clinical trials using immune checkpoint inhibitor monotherapy have not shown compelling clinical benefits, although combination therapy with dual checkpoint inhibitors or in combinations with other agents has yielded more promising results in de-differentiated LPS, UPS, angiosarcoma and alveolar soft-part sarcoma [32]. In the advanced stages of STS, nutrition and the immune system may be affected by chemotherapy, cachexia, and organ dysfunction [33,34]. Also, the utility of PNI was reported in patients with primary retroperitoneal STS, because these are prone to encase or abut vital viscera and major vessels, and patients with these STS are particularly affected by their nutritional status due to the similar cause of digestive system cancers [9,10]. Xe et al. reported 189 consecutive patients with retroperitoneal liposarcomas who underwent surgical treatment [9]. They showed that the low PNI group was observed with significantly worse median survival time and 5-year OS rates than that of the high PNI group (26 vs. 86 months, p < 0.001; 25.2% vs. 68.7%, p < 0.001; respectively). Garcia-Ortega et al. conducted a retrospective cohort study of adult 142 patients undergoing curative surgical resection of primary or recurrent retroperitoneal STS [10]. They showed that low PNI was associated with inferior 3-year OS (55% vs. 74%, p = 0.008) and recurrent-free survival (44% vs. 63%, p = 0.022). In this study, only three patients with retroperitoneal STS were included. Therefore, further studies on the utility of the CALLY index and PNI should be conducted in patients with advanced STS or primary retroperitoneal STS. Furthermore, the CALLY index was a statistically significant prognostic variable for survival in patients with UPS and DDLPS individually. Although there was no significant difference owing to the small number of the patients, the CALLY index may be useful in the patient with MFS. Therefore, further study targeting the patients with those STSs for which CALLY index can be used as a prognostic tool may be encouraged.
This study had some limitations. First, we focused on the preoperative assessment of the scoring system and its derivatives without evaluating postoperative changes. Second, we cannot focus deeply on individual histology owing to the limited number of patients in this study, although DSS seems to be worse for each histology with a lower CALLY index, except for LMS. Third, the optimal cut-off values for the nutritional indices and CALLY index may fluctuate with different sample sizes. In particular, absolute lymphocyte count may differ between study cohorts. Regarding the relationship between absolute lymphocyte count and STS, Brewster et al. reported that absolute lymphocyte count was significantly inversely associated with OS in 634 patients with musculoskeletal sarcomas [6]. The median absolute lymphocyte count was 1120/µL in their study. However, in another study, the median absolute lymphocyte count was 1770/µL and absolute lymphocyte count was not related with oncological outcome [35]. In addition, some patient-specific variables, such as alcoholism, medical comorbidities, smoking status, inflammation disease such as collagen disease, hepatitis, and access to healthy food, may affect the evaluation of the prognostic tools. Finally, the retrospective nature of this study is another limitation.
5. Conclusions
The CALLY index is a useful marker for predicting oncological outcomes in patients with primary STS. In particular, the CALLY index was a statistically significant prognostic variable for survival in patients with UPS and DDLPS individually. However, we suggest that the mGPS remains a reliable system for identifying patients with primary STSs who are at a high risk of death and relapse because we showed the significant difference for survival and event-free survival between the patients with mGPS of 1 and 2.
Author Contributions
Conceptualization, T.N.; methodology, all authors; software, T.N.; validation, T.N.; formal analysis, T.N.; investigation, T.N.; resources, all authors; data curation, T.N., M.H.; writing—original draft preparation, T.N.; writing—review and editing, all authors; visualization, T.N.; supervision, M.H.; project administration, T.N.; funding acquisition, M.H. All authors have read and agreed to the published version of the manuscript.
Institutional Review Board Statement
This study was approved by the Clinical Research Ethics Review Committee of Mie University Hospital, Japan (H2020-224) on 18 November 2020, and was conducted in accordance with the principles of the Declaration of Helsinki.
Informed Consent Statement
The need for informed consent was waived due to the retrospective study design; instead, patients were allowed to opt out.
Data Availability Statement
The original contributions presented in this study are included in the article. Further inquiries can be directed to the corresponding author.
Conflicts of Interest
The authors declare no conflicts of interest.
Funding Statement
This research received no external funding.
Footnotes
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The original contributions presented in this study are included in the article. Further inquiries can be directed to the corresponding author.