Development and Validation a nomogram to predict the risk of pulmonary metastasis in pediatric osteosarcoma

doi:10.21203/rs.3.rs-2432677/v1

Background

Most malignant bone tumors in children and adolescents are osteosarcomas. Pediatric osteosarcoma has a high mortality rate due to pulmonary metastasis, which occurs in a short period of time. We would like to establish a nomogram to predict the risk of pulmonary metastasis of pediatric osteosarcoma to help doctors conduct early intervention and and improve their survival rate.

Methods

The clinicopathological information of patients was downloaded from SEER to identify pediatric osteosarcoma from 2004 to 2018. We analyzed the independent risk factors for pulmonary metastasis of pediatric osteosarcoma in the training cohort using univariate and multivariate logistic regression. Using these risk factors, we established a Nomogram prediction for pulmonary metastasis of pediatric osteosarcoma. We used three indicators to evaluate the accuracy of the nomogram. These three were calibration curve, c-index and area under the receiver operating curve (AUC). The clinical value of this nomogram was evaluated using Decision curve analysis (DCA).

Results

A sum of 1362 pediatric patients with osteosarcoma were involved in this research. They were randomly divided into the training cohort (N = 965) and the validation cohort (N = 397). In training cohort, univariate and multivariate logistic regression analysis showed that there were four independent risk factors, namely T stage, N stage, surgery, and radiotherapy. We constructed a new Nomogram to predict the risk of pulmonary metastasis in pediatric osteosarcoma. In the training cohorts and validation cohorts, the C-index was 0.699 (95% CI, 0.656–0.741) and 0.736 (95% CI, 0.675–0.797),respectively, indicating that the nomogram had good accuracy. The AUC of training group and validation group showed good predictive ability.

Conclusion

This study constructed a new nomogram to predict the risk of pulmonary metastasis in pediatric osteosarcoma. Our nomogram can help doctors provide accurate assessment of individual risk, active monitoring and follow-up of patients, and prevent pulmonary metastasis in pediatric osteosarcoma.

pediatric osteosarcoma

nomogram

risk

pulmonary metastasis

SEER

Most malignant bone tumors in children and adolescents are osteosarcomas, even though it accounts for less than 0.5% of all cancers[1]. It is estimated that approximately 400 kids and teenagers in the US receive an OS diagnosis annually[2]. With chemotherapy for osteosarcoma, the overall survival rate for patients with non-metastatic osteosarcoma has increased from 20% to more than 70% since the 1980s[3]. About one-fifth of patients with osteosarcoma had metastatic disease when it was first diagnosed. The most common type of metastasis is pulmonary metastasis, which occurs in more than 80% of cases[4–5]. Pediatric osteosarcoma has a high mortality rate due to pulmonary metastasis, which occurs in a short period of time.[6–7]. The 5-year survival rate for patients with pulmonary metastasis of osteosarcoma was 37% compared with 60–70% for patients without pulmonary metastasis of osteosarcoma..[8–9]. There is some evidence that metastatic resection combined with adjuvant chemotherapy is the best outcome for patients with lung metastases[10–13]. Osteosarcoma, like other malignant bone tumors, metastasizes mainly by hematogenous spread resulting in lung metastases, with a major impact on patients’ prognosis. However, radiography barely captures metastases until they physically form. In consequence, it is very important to confirm the presence of pulmonary metastasis in the early diagnosis of osteosarcoma. Currently, radiography is one of the most widely applied clinical screening strategies. There are still few reports assessing the risk factors for pulmonary metastasis of pediatric osteosarcoma.Normogram is widely used to predict risk factors and prognosis of various tumors. .Applying the Surveillance, Epidemiology, and End Results (SEER) database, the collected data were analyzed to identify independent risk factors for pulmonary metastasis in pediatric osteosarcoma patients at the time of first diagnosis. In addition, we constructed and validated normographs for predicting lung metastasis in pediatric osteosarcoma. The SEER database is the most comprehensive and whole database of cancer survival and incidence in the US. Since 1973, the SEER database compiles cancer infomation that are gathered from registries nationally and stands for 28% of the United States population presently [14–15].

Data Source and Data Extraction

All eligible pediatric osteosarcoma patients from 2004 to 2018 from the SEER database were collected. Demographic, clinicopathological, and follow-up data for pediatric osteosarcoma patients can be downloaded from the SEER database. As patient’ information in this database is public and anonymous, and we did not collect personally identifiable information from patients, neither moral clearance nor informed consent is required in this study. T stage, N stage,tumor size, primary site, laterality, chemotherapy, radiotherapy, surgery, pulmonary metastasis, cancer-specific survival(CSS), survival months and status. Inclusion criteria: (1) the years of diagnosis were 2004–2018 ; (2) be under 18 years of age. Exclusion criteria: (1) the surgical method is unknown; (2) osteosarcoma is non-primary tumor; (3) tumor size is unknown; (4) the location of the tumor is not clear; (5) the survival time less than 1 month. The patient screening flow chart is shown in Figure 1. Patients’ race was divided into three categories: white, black,and other. The patients’ years of diagnosis were between 2004 and 2018. Grade was divided into five categories: I, II, III and IV, unknow. T stage included T1, T2, T3 and T4. N stage was divided into N0 and N1. Primary site included limbs and axial. Chemotherapy and radiation were divided into No/Unknow and Yes. Surgery was classified as no surgery, partial resection, radical excision and amputation.

Construction and Validation of the Nomogram

All screened pediatric osteosarcoma patients were randomly assigned to training cohort (70%) or validation cohort (30%).Analyzing independent hazards, hazard ratios (HR) , 95% confidence intervals (CI) in pediatric osteosarcoma lung metastasis used univariate and multivariate logistic regression models. A nomogram model was established to predict the risk of pulmonary metastasis from pediatric osteosarcoma using screening independent risk factors.. The consistency of normogram was validated by calibration curve and consistency index (C-index). The greater the area under the curve (AUC) value, the better normogram's prediction accuracy.

Clinical utility

Decision curve analysis (DCA) was used to verify the clinical value of the nomogram. Additionally, a risk stratification system was used to group all patients according to their nomogram scores into high-risk and low-risk groups. We compared the survival and outcomes of patients in different risk groups by log-rank tests and Kaplan-Meier (K-M) curves.

Statistical Analysis

Data were counted using frequency description (%), and groups were compared using chi-square or non-parametric U-tests. Measurement data (age, survival months, tumor size) were described using mean and standard deviation and non-parametric U-tests were used to compare groups. Univariate and multivariate logistic regression models analyzed the risk of pulmonary metastasis in children with osteosarcoma. The log-rank test and K-M curve and compared the survival differences between groups. All statistical analyses were performed using SPSS 26.0 (IBM, Chicago, IL, USA) and R software 4.1.0 (http://www.Rproject.org). P < 0.05 was considered statistically significant.

Demographic baseline characteristics

This study enrolled 1362 pediatric patients with osteosarcoma based on inclusion and exclusion criteria.The mean age of the patients was 12.8 years. Among them, 1015 (74.5 %) were white and 210 (15.4%) were black. 754 (56.1%) were male and 598(43.9%) were female. Grade included 23 (1.69%) I, 44 (3.23%) II, 320 (23.5%) III, 615 (45.2%) IV, and 360 (26.4%) unknow. T stage included 497 (36.5%) T1, 817 (60.0%) T2, 46 (3.38%) T3, 2 (0.15%) T4. 1332 patients (97.8%) had stage N0. The mean tumor size was 105 mm. The primary site of osteosarcoma in 1237(90.8%) children was in the limbs. 1,292(94.9%) received chemotherapy and only 43(3.16%) received radiation. There were 79 (5.80%) patients without surgery, 111 (8.15%) patients with partial resection, 885 (65.0%)patients with radical excision, and 287 (21.1%) patients with amputation. Cancer-specific survival (CSS) was 0.73. The mean survival time was 64.6 months. By 2018, 71 percent of patients were alive. The clinicopathological data of all patients are shown in Table 1. Based on the baseline information, the training cohort and validation cohort showed no statistically significant differences (P > 0.05).

Table 1. Clinicopathological information descrition table of pediatric osteosarcoma group.

	ALL	Training set	Validation set	p
	*N=1362*	*N=965*	*N=397*
Age	12.8 (3.47)	12.8 (3.44)	12.8 (3.54)	0.954
Race				0.999
white	1015 (74.5%)	719 (74.5%)	296 (74.6%)
black	210 (15.4%)	149 (15.4%)	61 (15.4%)
other	137 (10.1%)	97 (10.1%)	40 (10.1%)
Sex				0.075
Male	764 (56.1%)	526 (54.5%)	238 (59.9%)
Female	598 (43.9%)	439 (45.5%)	159 (40.1%)
Grade				0.601
I	23 (1.69%)	16 (1.66%)	7 (1.76%)
II	44 (3.23%)	30 (3.11%)	14 (3.53%)
III	320 (23.5%)	230 (23.8%)	90 (22.7%)
IV	615 (45.2%)	424 (43.9%)	191 (48.1%)
Unknown	360 (26.4%)	265 (27.5%)	95 (23.9%)
T				0.911
T1	497 (36.5%)	347 (36.0%)	150 (37.8%)
T2	817 (60.0%)	583 (60.4%)	234 (58.9%)
T3	46 (3.38%)	33 (3.42%)	13 (3.27%)
T4	2 (0.15%)	2 (0.21%)	0 (0.00%)
N				0.362
N0	1332 (97.8%)	941 (97.5%)	391 (98.5%)
N1	30 (2.20%)	24 (2.49%)	6 (1.51%)
Tumor size	105 (61.3)	107 (65.1)	101 (50.7)	0.080
Primary site				0.220
Limbs	1237 (90.8%)	870 (90.2%)	367 (92.4%)
Axial	125 (9.18%)	95 (9.84%)	30 (7.56%)
Laterality				0.390
Left	682 (50.1%)	486 (50.4%)	196 (49.4%)
Right	621 (45.6%)	433 (44.9%)	188 (47.4%)
Not pairs	59 (4.33%)	46 (4.77%)	13 (3.27%)
Chemotherapy				0.767
No/Unknown	70 (5.14%)	48 (4.97%)	22 (5.54%)
Yes	1292 (94.9%)	917 (95.0%)	375 (94.5%)
Radiation				0.040
No/Unknown	1319 (96.8%)	928 (96.2%)	391 (98.5%)
Yes	43 (3.16%)	37 (3.83%)	6 (1.51%)
Surgery				0.082
No	79 (5.80%)	66 (6.84%)	13 (3.27%)
Partial resection	111 (8.15%)	76 (7.88%)	35 (8.82%)
Radical excision	885 (65.0%)	622 (64.5%)	263 (66.2%)
Amputation	287 (21.1%)	201 (20.8%)	86 (21.7%)
Mets at lung				0.603
No	1105 (81.1%)	779 (80.7%)	326 (82.1%)
Yes	257 (18.9%)	186 (19.3%)	71 (17.9%)
CSS	0.73 (0.44)	0.72 (0.45)	0.77 (0.42)	0.049
Survival months	64.6 (49.8)	63.3 (48.8)	68.0 (52.0)	0.119

Univariate and Multivariate Logistic Regression Analysis

Using univariate logistic regression model, seven important prognostic factors were screened, including age (hazard ratio (HR)=1.06, 95% CI 1.01-1.11, P < 0.05), laterality (HR=0.27, 95% CI 0.08-0.87, P < 0.05), T stage (HR=4.51, 95% CI 2.06-9.88, P < 0.05), N stage (HR=6.26, 95% CI 2.73-14.33, P < 0.05), surgery (HR=0.39, 95% CI 0.22-0.69, P < 0.05), radiotherapy (HR=6.07, 95% CI 3.1-11.88, P < 0.05), tumor Size (HR=1.001, 95% CI 1-1.01, P < 0.05). Then,multivariate logistic regression was used to analyze these factors.There were four independent prognostic factors, which were T stage(HR=2.194, 95% CI 1.457-3.305, P < 0.05), N stage (HR=5.288, 95% CI 2.155-12.975, P < 0.05), surgery (HR=0.366, 95% CI 0.195-0.688, P < 0.05) and radiotherapy (HR=5.155, 95% CI 2.417-10.996, P < 0.05).(Table 2) We can combine these risk factors into a nomogram to predict the risk of pulmonary metastasis of pediatric osteosarcoma.

Table 2. Univariate and multivariate analyses of CSS in training cohort.

	Univariate			Multivariate
	HR	95%CI	P	HR	95%CI	P
Age	1.06	1.01-1.11	0.03	1.048	0.995-1.103	0.076
Race
white	reference
black	1.09	0.7-1.7	0.7
other	1.2	0.71-2.01	0.5
Sex
Male	reference
Female	0.79	0.57-1.1	0.16
Grade
I	reference
II	1.67	0.16-17.47	0.67
III	3.25	0.42-25.33	0.26
IV	3.71	0.48-28.45	0.21
Unknown	4.11	0.53-31.78	0.18
T
T1	reference
T2	2.36	1.6-3.46	0	2.194	1.457-3.305	0
T3	4.51	2.06-9.88	0	3.888	1.666-9.072	0.002
T4	7.9	0.48-128.81	0.15	15.933	0.764-332.179	0.074
N
N0	reference
N1	6.26	2.73-14.33	0	5.288	2.155-12.975	0
Tumor size	1.001	1-1.01	0
Primary site
Limbs	reference
Axial	0.7	0.39-1.32	0.24
Laterality
Left	reference
Right	0.89	0.64-1.23	0.48	0.873	0.617-1.234	0.442
Not pairs	0.27	0.08-0.87	0.03	0.285	0.079-1.023	0.054
Chemotherapy
No/Unknown	reference
Yes	2.27	0.97-7.68	0.06
Radiation
No/Unknown	reference
Yes	6.07	3.1-11.88	0	5.155	2.417-10.996	0
Surgery
No	reference
Partial resection	0.18	2.73-11.33	0	0.211	0.088-0.505	0
Radical excision	0.22	0.08-0.41	0	0.243	0.137-0.432	0
Amputation	0.39	0.13-0.38	0	0.366	0.195-0.688	0.002

Construction and validation a novel nomogram

We constructed a novel Nomogram to predict the risk of pulmonary metastasis for pediatric osteosarcoma (Figure 2). T stage was the most significant risk factor for pulmonary metastasis, followed by N stage, radiotherapy and surgery. Verify the nomogram accuracy of the training and validation queues using calibration curves. Calibration curves showed a good degree of consistency between the two groups..(Figure 3). In the training cohorts and validation cohorts, the C-index was 0.699 (95% CI, 0.656-0.741) and 0.736(95% CI, 0.675-0.797), respectively, indicating good accuracy. The AUC of the training cohort and the validation cohort also suggested excellent predictive power, with 0.676 (95%CI, 0.632–0.719) and 0.587 (95%CI, 0.517–0.657), respectively(Figure 4).

Clinical Application of Nomogram

DCA shown good clinical application in training and validation cohorts(Figure 5). Nomogram has significant predictive advantages over traditional TN staging. There was a high-risk group (total score > 71.3) and a low-risk group (≤71.3 overall) in the training and validation cohorts. The K-M curve indicated that the 1-, 3-, and 5-year survival rates in the high-risk group were 0.936 (95% CI, 0.917–0.955),0.727 (95% CI, 0.692–0.764), and 0.655 (95% CI, 0.617–0.696), respectively. The 1-, 3- and 5-year survival rates of patients in the low-risk group were 0.964 (95% CI, 0.949–0.978), 0.847 (95%CI, 0.818–0.877), and 0.783 (95% CI, 0.749–0.819), respectively(Figure 6). Outcomes proved the high-risk group had a poor prognosis and was more prone to distant metastasis.We analyzed surgical procedures in the high-risk and low-risk groups.In the low-risk group, partial resection had the highest survival rate, followed by radical resection and amputation. Patients who did not have surgery had the lowest survival rates(Figure 7A). In the high-risk group, most children received radical resection, and patients undergoing radical resection possessed substantially higher survival rates than other groups. Patients who underwent surgery had significantly higher survival rates than those who did not (Figure 7B).

Osteosarcoma is the most common malignant bone tumor in kids, although it makes up less than 0.5% of all tumors. Some studies have shown that about 11–20% of pediatric osteosarcoma patients have pulmonary metastasis at diagnosis, while about 40–55% of non-metastatic osteosarcoma patients have pulmonary metastasis[16–19]. Total survival in non-metastatic osteosarcoma has become better significantly due to the mid-1970s with effectual chemotherapy combinations' growth. Treatments of non-metastatic osteosarcoma include complete surgical excision with neoadjuvant and adjuvant chemotherapy, which includes some drugs such as doxorubicin, ifosfamide, cisplatin, or methotrexate[20]. When pediatric osteosarcoma patients develop lung metastases, their long-term survival rate is less than 40%[21]. The prerequisite for cure is complete elimination of all known metastases. In published studies, complete resection of all known metastases has been proved to be a consistent prerequisite for survival[4, 22–25]. Even with combination therapy, metastatic disease still has a poor prognosis, with a majority of cases relapsing[26]. Chest CT is the most effective method to detect pulmonary nodules. One limitation of CT scanning is the possibility of motion artifacts due to the patient's movement or breathing, which can reduce resolution. The few seconds it takes to hold your breath can cause some difficulties for younger children, who may need sedation to be successfully imaged[27]. The development of multi-detector CT scanners, which allow the detection of smaller pulmonary nodules, may improve the sensitivity of the diagnosis of lung metastases, but may reduce the specificity[28].In order to prevent distant metastasis in pediatric osteosarcoma patients, we need to accurately predict the risk factors, improve the appropriate examinations. Bieling et al. and Kaste et al. found that tumor volume was a an important predictor of lung metastasis and survival.They propose that lung metastasis occurs earlier as the tumor size increases[29–30]. However, our study did not find a significant association between primary osteosarcoma size and pulmonary metastasis. Ugo et al. studied 463 children, adolescents, and young adults with pulmonary metastases from osteosarcoma, with a median age of 15.9 years (range 0.2–23.2 years). The multivariate analysis revealed that the disease-free interval, the number of metastases, and complete resection of the primary tumor were the most important factors predicting survival[31]. The independent risk factors for pulmonary metastasis of pediatric osteosarcoma were investigated. Finally, a predictive model was established to predict the probability of pulmonary metastasis of pediatric osteosarcoma. Based on univariate and multivariate analyses, T stage was the most significant independent risk factor at lung metastasis, followed by N stage, radiotherapy and surgery.. Our results suggest that the higher the T stage, the higher the risk of pulmonary metastasis of pediatric osteosarcoma. It is possible that tumor cells invade blood vessels, causing the tumor cells to find distant metastases. Our study found that N stage is also a key factor in pulmonary metastasis of pediatric osteosarcoma. Osteosarcomas might involve local lymph nodes because tumor parenchyma for instance synovium or joint capsule might invade the lymphatic system[32–33]. Thampi et al. concluded that osteosarcoma lymphatic metastasis was significantly associated with distant metastasis[34]. Osteosarcoma is generally considered to be a radio-resistant tumor. Our study found that radiation therapy increases the risk of pulmonary metastasis in children with osteosarcoma. Preclinical evidence presented by Talmadge et al. on the effects of radiation on three major steps in the metastasis process, namely angiogenesis, movement and invasion, and metastasis[35]. Evidence from clinical and preclinical studies suggests that ionizing radiation increases metastasis at the primary tumor site and to normal tissues in some instances[36–37]. We discovered that operative resection of osteosarcoma's primary site is an important prognostic factor for pediatric osteosarcoma's pulmonary metastasis. Surgical excision of all tumor sites is a major, independent prognostic factor that has been reported in other studies[38–39]. Because surgery can destroy or remove tumor tissue, it reduces the chance of distant metastasis. We analyzed surgical procedures in the high-risk and low-risk groups. In the low-risk group, partial resection had the highest survival rate, followed by radical resection and amputation. Patients who did not have surgery had the lowest survival rates. Surgery had a significantly higher survival rate in the high-risk group than no surgery. Most patients underwent radical resection, and patients who underwent radical resection had significantly higher survival rates than the other groups. This is the first reasearch to explore the risk factors for lung metastasis of pediatric osteosarcoma using SEER database. We used these risk factors to construct a nomogram to predict distant metastasis. After internal verification, the C-index was 0.699, and the correction curve also showed good accuracy of the prediction model. However, there are some limitations in our studyFirstly, this was a retrospective analysis. All the data comes from the SEER database, so inevitably there will be biased. Additionally, SEER did not contain data that might have influenced the outcome of the survival analysis, such as radiation dose, the number of lung nodules at metastasis, and surgical treatment after the occurrence of lung metastasis. These may be confounding factors affecting the results of survival analysis. Thirdly, the incidence of pulmonary metastases in this study might have been underestimated because pulmonary metastases occurring during the progression of osteosarcoma were not included in the SEER database. Fourthly, In addition, our approach in a single-center study by dividing patients into training and validation cohorts may not be comparable to other external validation. In order for the model to be accurate and reliable, it requires external validation.

Using univariate and multivariate analyses, we identified four independent risk factors for lung metastasis in pediatric osteosarcoma patients. We established a new Nomogram to predict the risk of pulmonary metastasis of pediatric osteosarcoma. By combining correction curve, C-index and the AUC, our nomogram has good accuracy and reliability. Our nomogram can help doctors provide accurate assessment of individual risk, active monitoring and follow-up of patients, and prevent pulmonary metastasis of pediatric osteosarcoma.

Acknowledgements

Not applicable.

Authors’ contributions

HO and JKW designed the study; ZLW, JKW, and HO collected and analyzed the data; HO drafted the initial manuscript; ZLW, JKW, and HO revised the article critically; ZLW, JKW, and HO reviewed and edited the article; All authors approved the final manuscript.

Funding

None.

Availability of data and materials

The SEER data analyzed in this study is available at https://seer.Cancer.gov/. Ethics approval and consent to participate The data of this study is obtained from the SEER database. The patients’ data is public and anonymous, so this study does not require ethical approval and informed consent.

Consent for publication

None.

Competing interests

The authors declare that they have no competing interests.

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No competing interests reported.

Development and Validation a nomogram to predict the risk of pulmonary metastasis in pediatric osteosarcoma

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Abstract

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Introduction

METHOD

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Version 1