To provide a better insight into the epidemiology, characteristics, therapeutics, and outcomes of pediatric RMS. Data of 1,623 pediatric RMS were acquired from the Surveillance, Epidemiology and End Results (SEER) database. Detailed information on demographics, primary site, size, subtype, stage, surgery, and survival had been recorded during 1975-2016. The most common subtype was embryonal RMS (64.9%) followed by alveolar RMS (29.9%). Additionally, the majority of RMS size was larger than 5 cm. Multivariable analysis exhibited that the age over 10, unfavorable primary site, distant metastasis was respectively correlated with the poor OS, whereas surgery could improve the outcomes of pediatric RMS. In conclusion, our large population-based analysis described that age, subtype, primary tumor sites, stage and surgery are all independent prognosis factors for RMS

Chen, Xu

Hu, Shaoyan

Wan, Lin

English

Advanced Emergency Medicine (E-Journal)

Advanced Emergency Medicine- 10 -Impact of Rhabdomyosarcoma (RMS) Characteristics onPrognosis of Pediatric RMS: A SEER Database Large PopulationStudyLin Wan1, Xu Chen2, Shaoyan Hu1*1. Department of Hematology & Oncology, Children’s Hospital of Soochow University, Suzhou215000, P.R. China.2. Air Force Health Care Center for Special Services, Hangzhou 310007, P.R. China.Abstract: To provide a better insight into the epidemiology, characteristics, therapeutics, and outcomes of pediatric RMS.Data of 1,623 pediatric RMS were acquired from the Surveillance, Epidemiology and End Results (SEER) database. Detailedinformation on demographics, primary site, size, subtype, stage, surgery, and survival had been recorded during 1975-2016.The most common subtype was embryonal RMS (64.9%) followed by alveolar RMS (29.9%). Additionally, the majority ofRMS size was larger than 5 cm. Multivariable analysis exhibited that the age over 10, unfavorable primary site, distantmetastasis was respectively correlated with the poor OS, whereas surgery could improve the outcomes of pediatric RMS. Inconclusion, our large population-based analysis described that age, subtype, primary tumor sites, stage and surgery are allindependent prognosis factors for RMS.Keywords: Rhabdomyosarcoma; Prognosis; Subtype; Survival; Surgery; SEERIntroductionRhabdomyosarcoma (RMS), mainly derived from certain mesenchymal cells that undergo an aberrant differentiationprocess in the embryonal development, is the most common malignant soft-tissue neoplasm of children. Identification theimpact of biological characteristics and treatments on RMS survival is of significance for the patients, especially for thepediatric patients. To better optimize the RMS treatment procedures, it is critical to explore and identify sensitive prognosisfactors, especially comparing the risk factors within tumor-related biological characteristics. In this study, we performed acomprehensive analysis of the RMS cases that were registered in the Surveillance, Epidemiology and End Results (SEER)database to investigate the clinical characteristics and outcomes of pediatric RMS.1. Materials and methods1.1 SEER databaseSEER serves as a public database provided by the National Cancer Institute (NCI), which includes information frompopulation-based cancer registries of 20 geographic areas, and covers approximately 34.6% of the United States population.Data of the pediatric patients with RMS from 1975 to 2016 in this study were extracted from the SEER database.1.2 Identification of RMS casesAll of the pediatric RMS patients were diagnosed by the histological confirmation according to biopsy or surgicalpathology. Total 1,103 in 2,726 cases were excluded because of unknowns in the pediatric age, gender, race, tumor size, vitalstatus, survival months, primary site, subtype or stage.Volume 11 Issue 1·2022 - 11 -1.3 Statistical analysisFor analysis, “age” was converted from a continuous variant to a categorical variant as “< 10” and “≥ 10”. The “race”was classified as white or non-white, and “stage” was used to define the RMS neoplasm development including “localized”,“regional”, and “distant”. “Localized” was identified as an invasive tumor confined entirely to the origin organ; “regional”was identified as an extended neoplasm, which invades 1) beyond the limitations of origin organs and directly to surroundingorgans; 2) to the regional lymph nodes; 3) with extension and to regional lymph nodes; “distant” was identified as metastasis.The “subtype” was categorized into three sections: the “alveolar”, “embryonal” as well as “others” which containspleomorphic, spindle cell, mixed type and ganglionic differentiation.IBM SPSS Statistics (version 25.0) was used for analyzing the statistical significance. A nomogram and calibration plotswere formed according to the results of multivariate analysis via the package rms26 in R program language (version i3863.6.0). Results were considered statistically significant at P < 0.05.2. Results2.1 A prognosis nomogram for OS of pediatric RMS patientsA nomogram was used to analyze the potential prognosis factors in pediatric patients with RMS. Results showed a 0.742index of concordance (C-index) for OS prediction (95% CI, 0.7234 - 0.7606), indicating that this nomogram is useful for theOS forecast of pediatric RMS patients (Fig. 1A). The calibration plot of survival probabilities at 3- and 5-year also presenteda similar result in the RMS prediction via a nomogram and clinical observations (Fig. 1B and 1C).Fig 1. (A) A nomogram for pediatric RMS.An individual child’s value was located on each variable axis, and a solid line was drawn upward to define the numberof points received for each variable value. The sum of above numbers was located on the total point axis, and a solid line wasdrawn to the survival axes to define the likelihood of 3- or 5-year survival. (B-C) Two calibration curves were used forAdvanced Emergency Medicine- 12 -predicting the 3-year OS (B) and 5-year OS (C) of pediatric RMS patients, respectively. X-axis refers to nomogram-predictied survival probability; y-axis refers to actual OS.Abbreviations: Alv, Alveolar; Emb, Embryonal; Uri, urinary system; H/N, head/neck; Lim, limbs; Oth, other sites; L,localized; R, regional; D, distant.2.2 Independent prognosis factors for pediatric RMSAs shown in Table 1, children older than 10 years old exhibited a higher risk of death (HR, 1.4673; 95% CI, 1.2218 -1.7620; P < 0.001) compared with those of control. Then, the mortality was different according to each primary site.Compared with the reproductive system, HR for RMS in other sites rather than urinary system, head/neck and limbs was1.5521 (95% CI, 1.1365 - 2.1199; P < 0.001). In addition, pediatric RMS patients in regional and distant stage presented asignificantly higher mortality rate. HR was notably higher in patients with a regional stage (1.9683; 95% CI 1.5069 - 2.5710;P < 0.001) or a distant metastasis (4.5493; 95% CI, 3.4944 - 5.9225; P < 0.001). Taken together, these data show that age,primary site, and stage were all poor prognosis factors for outcomes of pediatric RMS.We also found that the embryonal subtype and surgery could increase the OS of pediatric RMS. Embryonal RMSpresented a higher survival rate (HR, 0.6196; 95% CI, 0.5019 - 0.7648; P < 0.001) compared with other subtypes. Surgerycould also help to improve the survival rate of pediatric RMS (HR, 0.6638; 95% CI, 0.5467 - 0.8058; P < 0.001).Volume 11 Issue 1·2022 - 13 -Table 1 Multivariable analysis of factors associated with overall survival in the pediatric RMS patientsVariables HR[1] 95% CI[2] PAge (year) < 10 1 Reference≥ 10 1.4673 1.2218-1.7620 0.00004 < 0.01Gender Female 1 ReferenceMale 1.1096 0.9254-1.3304 0.26173Race White 1 ReferenceNon-white 1.2051 0.9892-1.4680 0.06399Subtype Alveolar 1 ReferenceEmbryonal 0.6196 0.5019-0.7648 0.000008 < 0.01Other 0.7716 0.4997-1.1915 0.24213Primary siteReproductivesystem1 ReferenceUrinarysystem0.8084 0.4289-1.5235 0.51065Head/neck 1.1212 0.8053-1.5609 0.49810Limbs 1.4199 0.9966-2.0288 0.05221Other 1.5521 1.1365-2.1199 0.00571 < 0.01Tumorsize (cm) ≤ 5 1 Reference> 5 1.0308 0.8605-1.2351 0.74273Stage Localized 1 ReferenceRegional 1.9683 1.5069-2.5710 0.0000006 < 0.01Distant 4.5493 3.4944-5.9225 0.0000002 < 0.01Surgery No 1 ReferenceYes 0.6638 0.5467-0.8058 0.00003 < 0.01Advanced Emergency Medicine- 14 -2.3 Independent prognosis factors for pediatric-alveolar/embryonal RMSTable 2 displayed that in the pediatric alveolar RMS, the primary site was no longer a prognosis factor for OS. However,the death risk was increased to 1.89 times (HR, 1.8915; 95% CI, 1.0693 - 3.3459; P < 0.05) in the embryonal RMS located inlimbs. This observation highlights that oncologists should thoroughly consider the impact of primary sites on outcomes ofpediatric RMS according to different RMS subtypes.Volume 11 Issue 1·2022 - 15 -Table 2 Multivariable analysis of factors associated with overall survival in the pediatric RMS patients according tothe subtypeVariables Alveolar (N = 485) Embryonal (N = 1,053)Age (year) HR 95% CI P HR 95% CI P< 10 1 Reference 1 Reference≥ 10 1.5803 1.21323-2.0584 0.000691 < 0.01 1.3490 1.0281-1.7701 0.03080 < 0.05GenderFemale 1 Reference 1 ReferenceMale 1.2792 0.98170-1.6669 0.068266 0.9797 0.7489-1.2818 0.88136RaceWhite 1 Reference 1 ReferenceNon-white 1.1932 0.90176-1.5789 0.216322 1.1354 0.8380-1.5382 0.41252Primary siteReproductivesystem1 Reference 1 ReferenceUrinary system 0.4880 0.06105-3.9012 0.498779 0.7898 0.3990-1.5635 0.49821Head/neck 1.0087 0.49130-2.0711 0.981090 1.0472 0.6953-1.5772 0.82546Limbs 1.1848 0.59281-2.3680 0.631220 1.8915 1.0693-3.3459 0.02851 < 0.05Other 1.4826 0.73067-3.0084 0.275357 1.4117 0.9719-2.0506 0.07028StageLocalized 1 Reference 1 ReferenceRegional 1.4768 0.97352-2.2403 0.066694 2.2201 1.5541-3.1715 0.00001 < 0.01Distant 3.4562 2.29728-5.1998 0.000002 < 0.01 5.0804 3.5716-7.2266 0.0000001 < 0.01Tumor size (cm)≤ 5 1 Reference 1 Reference> 5 0.8702 0.66835-1.1330 0.301729 1.2412 0.9532-1.6161 0.10865SurgeryNo 1 Reference 1 ReferenceYes 0.7343 0.55174-0.9772 0.034187 < 0.05 0.6347 0.4822-0.8356 0.00119 < 0.01Advanced Emergency Medicine- 16 -2.4 Independent prognosis factors for metastasis or non-metastasis RMSTable 3 was shown that age, subtype, and surgery were independent factors related to the survival rate of pediatric RMS patients regardless of metastasis. To our surprise, primary site was a negative prognosis factor in non-metastasis RMS, while this phenomenon could not be observed in metastasis RMS. According to the observation in the non-metastasis group, pediatric RMS located in both head/neck and limbs displayed a significantly higher mortality with an estimated HR 1.6325 (95% CI, 1.0195 - 1.2.6141; P < 0.05) in head/neck group and 1.7147 (95% CI, 1.0067 - 2.9206; P < 0.05) in limbs group, respectively.Volume 11 Issue 1·2022 - 17 -Table 3 Multivariable analysis of factors associated with overall survival in the pediatric RMS patients with orwithout metastasisVariables No metastasis (N = 1,175) Metastasis (N = 448)Age (year) HR 95% CI P HR 95% CI P< 10 1 Reference 1 Reference≥ 10 1.4870 1.1482-1.9257 0.002637 < 0.01 1.4492 1.1100-1.8919 0.00638 < 0.01GenderFemale 1 Reference 1 ReferenceMale 1.0661 0.8258-1.3763 0.623187 1.1337 0.8733-1.4719 0.34594RaceWhite 1 Reference 1 ReferenceNon-white 1.0942 0.8236-1.4535 0.534620 1.2412 0.9380-1.6425 0.13054SubtypeAlveolar 1 Reference 1 ReferenceEmbryonal 0.4836 0.3608-0.6481 0.000001 < 0.01 0.7121 0.5279-0.9605 0.02617 < 0.05Other 0.4863 0.2434-0.9716 0.041208 < 0.05 1.1441 0.6462-2.0258 0.64414Primary siteReproductivesystem1 Reference 1 ReferenceUrinarysystem1.0841 0.3722-3.1579 0.882279 0.6602 0.2989-1.4582 0.30446Head/neck 1.6325 1.0195-2.6141 0.041300 < 0.05 0.7771 0.4796-1.2592 0.30575Limbs 1.7147 1.0067-2.9206 0.047215 < 0.05 1.0552 0.6540-1.7025 0.82586Other 2.4004 1.5165-3.7994 0.000186 < 0.05 1.0320 0.6766-1.5742 0.88368Tumorsize(cm)≤ 5 1 Reference 1 Reference> 5 1.0772 0.8273-1.4026 0.580707 0.9607 0.7455-1.2380 0.75669SurgeryNo 1 Reference 1 ReferenceYes 0.5691 0.4322-0.7495 0.00005 < 0.01 0.6818 0.5199-0.8940 0.00560 < 0.01Advanced Emergency Medicine- 18 -3. DiscussionIn our study, the RMS embryonal and alveolar subtypes were both frequent in pediatric patients, and embryonal subtypeaccounted for 64.9% of all the subtypes. And embryonal subtype was a positive prognosis factor for the OS of pediatric RMS(P = 0.000008 < 0.01). We moved on to compare the risk factors in these two subtypes. Notably, compared with the alveolarsubtype, the OS for embryonal RMS located in limbs was in a higher mortality rate (HR, 1.8915; 95% CI, 1.0693 - 3.3459; P< 0.05). In summary, these observations not only highlight that the embryonal subtype is the prognosis factor of RMS, butalso indicates that the outcomes of embryonal RMS is strongly correlated with the tumor location.Genitourinary and head/neck are the frequently original sites of pediatric RMS, even though RMS can be found in anyanatomy area of human body. Bradley et al. showed that the most common primary site of RMS was reproductive system(40%), followed by para-meningeal (14%) and limbs (11%) [1]. However, the outcomes of RMS with different primary sitesare controversial. Kirsch et al. confirmed that the survival rates were of no difference in multiple primary sites in femalepediatric RMS patients in the period of 1973-2006 [3], while a lower 5-year survival rate of RMS was also reported withprimary sites in extremities (25%), and other sites (28.9%) rather than orbit (57.2%), head/neck (51.3%), para-meningeal(41.2%), and genitourinary (79.8%) [2]. In fact, our study confirms this observation and suggests that the mortality was higherin the pediatric RMS located in other primary sites (P = 0.00571 < 0.01) rather than reproductive system, urinary system,head/neck, and limbs.For the RMS stage, the majority is localized and less than 30% of the RMS neoplasms are with metastasis. In fact,distant metastasis is a poor prognosis factor for pediatric RMS. Kirsch et al. mentioned that 38.8% (N = 26) of, 16.2% (N =11) of and 28.4% (N = 15) of RMSs were in the stage of localized, regional and distant, respectively [3]. Notably, tumor stageis a key biological characteristic in the diagnosis and treatment of pediatric RMS. Some prior studies on pediatric RMS hadmentioned that a distant metastasis was correlated with a poor prognosis [4, 5]. Meanwhile, several studies also concluded thatlocalized stage is the most favorable prognosis factor of RMS [6, 9]. Our multivariate analysis results identified the regional(HR, 1.9683; 95%, 1.5069 - 2.5710; P < 0.001) and distant (HR, 4.5493; 95%, 3.4944 - 5.9225; P < 0.001) stage as twoindependent predictors for mortality of pediatric RMS. In summary, these data display evidences that distant metastasis is apoor prognosis factor of pediatric RMS.In conclusion, we studied a large population-based cohort of RMS and suggested that the biological characteristics, suchas age, subtype, primary site, stage and no surgery are correlated with a poor outcome of pediatric RMS patients. Therefore,differences of the prognostic factors among populations with various characteristics should be thoroughly considered, andfurther investigations are needed to identify long-term poor prognosis impact from each RMS characteristics.Disclosure of potential conflict of interestNo potential conflicts of interest were disclosed.AcknowledgementsOur work was supported by the grants from National Natural Science Foundation of China (81800185), and JiangsuGovernment Scholarship for Overseas Studies.Volume 11 Issue 1·2022 - 19 -References[1] Bradley, J.A., et al., Treatment Approach and Outcomes in Infants with Localized Rhabdomyosarcoma: A Report from theSoft Tissue Sarcoma Committee of the Children's Oncology Group. Int J Radiat Oncol Biol Phys, 2019. 103(1): p. 19-27.[2] Company, F., M. Pedram, and N. Rezaei, Clinical characteristics and the prognosis of childhood rhabdomyosarcoma in 60patients treated at a single institute. Acta Med Iran, 2011. 49(4): p. 219-24.[3] Kirsch, C.H., M. Goodman, and N. Esiashvili, Outcome of female pediatric patients diagnosed with genital tractrhabdomyosarcoma based on analysis of cases registered in SEER database between 1973 and 2006. Am J Clin Oncol, 2014.37(1): p. 47-50.[4] El-Kholy, E., et al., Added predictive value of 18F-FDG PET/CT for pediatric rhabdomyosarcoma. Nucl Med Commun,2019.[5] Ren, S., et al., Prognostic factors for postoperative survival among patients with rhabdomyosarcoma of the limbs. CancerManag Res, 2018. 10: p. 4181-4189.

Impact of Rhabdomyosarcoma (RMS) Characteristics on Prognosis of Pediatric RMS: a SEER Database Large Population Study

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Impact of Rhabdomyosarcoma (RMS) Characteristics on Prognosis of Pediatric RMS: a SEER Database Large Population Study

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