==== Front BMC Med Inform Decis Mak BMC Med Inform Decis Mak BMC Medical Informatics and Decision Making 1472-6947 BioMed Central London 1365 10.1186/s12911-020-01365-x Research Article Risk-adapted treatment reduced chemotherapy exposure for clinical stage I pediatric testicular cancer Ye Yun-lin 1 Chen Zhuang-fei 12 Bian Jun 23 Liang Hai-tao 1 http://orcid.org/0000-0001-7346-0305Qin Zi-ke qinzk@sysucc.org.cn 1 1 Department of Urology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060 Guangdong China 2 grid.284723.80000 0000 8877 7471Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515 China 3 grid.410737.60000 0000 8653 1072Department of Urology, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510090 Guangdong China 14 12 2020 14 12 2020 2020 20 33712 4 2020 8 12 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background Different from adult clinical stage I (CS1) testicular cancer, surveillance has been recommended for CS1 pediatric testicular cancer. However, among high-risk children, more than 50% suffer a relapse and progression during surveillance, and adjuvant chemotherapy needs to be administered. Risk-adapted treatment might reduce chemotherapy exposure among these children. Methods A decision model was designed and calculated using TreeAge Pro 2011 software. Clinical utilities such as the relapse rates of different groups during surveillance or after chemotherapy were collected from the literature. A survey of urologists was conducted to evaluate the toxicity of first-line and second-line chemotherapy. Using the decision analysis model, chemotherapy exposure of the risk-adapted treatment and surveillance strategies were compared based on this series of clinical utilities. One-way and two-way tests were applied to check the feasibility. Results In the base case decision analysis of CS1 pediatric testicular cancer, risk-adapted treatment resulted in a lower exposure to chemotherapy than surveillance (average: 0.7965 cycles verse 1.3419 cycles). The sensitivity analysis demonstrated that when the relapse rate after primary chemotherapy was ≤ 0.10 and the relapse rate of the high-risk group was ≥ 0.40, risk-adapted treatment would result in a lower exposure to chemotherapy, without any association with the proportion of low-risk patients, the relapse rate of the low-risk group, the relapse rate after salvage chemotherapy or the toxicity utility of second-line chemotherapy compared to first-line chemotherapy. Conclusions Based on the decision analysis, risk-adapted treatment might decrease chemotherapy exposure for these high-risk patients, and an evaluation after orchiectomy was critical to this process. Additional clinical studies are needed to validate this statement. issue-copyright-statement© The Author(s) 2020 ==== Body Background Despite the low incidence of pediatric testicular tumors, yolk sac tumors are the most common malignant type in children, which are very different from their adult counterparts [1–6]. Approximately 70% to 80% of pediatric patients have clinical stage I (CS1) disease, and due to its hematogenous predilection for metastasis in children, primary retroperitoneal lymph node dissection (RPLND) is not recommended for CS1 yolk sac tumors [1, 6, 7]. In a recent summary of the PDQ Pediatric Treatment Editorial Board and based on the recommendations of the POG/CCG, surveillance is recommended for children with CS1 testicular cancer after radical inguinal orchiectomy (RIO) [8, 9]. In recent studies, approximately 20% of children with CS1 testicular germ cell tumors (GCT) have suffered a relapse within 4 years after RIO, and they underwent 3–4 cycles of salvage chemotherapy [1, 9]. Advanced analysis demonstrated that an age > 10 years, mixed histology and lymphovascular invasion (LVI) were associated with disease relapse [10, 11]. In high-risk children, more than 50% of them suffered a relapse and progression [6, 10]. Among their adult counterparts, risk-adapted management has achieved a favorable outcome for CS1 testicular nonseminomatous germ cell tumors (NSGCT) [12, 13]. This procedure might also be feasible for pediatric patients and reduce their exposure to chemotherapy, and their outcomes are excellent with surveillance and salvage chemotherapy. However, no study has directly compared the cost and toxicity between surveillance and risk-adapted management. In this study, using a decision analysis model, we evaluated the chemotherapy burden of CS1 pediatric testicular cancer between risk-adapted treatment and surveillance. Methods The decision model was designed and calculated using TreeAge Pro 2011 Software (http://www.treeage.com), and the decision trees of the surveillance and risk-adapted treatment and flowchart of the analysis are listed in Figs. 1 and 2.Fig. 1 Flowchart of this decision analysis Fig. 2 Decision analysis tree of risk-adapted treatment and surveillance For these two groups, the cost of radical inguinal orchiectomy and regular follow-up was similar. In China, the cost of the operation, drugs, enrollment and so forth were generally consistent with the legal regulations in the last decade. Generally, chemotherapy toxicity was associated with the number of chemotherapy cycles. Therefore, we just compared the exposure to chemotherapy between the two groups. Our analysis consisted of the following hypothetical clinical scenarios for the two groups: First, patients in both groups with CS1 testicular cancer were diagnosed with histopathology, serum markers and imaging. Then, for the surveillance group, patients who suffered a relapse during follow-up received salvage chemotherapy consisting of 3 cycles of PEB (cisplatin, VP-16 and bleomycin) chemotherapy. If a complete response (CR) was not achieved after 3 cycles of PEB, second-line chemotherapy with 3 cycles of VIP (VP-16, ifosfamide and cisplatin) was performed. For the risk-adapted group, the high-risk group received primary chemotherapy with 1 cycle of PEB, and the low-risk group underwent surveillance. Then, salvage chemotherapy with 3 cycles of PEB was performed when a relapse was detected. If a CR was not achieved after 3 cycles of PEB, second-line chemotherapy with VIP was performed. According to recent studies, the overall survival of CS1 pediatric testicular cancer was nearly 100% with systemic chemotherapy, and the progression rates after primary and salvage chemotherapy were both approximately 5% (2.3–6.8%) (Table 1) [6, 9, 12, 14–20]. The rare cases of an operation or radiation after chemotherapy were reported as recommended by the guidelines.Table 1 Proportions used in decision model Point estimate Range References Relapse of low risk group 0.15 0.10–0.20 [6, 9, 12, 14, 15] Relapse of high risk group 0.60 0.38–0.73 [6, 9, 12, 14] Progression after primary chemotherapy 0.05 0.01–0.10 [12, 15–18] Progression after salvage chemotherapy 0.05 0.01–0.22 [6, 9, 14, 16, 18–20] Progression after second-line chemotherapy 0 Toxicity of Primary chemotherapy 1 Toxicity of Salvage chemotherapy 3 × 1 Toxicity of Second-line chemotherapy 3 × 1.3 3 × 1.0–3 × 2.0 Interview Based on these studies, we defined the relapse rates of high- and low-risk patients who underwent surveillance as 0.60 (0.38–0.73) and 0.15 (0.10–0.20), respectively; the proportion of low-risk patients was 0–1, the progression rates after primary and salvage chemotherapy were both 0.05 (0.01–0.10), and second-line chemotherapy was the last treatment with a 100% success rate (as shown in Fig. 2 and Table 1) [6, 9, 12, 14–20]. To evaluate treatment-related toxicity between first-line and second-line chemotherapy, digital values were obtained in an interview with urological oncologists. Before the interview, the consensus about short- and long-term toxicity of chemotherapy for testicular cancer was acquired. By means of a visual analog scale, compared to surveillance, values of salvage chemotherapy and second-line chemotherapy were assessed as 0.841 (95% confidence interval: 0.811–0.871) and 0.635 (95% confidence interval: 0.578–0.697), respectively. Therefore, we defined the toxicity of second-line chemotherapy as approximately 0.814/0.635 = 1.3 times that of salvage chemotherapy. The range was defined as 1.0–2.0 in the decision analysis. Results In all, 24 urologists and oncologists took part in the interview to evaluate the toxicity of chemotherapy for pediatric testicular cancer. As shown in Table 2, compared to orchiectomy without chemotherapy (value = 1.0), the value of first-line chemotherapy was from 0.682–1.000, and the value of second-line chemotherapy was from 0.435–0.960. The average number and standard deviation were 0.841 and 0.081, and 0.635 and 0.151, respectively. We defined the toxicity of second-line chemotherapy as approximately 0.814/0.635 = 1.3 times that of salvage chemotherapy, ranging from 1.0 to 2.0 in the decision analysis.Table 2 Results of survey for chemotherapy toxicity No No chemotherapy First-line chemotherapy Second-line chemotherapy Relative value Relative value 1 95 85 0.895 75 0.789 2 95 75 0.789 50 0.526 3 80 70 0.875 65 0.813 4 95 70 0.737 50 0.526 5 95 70 0.737 50 0.526 6 90 70 0.778 50 0.556 7 95 80 0.842 50 0.526 8 100 80 0.8 60 0.6 9 90 85 0.944 60 0.667 10 95 80 0.842 65 0.684 11 90 80 0.889 60 0.667 12 90 70 0.778 50 0.556 13 90 80 0.889 70 0.778 14 85 58 0.682 37 0.435 15 100 90 0.9 87 0.87 16 100 100 1 96 0.96 17 100 99 0.99 93 0.93 18 95 70 0.737 45 0.474 19 100 80 0.8 50 0.5 20 85 70 0.824 50 0.588 21 95 75 0.789 50 0.526 22 90 80 0.889 40 0.444 23 95 85 0.895 60 0.632 24 90 80 0.889 60 0.667 Average 0.841 0.635 SD 0.081 0.151 Our analysis demonstrated that risk-adapted treatment resulted in a lower exposure to chemotherapy than surveillance (average: 0.7965 cycles verse 1.3419 cycles). A 1-way sensitivity analysis demonstrated that the differences in chemotherapy exposure between the two treatments were associated with the proportion of low-risk patients (pLowRisk): when pLowRisk = 0, all of the patients were in the high-risk group, and the two treatments had significantly different exposures to chemotherapy; when pLowRisk = 1, all patients were in the low-risk group, and the two groups had the same exposure to chemotherapy (Fig. 3a). Similarly, when the relapse rate of the high-risk group (pRelapseHighrisk) was ≥ 0.40 and relapse rate after primary chemotherapy (pRelapsePostPrimChemo) was ≤ 0.25, risk-adapted treatment was associated with lower chemotherapy exposure (Fig. 3b, c). Risk-adapted treatment was associated with lower chemotherapy exposure without association with the relapse rate of the low-risk group (pRelapseLowrisk), the relapse rate after salvage chemotherapy (pRelapsePostSalvChemo) and the toxicity utility of second-line chemotherapy compared to salvage chemotherapy (tSecondChemo) (Fig. 3d–f). This means only pRelapseHighrisk and pRelapsePostPrimChemo were associated with the utility of chemotherapy exposure, so we focused on these two factors in the 2-way sensitivity analysis.Fig. 3 1-way sensitivity analysis. a In any value of pLowRisk (proportion of low-risk patients), surveillance was associated with higher exposure of chemotherapy; b When pRelapseHighrisk (relapse rate of high-risk group) > 0.365, surveillance was associated with higher exposure of chemotherapy; c When pRelapsePostPrimChemo (relapse rate after primary chemotherapy) < 0.287, surveillance was associated with higher exposure of chemotherapy; d in any value of pRelapseLowrisk (relapse rate of low-risk group), surveillance was associated with higher exposure of chemotherapy; e in any value of pRelapsePostSalvChemo (relapse rate after salvage chemotherapy), surveillance was associated with higher exposure of chemotherapy; f in any value of tSecondChemo (toxicity utility of second-line chemotherapy compared to salvage chemotherapy), surveillance was associated with higher exposure of chemotherapy. Red: risk-adapted treatment, blue: surveillance In the 2-way sensitivity analysis, we found that when the pRelapseHighrisk was ≥ 0.40, risk-adapted treatment was associated with lower chemotherapy exposure without an association with pLowRisk, pRelapseLowrisk, pRelapsePostSalvChemo or tSecondChemo (Fig. 4a, Additional file 1: Fig. 1A, B, C). When pRelapsePostPrimChemo was ≤ 0.25, and pLowRisk was ≤ 0.90, risk-adapted treatment was associated with less chemotherapy exposure (Fig. 4b). When pRelapsePostPrimChemo was ≤ 0.25, risk-adapted treatment would result in a lower exposure to chemotherapy without an association with pRelapseLowrisk, pRelapsePostSalvChemo or tSecondChemo (Fig. 4c–e). In the 2-way sensitivity analysis of pRelapseHighrisk and pRelapsePostPrimChemo, when pRelapsePostPrimChemo was ≤ 0.10 and pRelapseHighrisk was ≥ 0.40, risk-adapted treatment would result in a lower exposure to chemotherapy (Fig. 4f).Fig. 4 2-way sensitivity analysis. a In any value of pLowRisk (proportion of low-risk patients), when pRelapseHighrisk (relapse rate of high-risk group) > 0.365, risk-adapted treatment was associated with lower exposure of chemotherapy; b in any value of pLowRisk (proportion of low-risk patients), when pRelapsePostPrimChemo (relapse rate after primary chemotherapy) < 0.287, risk-adapted treatment was associated with lower exposure of chemotherapy; c in any value of pRelapseLowrisk (relapse rate of low-risk group), when pRelapsePostPrimChemo (relapse rate after primary chemotherapy) < 0.287, risk-adapted treatment was associated with lower exposure of chemotherapy; d in any value of pRelapsePostSalvChemo (relapse rate after salvage chemotherapy), when pRelapsePostPrimChemo (relapse rate after primary chemotherapy) < 0.287, risk-adapted treatment was associated with lower exposure of chemotherapy; e in any value of tSecondChemo (toxicity utility of second-line chemotherapy compared to salvage chemotherapy), when pRelapsePostPrimChemo (relapse rate after primary chemotherapy) < 0.287, risk-adapted treatment was associated with lower exposure of chemotherapy; f when pRelapsePostPrimChemo (relapse rate after primary chemotherapy) < 0.1, and pRelapseHighrisk (relapse rate of high-risk group) > 0.4, risk-adapted treatment was associated with lower exposure of chemotherapy. Red: risk-adapted treatment, blue: surveillance Discussion Since pediatric testicular cancer is generally universally curable, surveillance is recommended for clinical stage 1 patients, and salvage chemotherapy is given when relapsed disease is detected [8, 9]. In their adult counterparts, risk-adapted management has favorable outcomes, and decision analysis has demonstrated that surveillance is the preferred intervention, except for those patients with a high risk of relapse [12, 13]. Meanwhile, due to the extremely long survival time of these pediatric patients, treatment-related toxicity also should be taken into consideration [21]. In some studies, primary chemotherapy was associated with an extremely low relapse rate, and it decreased the relapse rate in the high-risk group significantly [6]. Therefore, we used decision analysis to develop a model to evaluate the chemotherapy exposure between the two protocols. Risk-adapted management might reduce the exposure to chemotherapy by primary chemotherapy among high-risk patients. TreeAge Pro is the leading software for decision analysis, and the decision model was developed based on historical data from the previous literature. Although this model is simple, the exposure to chemotherapy could be clearly calculated. Several prediction methods based on artificial intelligence have been developed, but clouds of data or lots of instruments are needed [22–24]. For this rare cancer, which is sporadic, big data are not available. Therefore, we chose a simple decision model focused on chemotherapy exposure. In this study, risk-adapted treatment resulted in less exposure to chemotherapy than surveillance, which is not consistent with the clinical decisions made by following the current guidelines. In the 1-way sensitivity analysis, only the relapse rate of the high-risk group (pRelapseHighrisk) and the relapse rate after primary chemotherapy (pRelapsePostPrimChemo) were associated with chemotherapy exposure. When pRelapseHighrisk was ≥ 0.40 or pRelapsePostPrimChemo was ≤ 0.25, risk-adapted treatment resulted in lower chemotherapy exposure, and these two utilities are reasonable in clinical practice (Fig. 3). Within a 2-way analysis, when pRelapsePostPrimChemo was ≤ 0.10 and pRelapseHighrisk was ≥ 0.40, risk-adapted treatment would decrease chemotherapy exposure, without any association with the other four factors. These results implied that with the more precise stratification of the high-risk group and the higher CR rate of primary chemotherapy, better individualized management would be accomplished, and less treatment-related toxicity would occur. In recent studies, the rate of relapse was approximately 20% for CS1 pediatric testicular cancer, and most cases occurred in the first 2 years [9]. In some limited series, the relapse rate of the high-risk group was approximately 60%, and that of the low-risk group was 15% [6, 9, 12, 14–20]. The relapse rate of patients with primary chemotherapy was less than 5% and the overall survival rate was nearly 100%. In our prior study, the relapse rate was approximately 33% and the overall survival was 98%. Meanwhile, necrosis, a new predictor of tumor relapse, when combined with LVI stratified the patients into 2 groups, and the relapse rates were 73% and 17%, respectively [6]. In other studies, the relapse rate of the high-risk group was 0.38–0.55, and the relapse rate of the low-risk group was 0.16–0.19 [9, 12, 14–20]. Based on these data, we found that the chemotherapy exposure was lower in the risk-adapted treatment in our model. Due to the favorable outcome of salvage chemotherapy for clinical stage 1 patients, primary chemotherapy was not common in these studies. However, some studies also demonstrated that primary chemotherapy was associated with an extremely low relapse rate [6]. In adult patients with CS1 testicular NSGCT, primary chemotherapy achieved an excellent oncological outcome and this procedure might also be effective in pediatric patients [12, 13]. Actually, based on the contemporary scenario, this study revealed that risk-adapted treatment was associated with significantly less chemotherapy exposure. pRelapsePostPrimChemo and pRelapseHighrisk were significant factors that decreased exposure to chemotherapy, which implied that the effectiveness of primary chemotherapy and the identification of high-risk patients were critical to individualized management. For primary chemotherapy, the outcome is favorable and a lower-toxicity regimen might be available [19]. In a recent study, the relapse rate of the high-risk group was > 70% with a combination of two high-risk factors (LVI and necrosis), and further research into prognostic markers is necessary [6]. As precise management of cancers has developed, the differentiation of boys with testicular cancer into risk groups would allow for more precisely tailored treatment, and risk-adapted treatment would reduce chemotherapy exposure substantially [25]. Our study had some limitations worth noting. To simplify the analysis of chemotherapy toxicity, we calculated cycles of chemotherapy instead of the detailed side effects, such as cardiovascular disease, neurotoxicity, ototoxicity, chronic kidney disease, and infertility. The proportions were defined according to recent studies, but since these cases are rare, bias was present, and some of them were included in studies about their adult counterparts. Due to the shortage of life-long follow-up of this curable disease, quality-adjusted life-years and cost-effectiveness analyses were not performed in this study. Despite these limitations, we believe this model could imply some advantages of risk-adapted management in CS1 pediatric testicular cancer. This is the first report regarding the chemotherapy burden of CS1 pediatric testicular cancer. Conclusions Our decision model of management for clinical stage 1 pediatric testicular cancer demonstrated that risk-adapted treatment was associated with a lower exposure to chemotherapy. Additional clinical studies are needed to validate this statement. Supplementary Information Additional file 1: Figure 1. Way sensitivity analysis. A: In any value of pRelapseLowrisk (relapse rate of low-risk group), when pRelapseHighrisk (relapse rate of high-risk group) > 0.4, risk-adapted treatment was associated with lower exposure of chemotherapy; B: In any value of pRelapsePostSalvChemo (relapse rate after salvage chemotherapy), when pRelapseHighrisk (relapse rate of high-risk group) > 0.4, risk-adapted treatment was associated with lower exposure of chemotherapy; C: In any value of tSecondChemo (toxicity utility of second-line chemotherapy compared to salvage chemotherapy), when pRelapseHighrisk (relapse rate of high-risk group) > 0.4, risk-adapted treatment was associated with lower exposure of chemotherapy. Red: risk-adapted treatment, Blue: surveillance. Abbreviations CS1Clinical stage 1 RPLNDRetroperitoneal lymph node dissection POG/CCGPediatric Oncology Group and Children's Cancer Group RIORadical inguinal orchiectomy GCTGerm cell tumors LVILymphovascular invasion NSGCTNonseminomatous germ cell tumors PEBCisplatin, VP-16 and bleomycin CRComplete response VIPVP-16, ifosfamide and cisplatin pLowRiskProportion of low-risk patients pRelapseHighriskRelapse rate of high-risk group pRelapsePostPrimChemoRelapse rate after primary chemotherapy pRelapseLowriskRelapse rate of low-risk group pRelapsePostSalvChemoRelapse rate after salvage chemotherapy tSecondChemoToxicity utility of second-line chemotherapy compared to salvage chemotherapy Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Yun-lin Ye, Zhuang-fei Chen and Jun Bian have contributed equally to this work Supplementary Information The online version contains supplementary material available at 10.1186/s12911-020-01365-x. Not applicable. Authors’ contributions YLY, ZFC, JB and HTL were responsible for data collection and analysis, interpretation of the results, and writing the manuscript. JB and ZKQ were responsible for conducting the study design, data analysis and interpretation. All authors read and approved the final manuscript. Funding No funding was obtained for this study. Availability of data and materials Most data was derived from literature as referred in manuscript, and the survey data was shown in Table 2. Ethics approval and consent to participate Due to most data was derived from referred literature, ethics approval and consent to participate was not applicable. For survey data, it was approved by Ethics committee of Sun Yat-sen University Cancer Center: 2016-FXY-081. Consent to publish Not applicable. Competing interest The authors declare that they have no competing interest. ==== Refs References 1. Schlatter M Rescorla F Giller R Excellent outcome in patients with stage I germ cell tumors of the testes: a study of the Children's Cancer Group/Pediatric Oncology Group J Pediatr Surg 2003 38 319 324 10.1053/jpsu.2003.50101 12632342 2. Pohl HG Shukla AR Metcalf PD Prepubertal testis tumors: actual prevalence rate of histological types J Urol 2004 172 2370 2372 10.1097/01.ju.0000144402.13556.74 15538270 3. Lee SD Epidemiological and clinical behavior of prepubertal testicular tumors in Korea J Urol 2004 172 674 678 10.1097/01.ju.0000129571.13955.6b 15247758 4. Ye YL Sun XZ Zheng FF Clinical analysis of management of pediatric testicular germ cell tumors Urology 2012 79 892 897 10.1016/j.urology.2011.07.1422 22305424 5. Cornejo KM Frazier L Lee RS Kozakewich HP Young RH Yolk Sac tumor of the testis in infants and children: a clinicopathologic analysis of 33 cases Am J Surg Pathol 2015 39 1121 1131 10.1097/PAS.0000000000000432 25828390 6. Ye YL Zheng FF Chen D Relapse in children with clinical stage I testicular yolk sac tumors after initial orchiectomy Pediatr Surg Int 2019 35 3 383 389 10.1007/s00383-018-04426-5 30539226 7. Grady RW Ross JH Kay R Patterns of metastatic spread in prepubertal yolk sac tumor of the testis J Urol 1995 153 1259 1261 10.1016/S0022-5347(01)67581-5 7869524 8. PDQ Pediatric Treatment Editorial Board. Childhood extracranial germ cell tumors treatment (PDQ®): Health Professional Version. In: PDQ cancer information summaries. Bethesda (MD): National Cancer Institute (US); 2002. 2020 May 28. 9. Rescorla FJ Ross JH Billmire DF Surveillance after initial surgery for Stage I pediatric and adolescent boys with malignant testicular germ cell tumors: report from the Children's Oncology Group J Pediatr Surg 2015 50 1000 1003 10.1016/j.jpedsurg.2015.03.026 25812445 10. Frazier AL Hale JP Rodriguez-Galindo C Revised risk classification for pediatric extracranial germ cell tumors based on 25 years of clinical trial data from the United Kingdom and United States J Clin Oncol 2015 10 33 195 201 10.1200/JCO.2014.58.3369 11. Cost NG Lubahn JD Adibi M Risk stratification of pubertal children and postpubertal adolescents with clinical stage I testicular nonseminomatous germ cell tumors J Urol 2014 191 1485 1490 10.1016/j.juro.2013.08.047 24679874 12. Tandstad T Dahl O Cohn-Cedermark G Risk-adapted treatment in clinical stage I nonseminomatous germ cell testicular cancer: the SWENOTECA management program J Clin Oncol 2009 01 27 2122 2128 10.1200/JCO.2008.18.8953 13. Tandstad T Stahl O Hakansson U One course of adjuvant BEP in clinical stage I nonseminoma mature and expanded results from the SWENOTECA group Ann Oncol 2014 25 2167 2172 10.1093/annonc/mdu375 25114021 14. Kollmannsberger C Moore C Chi KN Non-risk-adapted surveillance for patients with stage I nonseminomatous testicular germ-cell tumors: diminishing treatment-related morbidity while maintaining efficacy Ann Oncol 2010 21 6 1296 1301 10.1093/annonc/mdp473 19875756 15. Fan G Zhang L Yi L Comparative effectiveness of risk-adapted surveillance vs retroperitoneal lymph node dissection in clinical stage i nonseminomatous germ cell testicular cancer: a retrospective follow-up study of 81 patients Asian Pac J Cancer Prev 2015 16 8 3267 3272 10.7314/APJCP.2015.16.8.3267 25921130 16. Oliver RT Ong J Shamash J Long-term follow-up of Anglian Germ Cell Cancer Group surveillance versus patients with Stage 1 nonseminoma treated with adjuvant chemotherapy Urology 2004 63 3 556 561 10.1016/j.urology.2003.10.023 15028457 17. Albers P Siener R Krege S Randomized phase III trial comparing retroperitoneal lymph node dissection with one course of bleomycin and etoposide plus cisplatin chemotherapy in the adjuvant treatment of clinical stage I Nonseminomatous testicular germ cell tumors: AUO trial AH 01/94 by the German Testicular Cancer Study Group J Clin Oncol 2008 26 18 2966 2972 10.1200/JCO.2007.12.0899 18458040 18. Heidenreich A Pfister D Management of patients with clinical stage I nonseminomatous testicular germ cell tumours: active surveillance versus primary chemotherapy versus nerve sparing retroperitoneal lymphadenectomy Arch Esp Urol 2012 65 2 215 226 22414450 19. Lopes LF Macedo CR Aguiar Sdos S Lowered cisplatin dose and no bleomycin in the treatment of pediatric germ cell tumors: results of the GCT-99 protocol from the Brazilian germ cell pediatric oncology cooperative group J Clin Oncol 2016 34 6 603 610 10.1200/JCO.2014.59.1420 26729441 20. Jones RH Vasey PA Part II: testicular cancer—management of advanced disease Lancet Oncol 2003 4 12 738 747 10.1016/S1470-2045(03)01279-8 14662430 21. Grantham EC Caldwell BT Cost NG Current urologic care for testicular germ cell tumors in pediatric and adolescent patients Urol Oncol 2016 34 2 65 75 10.1016/j.urolonc.2015.06.008 26187598 22. Mahdi MA Al-Janabi S Evaluation prediction techniques to achievement an optimal biomedical analysis Int J Grid Util Comput 2019 10 5 512 527 10.1504/IJGUC.2019.102021 23. Al-Janabi S Mohammad M Al-Sultan A A new method for prediction of air pollution based on intelligent computation Soft Comput 2020 24 661 680 10.1007/s00500-019-04495-1 24. Al-Janabi S Alkaim AF A nifty collaborative analysis to predicting a novel tool (DRFLLS) for missing values estimation Soft Comput 2020 24 555 569 10.1007/s00500-019-03972-x 25. Vasistha A Kothari R Mishra A Current insights into interethnic variability in testicular cancers: population pharmacogenetics, clinical trials, genetic basis of chemotherapy-induced toxicities and molecular signal transduction Curr Top Med Chem 2020 10.2174/1568026620666200618112205 32552648