Chemotherapy burden of risk-adapted treatment verse surveillance for clinical stage I pediatric testicular cancer: A decision tree model analysis

Background Different from adult clinical stage I (CS1) testicular cancer, surveillance was recommended for CS1 pediatric testicular cancer. This study was to compare chemotherapy exposure between risk-adapted treatment and surveillance in CS1 pediatric testicular cancer.Methods We collected clinical utilities from literature and survey. Using decision analysis model, we compared chemotherapy exposure between risk-adapted treatment and surveillance and sensitivity analysis was performed.Results In base case decision analysis of CS1 pediatric testicular cancer, risk-adapted treatment preferred lower exposure of chemotherapy than surveillance (average: 0.7965 cycle verse 1.3419 cycles). The sensitivity analysis demonstrated that when relapse rate after primary chemotherapy ≤ 0.10 and the relapse rate of high-risk group ≥ 0.40, risk-adapted treatment would expose lower chemotherapy, without association of the proportion of low-risk patients, the relapse rate of low-risk group, relapse rate after salvage chemotherapy and toxicity utility of second-line chemotherapy compared to salvage chemotherapy.Conclusion Decision analysis demonstrated that risk-adapted treatment was associated with lower exposure of chemotherapy for patients with CS1 pediatric testicular cancer. This might decrease chemotherapy-related toxicity for these high-risk patients and further clinical study was needed.


Background
n recent studies, about 20% of children with CS1 testicular germ cell tumors (GCT) suffered a relapse in 4 years after RIO and underwent 3-4 cycles of salvage chemotherapy. (1,9)  And in high-risk children, more than 50% of them suffered relapse and progress. (6,10)  This procedure might also be feasible for pediatric patients, and lower the exposure of chemotherapy, though the outcome was excellent with surveillance and salvage chemotherapy.However, no study was to compare 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 tree of surveillance and risk-adapted treatment was listed in Figure 1.
For these two groups, the cost of radical inguinal orchiectomy and regular follow-up was similar.And in China, the cost of operation, drugs, enrollment and etc was nearly consistent under legal regulations in the recent decade.Generally, chemotherapy toxicity was associated with the number of chemotherapy cycles.So we just compare the exposure of chemotherapy between the two groups.Our analysis consisted of the following hypothetical clinical scenarios for two groups: Firstly, patients in both groups with CS1 testicular cancer were diagnosed with histopathology, serum markers and imaging.Then, for the surveillance group, patients suffered relapse during follow-up and received salvage chemotherapy with 3 cycles of PEB (cisplatin, VP-16 and bleomycin) chemotherapy.If 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 low-risk group underwent surveillance.Then salvage chemotherapy with 3 cycles of PEB was performed when relapse was detected.If CR was not achieved after 3 cycles of PEB, secondline chemotherapy with VIP was performed.According to recent studies, the overall survival of CS1 pediatric testicular cancer was nearly 100% with system chemotherapy, and progression rates after primary and salvage chemotherapy both were about 5% (2.3-6.8%)6)(17)(18)(19)(20) And rare operation or radiation after chemotherapy was reported.(17)(18)(19)(20) To evaluate treatment-related toxicity between rst-line and second-line chemotherapy, digital values were obtained in an interview with urological oncologists.Before the interview, the consensus of short and long-term toxicity of chemotherapy for testicular cancer was acquired.By means of a visual analogue scale, compared to surveillance, values of salvage chemotherapy and second-line chemotherapy were assessed as 0.841 (95% con dence interval: 0.811-0.871)and 0.635 (95% con dence interval: 0.578-0.697),respectively.It meant that the toxicity of second-line chemotherapy was about 0.814/0.635=1.3times of those of salvage chemotherapy.And the range was de ned as 1.0-2.0 in decision analysis.

Results
Our analysis demonstrated that risk-adapted treatment preferred lower exposure of chemotherapy than surveillance (average: 0.7965 cycle verse 1.3419 cycles).
1-way sensitivity analysis demonstrated that difference of chemotherapy exposure between two treatments was associated with the proportion of low-risk patients (pLowRisk): when pLowRisk =0, all patients are in high-risk group, and two treatments have signi cantly different exposure of chemotherapy; when pLowRisk =1, all patients are in low-risk group, and two groups have same exposure of chemotherapy (Figure 2A).Similarly, when the relapse rate of high-risk group (pRelapseHighrisk) ≥0.40 and relapse rate after primary chemotherapy (pRelapsePostPrimChemo) ≤0.25, risk-adapted treatment was associated with lower chemotherapy exposure (Figure 2B, C).And the risk-adapted treatment was associated with lower chemotherapy exposure without association with the relapse rate of low-risk group (pRelapseLowrisk), relapse rate after salvage chemotherapy (pRelapsePostSalvChemo) and toxicity utility of second-line chemotherapy compared to salvage chemotherapy (tSecondChemo) (Figure 2D, E,  F).It means only pRelapseHighrisk and pRelapsePostPrimChemo were associated with the utility of chemotherapy exposure, so we focused on these two factors in 2-way sensitivity analysis.

Discussion
eanwhile, for 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 relapse rate in the high-risk group signi cantly. (6)So we used decision analysis to develop a model to evaluate the chemotherapy exposure between two protocols.Risk-adapted management might reduce the exposure of chemotherapy by primary chemotherapy for high-risk patients.
In this study, risk-adapted treatment exposed less chemotherapy than surveillance, which was not consistent with the clinical decision following current guidelines.In the 1-way sensitive analysis, only relapse rate of the high-risk group (pRelapseHighrisk) and relapse rate after primary chemotherapy (pRelapsePostPrimChemo) were associated with chemotherapy exposure.When pRelapseHighrisk ≥0.40 or pRelapsePostPrimChemo ≤0.25, risk-adapted treatment tied to lower chemotherapy exposure, meanwhile these two utilities were reasonable in clinical practice (Figure 2).Within 2-way analysis, when pRelapsePostPrimChemo ≤0.10 and pRelapseHighrisk ≥0.40, risk-adapted treatment would decrease chemotherapy exposure, without association of the other four factors.These results implied that the more precise strati cation of the high-risk group and the higher CR rate of primary chemotherapy, the better individualized management would be accomplished, and less treatment-related toxicity would be exposed.
In recent studies, the rate of relapse was about 20% for CS1 pediatric testicular cancer, and most occurred in the rst 2 years. (9)6)(17)(18)(19)(20) And the 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 about 33% and the overall survival was 98%.Meanwhile, necrosis, the new predictor of tumor relapse, combined with LVI strati ed patients into 2 groups, and the relapse rates were 73% and 17%, respectively. (6)In other studies, the relapse of high-risk group was 0.38-0.55,)(17)(18)(19)(20) Based on these data, we evaluated that the chemotherapy exposure was lower in risk-adapted treatment in our model.For 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)ctually, based on the contemporary scenario, this study revealed that risk-adapted treatment was associated with less chemotherapy exposure signi cantly.And pRelapsePostPrimChemo and pRelapseHighrisk were signi cant factors to decrease exposure of chemotherapy, which implying that the effectiveness of primary chemotherapy and differentiation of high-risk patients were critical to individualized management.For primary chemotherapy, the outcome is favorable and lower-toxicity regimen might be available. (19)While in a recent study, the relapse rate of high-risk group was >70% with a combination of two high-risk factors (LVI and necrosis), and further research about prognostic markers was needed. (6)r study had some limitations worth noting.To simplify the analysis of chemotherapy toxicity, we calculate cycles of chemotherapy instead of detailed side effects, such as cardiovascular disease, neurotoxicity, ototoxicity, chronic kidney disease, infertility, and etc.The proportions were de ned according to recent studies, for it is minor populated, bias was presented, and some of them were from studies about adult counterparts.Despite these shortages, we believe this model could imply some advantages of risk-adapted management in CS1 pediatric testicular cancer.And this is the rst report regarding the chemotherapy burden in CS1 pediatric testicular cancer.

Conclusions
Our model of management for clinical stage 1 pediatric testicular cancer demonstrated that risk-adapted treatment was associated with lower exposure of chemotherapy.This might decrease chemotherapy-Tables

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