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 (Figure 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.