For pediatric testicular cancer is nearly curable, surveillance is recommended for clinical stage 1 patients and salvage chemotherapy undergo when relapse disease is detected.(8-9) But in their adult counterpart, risk-adapted management acquired favorable outcome, and decision analysis demonstrated that surveillance was preferred intervention except for those patients with high risk for relapse.(12-13) Meanwhile, 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 significantly.(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.
TreeAge Pro is the leading software for decision analysis, and the decision model was developed based on historical data from previous literature. Though this model is simple, the exposure of chemotherapy could be calculated clearly. And several prediction methods based on artificial intelligence seems effective, but clouds of data or lots of instruments are needed.(22-24) For this rare cancer, which was sporadic, big data was not available. So we choose a simple decision model only focused on chemotherapy exposure.
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 3). 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 stratification 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 first 2 years.(9) In limited series, the relapse rate of high-risk group was about 60%, and that of the low-risk group was 15%.(6, 9, 12, 14-20) 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 stratified 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, and the relapse of low-risk group was 0.16-0.19.(9, 12, 14-20) 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) And 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 less chemotherapy exposure significantly. And pRelapsePostPrimChemo and pRelapseHighrisk were significant 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) As precise management of cancers developed, the differentiation of testicular cancer boys would be more accurate and risk-adapted treatment would reduce chemotherapy exposure robustly.(25)
Our 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 defined according to recent studies, for it is minor populated, bias was presented, and some of them were from studies about adult counterparts. For shortage of life-long follow-up of this curable disease, quality-adjusted life-year and cost-effectiveness analysis were not performed in this study. Despite these shortages, we believe this model could imply some advantages of risk-adapted management in CS1 pediatric testicular cancer. And this is the first report regarding the chemotherapy burden in CS1 pediatric testicular cancer.