Nomogram for the determination of primary-resistant forms of germ cell tumors in children

Introduction. Stratification of patients with germ cell tumors is primary carried out depends on stage and previous operation, at the same time is not considered the tumor markers decline.
The aim of the study was the nomogram creation for diagnostics of the prolonged alfa-fetoprotein (AFP) half-life (HL) in patients with germ cell tumors in order to identify of a patients cohort with chemoresistant malignancy and to find treatment modification with transition to the escalated and intensified modality therapy.
Materials and methods. Seventy-two patients less than 18 years old with extracranial germ cell tumors were treated in N.N. Petron National Medical Research Centre of Oncology between 1996 and 2017, among them with increased AFP were 46 (63.9 %) children. AFP half-life periods were calculated.
Results. AFP half-life varied from 3 to 138 days (the average value was 15.6 days). A cut-off point at 6 days was found. An unfavourable decline in AFP was predictive overall survival (OS). OS rates were 85.2 ± 7.9 % and 50.1 ± 12 % in patients with HL £ 6 days, and with > 6 days, respectively (p = 0.01873). Nomogram for diagnostics of the prolonged AFP HL in patients with childhood extracranial germ cell tumors was built. Sensitivity, specificity and diagnostic accuracy of nomogram were 92.9 %, 63.6 % and 72.3 %, respectively. False negative result was in one case (2.1 %).
Conclusions. Secondary stratification of patients has to be carried out after induction treatment with use of the principles of “response-based” of therapy. The nomogram allowing revealing the cohort of patients with prolongation of the period of AFP HL demanding early escalation and an intensification of medical programs helps with such cases for diagnostics of reduction in the rate of disintegration of AFP.

1. Olson T.A., Murray M.J., Rodriguez-Calindo C., Nicholson J.C., Billmire D.F., Krailo M.D., Dang H.M., Amatruda J.F., Thornton C.M., Arul G.S., Stoneham S.J., Pashankar F., Stark D., Shaikh F., Gershenson D.M., Covens A., Hurteau J., Stenning S.P., Feldman D.R., Grimison P.S., Huddart R.A., Sweeney C., Powles T., Lopes L.F., dos Santos Agular S., Chinnaswamy G., Khaleel S., Abouelnaga S., Hale J.P., Frazier A.L. Pediatric and adolescent extracranial germ cell tumors: the road to collaboration. J Clin Oncol 2015;33:3018–28. doi: 10.1200/JCO.2014.60.5337.

2. Mardiak J., Sálek T., Sycová-Milá Z., Obertová J., Recková M., Mego M., Hlavatá Z., Brozmanová K., Risnyovzská Z., Svetlovská D., Koza I. Paclitaxel, bleomycin, etoposide, and cisplatin (T-BEP) as initial treatment in patients with poor-prognosis germ cell tumors (GCT): a phase II study. Neoplasma 2007;54(3):240–5. PMID: 17447857.

3. Cushing B., Giller R., Cullen J.W., Marina N.M., Lauer S.J., Olson T.A., Rogers P.C., Colombani P., Rescorla F., Billmire D.F., Vinocur C.D., Hawkins E.P., Davis M.M., Perlman E.J., London W.B., Castleberry R.P. Randomized comparison of combination chemotherapy with etoposide, bleomycin, and either high-dose or standard-dose cisplatin in children and adolescents with high-risk malignant germ cell tumors: A pediatric intergroup study – Pediatric Oncology Group 9049 and Children’s Cancer Group 8882. J Clin Oncol 2004;22(13):2691–700. doi: 10.1200/JCO.2004.08.015.

4. Mann J.R., Pearson D., Barrett A., Raafat F., Barnes J.M., Wallendszus K.R. Results of the United Kingdom Children’s Cancer Study Group’s malignant germ cell tumor studies. Cancer 1989;63(9):1657–67. doi: 10.1002/1097-0142(19900501)63:9<1657::aidcncr2820630902>3.0.co;2-8.

5. Lopes L.F., Macedo C.R., Pontes E.M., Dos Santos Aguiar S., Mastellaro M.J., Melaragno R., Vianna S.M., Lopes P.A., Mendonça N., de Assis Almeida M.T., Sonaglio V., Ribeiro K.B., Santana V.M., Schneider D.T., de Camargo B. Cisplatin and etoposide in childhood germ cell tumor: Brazilian pediatric oncology society protocol GCT-91. J Clin Oncol 2009;27(8):1297–303. doi: 10.1200/JCO.2008.16.4202.

6. Feldman D.R., Huddart R., Hall E., Beyer J., Powles T. Is high dose therapy superior to conventional dose therapy as initial treatment for relapsed germ cell tumors? The TIGER Trial. J Cancer 2011;2:374–7. PMID: 21750688. PMCID: PMC3133961.

7. De Wit R., Collette L., Sylvester R., de Mulder P.H., Sleijfer D.T., ten Bokkel Huinink W.W., Kaye S.B., van Oosterom A.T., Boven E., Stoter G. Serum alpha-fetoprotein surge after the initiation of chemotherapy for non-seminomatous testicular cancer has an adverse prognostic significance. Br J Cancer 1998;78(10):1350–5. doi: 10.1038/bjc.1998.683.

8. Fizazi K., Culine S., Kramar A., Amato R.J., Bouzy J., Chen I., Droz J.P., Logothetis C.J. Early predicted time to normalization of tumor markers predicts outcome in poor-prognosis nonseminomatous germ cell tumors. J Clin Oncol 2004;22(19):3868–76. doi: 10.1200/JCO.2004.04.008.

9. Mazumdar M., Bajorin D.F., Bacik J., Higgins G., Motzer R.J., Bosl G.J. Predicting outcome to chemotherapy in patients with germ cell tumors: The value of the rate of decline of human chorionic gonadotrophin and alpha-fetoprotein during therapy. J Clin Oncol 2001;19(9):2534–41. doi: 10.1200/JCO.2001.19.9.2534.