Efficacy and tolerability of an induction chemotherapy regimen based on gemcitabine and cisplatin in children and adolescents with nasopharyngeal carcinoma. Preliminary results of the NPC-DGOI-2022 study

Background. Despite the high effectiveness of modern treatment protocols for localized (stage I–IVa) nasopharyngeal carcinoma (NPC) in children, some patients (15–20 %) fail to achieve a cure, which leads to an extremely unfavorable prognosis due to the low effectiveness of subsequent therapy. The prognosis of patients with primary metastatic NPC (stage IVb), whose 5-year overall survival does not exceed 60 %, remains unfavorable. The toxicity of treatment (primarily severe mucositis) is also a problem due to the 5-fluorouracil (5-FU)-containing induction regimens used in children with NPC. At the same time, it has been shown that the use of alternative gemcitabine-based induction therapy regimens and the introduction of new drugs (immune checkpoint inhibitors, capecitabine) into the therapy program leads to an increase in the effectiveness and safety of NPC treatment in adults. In order to improve the results of treatment of NPC in children, we have developed the original study NPC-DGOI-2022, the main difference between which and existing NPC treatment regimens in pediatric practice is the use of gemcitabine-containing induction regimen with or without the addition of pembrolizumab, depending on the risk group.

The aim of the study – to evaluate the efficacy and tolerability of induction therapy according to the NPC-DGOI-2022 protocol (gemcitabine + cisplatin +/– pembrolizumab regimen).

Materials and methods. The pilot analysis included 14 previously untreated patients with morphologically confirmed NPC who were treated according to the NPC-DGOI-2022 protocol in pediatric oncological institutions in Russia and the Republic of Kazakhstan from November 2022 to August 2024 (21 months). The average age of patients at the time of diagnosis was 14.4 years (range – 12–17 years); the ratio of boys and girls was 10:4. Among the 14 patients, 3 had stage II of the disease, 6 had stage III, 3 had IVa, and 2 had IVb. According to the protocol, patients in the standard and high-risk groups (stage II–IVa, n = 12) received induction therapy with gemcitabine and cisplatin, patients from the very high-risk group (IVb with metastatic foci that cannot be fully irradiated, n = 2) additionally received pembrolizumab. The objective response after completion of the induction stage of treatment was assessed according to RECIST 1.1, and the toxicity assessment was carried out according to CTCAE 5.0.

Results. All patients completed the induction therapy stage on schedule and without dose reduction. After completion of the induction stage of treatment, a complete response was found in 3/14 (21 %) patients, a partial response in 11/14 (79 %). The only adverse events of  III degrees of severity observed during induction therapy were leukopenia and neutropenia.

Conclusion. The induction chemotherapy regimen containing gemcitabine and cisplatin with or without the addition of pembrolizumab has been shown to be well tolerated and to have high immediate efficacy, at least comparable to 5-FU-containing induction regimens, in children with NPC. However, a multicenter study is needed to reach the planned number of patients included for the final analysis.

1. Bray F., Ferlay J., Soerjomataram I., Siegel R.L., Torre L.A., Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424. doi: 10.3322/caac.21492.

2. Casanova M., Bisogno G., Gandola L., Cecchetto G., Di Cataldo A., Basso E. A prospective protocol for nasopharyngeal carcinoma in children and adolescents: the Italian Rare Tumors in Pediatric Age (TREP) project. Cancer. 2012;118(10):2718–25. doi: 10.1002/cncr.26528.

3. Buehrlen M., Zwaan C.M., Granzen B., Lassay L., Deutz P., Vorwerk P. Multimodal treatment, including interferon beta, of nasopharyngeal carcinoma in children and young adults: preliminary results from the prospective, multicenter study NPC-2003-GPOH/DCOG. Cancer. 2012;118(19):4892–900. doi: 10.1002/cncr.27395.

4. Rodriguez-Galindo C., Krailo M.D., Krasin M.J., Huang L., McCarville M.B., Hicks J. Treatment of Childhood Nasopharyngeal Carcinoma With Induction Chemotherapy and Concurrent Chemoradiotherapy: Results of the Children's Oncology Group ARAR0331 Study. J Clin Oncol. 2019;37(35):3369–76. doi: 10.1200/JCO.19.01276.

5. Tabolinovskaya T.D., Mudunov A.M., Azizyan R.I., Pustynskiy I.N., Aketova T.A. Longterm results of nasopharyngeal carcinoma treatment (based on the analysis of cases from cancer registry of N.N. Blokhin Russian Cancer Research Center during 1980–2010). Opukholi golovy i shei = Head and Neck Tumors (HNT). 2016;6(4):15–8. (In Russ.). doi: 10.17650/2222-1468-2016-6-4-15-18.

6. Gorbunova T.V., Al-Ariki Galal Abdulrahman Ali, Glekov I.V., Susuleva N.A., Shishkov R.V., Ivanova N.V., Polyakov V.G. Analysis of Treatment of the Outcomes in Pediatric Patients With Nasopharyngeal Cancer: A Retrospective Cohort Study. Onkopediatriya = Onkopediatria. 2018;5(4):257–67. (In Russ.). doi: 10.15690/onco.v5i4.1969.

7. Zhukov N.V., Rabaeva L.L. Nasopharyngeal carcinoma in children and adolescents: a literature review and our own data. Voprosy gematologii/onkologii i immunopatologii v pediatrii = Pediatric Hematology/Oncology and Immunopathology. 2022;21(2):66–77. (In Russ.). doi: 10.24287/1726-1708-2022-21-2-66-77.

8. Altundag K., Aksoy S., Gullu I., Altundag O., Ozyar E., Yalcin S. Salvage ifosfamide-doxorubicin chemotherapy in patients with recurrent nasopharyngeal carcinoma pretreated with Cisplatin-based chemotherapy. Med Oncol. 2004;21(3):211–5. doi: 10.1385/MO:21:3:211.

9. Ma B.B., Tannock I.F., Pond G.R., Edmonds M.R., Siu L.L. Chemotherapy with gemcitabine-containing regimens for locally recurrent or metastatic nasopharyngeal carcinoma. Cancer. 2002;95(12):2516–23. doi: 10.1002/cncr.10995.

10. Ngan R.K., Yiu H.H., Lau W.H., Yau S., Cheung F.Y., Chan T.M. Combination gemcitabine and cisplatin chemotherapy for metastatic or recurrent nasopharyngeal carcinoma: report of a phase II study. Ann Oncol. 2002;13(8):1252–8. doi: 10.1093/annonc/mdf200.

11. Chua D.T., Kwong D.L., Sham J.S., Au G.K., Choy D. A phase II study of ifosfamide, 5-fluorouracil and leucovorin in patients with recurrent nasopharyngeal carcinoma previously treated with platinum chemotherapy. Eur J Cancer. 2000;36(6):736–41. doi: 10.1016/s0959-8049(00)00008-3.

12. McCarthy J.S., Tannock I.F., Degendorfer P., Panzarella T., Furlan M., Siu L.L. A phase II trial of docetaxel and cisplatin in patients with recurrent or metastatic nasopharyngeal carcinoma. Oral Oncol. 2002;38:686–90. doi: 10.1016/S1368-8375(01)00134-8.

13. Chua D.T., Sham J.S., Au G.K. A phase II study of capecitabine in patients with recurrent and metastatic nasopharyngeal carcinoma pretreated with platinum-based chemotherapy. Oral Oncol. 2003;39:361–6. doi: 10.1016/S1368-8375(02)00120-3.

14. Zhang Y., Chen L., Hu G.Q., Zhang N., Zhu X.D., Yang K.Y. Gemcitabine and Cisplatin Induction Chemotherapy in Nasopharyngeal Carcinoma. N Engl J Med. 2019;381(12):1124–35. doi: 10.1056/NEJMoa1905287.

15. Zhang L., Huang Y., Hong S., Yang Y., Yu G., Jia J. Gemcitabine plus cisplatin versus fluorouracil plus cisplatin in recurrent or metastatic nasopharyngeal carcinoma: a multicentre, randomised, open-label, phase 3 trial. Lancet. 2016;388(10054):1883–92. doi: 10.1016/S0140-6736(16)31388-5.

16. Hong S., Zhang Y., Yu G., Peng P., Peng J., Jia J. Gemcitabine Plus Cisplatin Versus Fluorouracil Plus Cisplatin as First-Line Therapy for Recurrent or Metastatic Nasopharyngeal Carcinoma: Final Overall Survival Analysis of GEM20110714 Phase III Study. J Clin Oncol. 2021;39(29):3273–82. doi: 10.1200/JCO.21.00396.

17. Richards M.K., Dahl J.P., Gow K., Goldin A.B., Doski J., Goldfarb M. Factors Associated With Mortality in Pediatric vs Adult Nasopharyngeal Carcinoma. JAMA Otolaryngol Head Neck Surg. 2016;142(3):217–22. doi: 10.1001/jamaoto.2015.3217.

18. Sultan I., Casanova M., Ferrari A., Rihani R., Rodriguez-Galindo C. Differential features of nasopharyngeal carcinoma in children and adults: a SEER study. Pediatr Blood Cancer. 2010;55(2):279–84. doi: 10.1002/pbc.22521.

19. Kontny U., Franzen S., Behrends U., Bührlen M., Christiansen H., Delecluse H. Diagnosis and Treatment of Nasopharyngeal Carcinoma in Children and Adolescents – Recommendations of the GPOH-NPC Study Group. Klin Padiatr. 2016;228(3):105–12. doi: 10.1055/s-0041-111180.

20. Yang Q., Cao S.M., Guo L., Hua Y.J., Huang P.Y., Zhang X.L. Induction chemotherapy followed by concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: long-term results of a phase III multicentre randomised controlled trial. Eur J Cancer. 2019;119:87–96. doi: 10.1016/j.ejca.2019.07.007.

21. Chen Y.P., Ismaila N., Chua M.L.K., Colevas A.D., Haddad R., Huang S.H. Chemotherapy in Combination With Radiotherapy for Definitive-Intent Treatment of Stage II-IVA Nasopharyngeal Carcinoma: CSCO and ASCO Guideline. J Clin Oncol. 2021;39(7):840–59. doi: 10.1200/JCO.20.03237.

22. Sultan I., Casanova M., Ferrari A., Rihani R., Rodriguez-Galindo C. Differential features of nasopharyngeal carcinoma in children and adults: a SEER study. Pediatr Blood Cancer. 2010;55(2):279–84. doi: 10.1002/pbc.22521.

23. Ma J., Wen Z.S., Lin P., Wang X., Xie F.Y. The results and prognosis of different treatment modalities for solitary metastatic lung tumor from nasopharyngeal carcinoma: a retrospective study of 105 cases. Chin J Cancer. 2010;29(9):787–95. doi: 10.5732/cjc.010.10098.

24. Gravara L.D., Battiloro C., Cantile R., Letizia A., Vitiello F., Montesarchio V. Chemotherapy and/or immune checkpoint inhibitors in NSCLC first-line setting: what is the best approach? Lung Cancer Manag. 2020;9(1):LMT22. doi: 10.2217/lmt-2019-0018.

25. Fang W., Yang Y., Ma Y., Hong S., Lin L., He X. Camrelizumab (SHR-1210) alone or in combination with gemcitabine plus cisplatin for nasopharyngeal carcinoma: results from two single-arm, phase 1 trials. Lancet Oncol. 2018;19(10):1338–50. doi: 10.1016/S1470-2045(18)30495-9.

26. Yang Y., Qu S., Li J., Hu C., Xu M., Li W. Camrelizumab versus placebo in combination with gemcitabine and cisplatin as first-line treatment for recurrent or metastatic nasopharyngeal carcinoma (CAPTAIN-1st): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2021;22(8):1162–74. doi: 10.1016/S1470-2045(21)00302-8.

27. Критерии общей терминологии для нежелательных явлений (CTCAE). Версия 5.0, 2017. [Электронный ресурс]: https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcae_v5_quick_reference_5x7.pdf.

28. Padhani A.R., Ollivier L. The RECIST (Response Evaluation Criteria in Solid Tumors) criteria: implications for diagnostic radiologists. Br J Radiol. 2001;74(887):983–6. doi: 10.1259/bjr.74.887.740983.

29. Casanova M., Özyar E., Patte C., Orbach D., Ferrari A., Veyrat-Follet C. International randomized phase 2 study on the addition of docetaxel to the combination of cisplatin and 5-fluorouracil in the induction treatment for nasopharyngeal carcinoma in children and adolescents. Cancer Chemother Pharmacol. 2016;77(2):289–98. doi: 10.1007/s00280-015-2933-2.

30. Jun M., Pinto H., Le Q.T., Quon A., Hara W., Coty J. In search for optimal induction chemotherapy for advanced nasopharyngeal cancer: Standard dosing of Docetaxel, Platinum, and 5-Fluorouracil (TPF) followed by chemoradiation. PLoS One. 2023;18(2):e0276651. doi: 10.1371/journal.pone.0276651.