Influence of the radiotherapy target volume and prognostic factors on the results of treatment of patients with cervical lymph nodes metastases of squamous cell carcinoma of unknown primary

Introduction: The issues of the radiotherapy target volumes in cases of cervical lymph nodes metastases of squamous cell carcinoma of unknown primary (SCCUP) remain unresolved due to the lack of clinical studies. Escalation or de-escalation of treatment may be directly related to prognostic factors. Purpose of this study was to evaluate the results of treatment using ipsilateral (only involved side of the neck) or total (bilaterally neck and pharyngeal mucosa) radiation therapy (RT) and to analyze the influence of clinical factors on overall survival (OS) and progression-free survival (PFS).

Methods: A retrospective non-randomized clinical trial was conducted. Two-year OS and PFS were assessed in 26 SCCUP patients, who underwent combined treatment, including radiation therapy. Inoperable patients received either definitive RT (3.85 %) or sequential chemoradiation therapy (CRT, 11.5 %), or concurrent CRT (3.85 %). Operable patients underwent neoadjuvant RT with lymph node dissection (34.6 %) or lymph node dissection with adjuvant RT (11.5 %) or adjuvant sequential CRT (7.7 %) or adjuvant concurrent CRT (27 %); 50 % of patients received RT in a dose of more than 60 Gy, in 50 % it was less than 60 Gy. In 54 % of patients, only the ipsilateral cervical lymph nodes were included in the irradiation volume while 46 % of patients received RT to the pharyngeal mucosa and lymph nodes of the neck bilaterally (total radiation therapy group).

Results: The median follow-up was 17 months. The 2‑year OS was 71.5 % (95 % CI 49.3–85.3 %), the 2‑year PFS was 72.1 % (95 % CI 44.5–87.6 %). There were no significant differences in 2‑year OS between the ipsilateral and total radiotherapy groups (HR = 1.08 [0.29–4.06], p = 0.904). Only a factor of extranodal extension (ENE) had a statistically significant impact on OS (HR = 6.05 [1.45–25.19], p = 0.0134).

Conclusion: There was no statistically significant difference in 2‑year OS and PFS between the ipsilateral and total radiation therapy groups. A negative prognostic factor is the extranodal extension (ENE) of a metastatic tumor. Prospective randomized trials are needed.

1. von der Grün J.M., Tahtali A., Ghanaati S., et al. Diagnostic and treatment modalities for patients with cervical lymph node metastases of unknown primary site - current status and challenges. Radiat Oncol 2017;12(1):82 https:// doi.org/10.1186/s13014-017-0817-9

2. Balk M., Rupp R., Mantsopoulos K., et al. Factors Influencing the Outcome of Head and Neck Cancer of Unknown Primary (HNCUP). J Clin Med 2022;11(10):2689 https://doi.org/10.3390/jcm11102689

3. Olivier T., Fernandez E., Labidi-Galy I., et al. Redefining cancer of unknown primary: Is precision medicine really shifting the paradigm? Cancer Treat Rev 2021;97:102204. https://doi.org/10.1016/j.ctrv.2021.102204

4. Losa F., Fernández I., Etxaniz O., et al. SEOM-GECOD clinical guideline for unknown primary cancer (2021). Clin Transl Oncol 2022;24(4):681–692. https://doi.org/10.1007/s12094-022-02806-x

5. Zarkavelis G., Mauri D., Pentheroudakis G. How I treat cancers of unknown primary. ESMO Open 2019;4(Suppl 2):e000502. https://doi.org/10.1136/esmoopen-2019-000502

6. Maghami E., Ismaila N., Alvarez A., et al. Diagnosis and Management of Squamous Cell Carcinoma of Unknown Primary in the Head and Neck: ASCO Guideline. J Clin Oncol 2020;38(22):2570–2596. https://doi.org/10.1200/JCO.20.00275

7. Krämer A., Bochtler T., Pauli C., et al. Cancer of unknown primary: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol 2023;34(3):228–246. https://doi.org/10.1016/j.annonc.2022.11.013

8. Nissan E., Amit U., Baron L., et al. The usefulness of [18F]FDG-PET/CT in detecting and managing cancers with unknown primary site depends on histological subtype. Sci Rep 2021;11(1):17732 https://doi.org/10.1038/s41598-02196451-z

9. Ye W., Arnaud E.H., Langerman A., et al. Diagnostic approaches to carcinoma of unknown primary of the head and neck. Eur J Cancer Care (Engl) 2021;30(6):e13459. https://doi.org/10.1111/ecc.13459

10. Podeur P., Mancini J., Delgrande J., et al. Role of Tonsillectomy in the Management of Carcinomas of Unknown Primary of the Head and Neck: A Retrospective Study Based on p16 Analysis. Front Oncol 2020;10:594168. https://doi.org/10.3389/fonc.2020.594168

11. Al-Lami A., Gao C., Saddiq M., et al. Reducing the unknowns: A systematic review & meta-analysis of the effectiveness of trans-oral surgical techniques in identifying head and neck primary cancer in carcinoma unknown primary. Oral Oncol 2022;126:105748. https://doi.org/10.1016/j.oraloncology.2022.105748

12. Strojan P., Kokalj M., Zadnik V., et al. Squamous cell carcinoma of unknown primary tumor metastatic to neck nodes: role of elective irradiation. Eur Arch Otorhinolaryngol 2016;273(12):4561–4569. https://doi.org/10.1007/s00405-0164172-5

13. Berzenji D., Monserez D.A., Verduijn G.M., et al. Treatment of head and neck carcinoma of unknown primary: Cracking a nut with a sledgehammer? Laryngoscope Investig Otolaryngol 2021;6(2):211–218. https://doi.org/10.1002/lio2.539

14. Platek A., Mix M., Chowdhry V., et al. Evaluation of radiation treatment volumes for unknown primaries of the head and neck in the era of FDG PET. PLoS One 2020;15(4):e0231042. https://doi.org/10.1371/journal.pone.0231042

15. Kim D.Y., Heo D.S., Keam B., et al. Failure patterns of cervical lymph nodes in metastases of unknown origin according to target volume. Radiat Oncol J 2020;38(1):18–25. https://doi.org/10.3857/roj.2020.00108

16. Li R., Liao K., Wei Z., et al. The prognostic role of radiotherapy and radiotherapy target in cervical lymph node metastatic squamous cell carcinoma with unknown primary: a retrospective study. J Cancer Res Clin Oncol 2022;148(6):1437–1445. https://doi.org/10.1007/s00432-021-03724-1

17. Ghatasheh H., Huang S.H., Su J., et al. Evaluation of risk-tailored individualized selection of radiation therapy target volume for head and neck carcinoma of unknown primary. Radiother Oncol 2022;175:56-64. https://doi.org/10.1016/j. radonc.2022.07.016

18. Pala M., Novakova P., Pechacova Z., et al. Long-term results of radio(chemo)therapy in metastatic carcinoma to cervical lymph nodes from an unknown primary. Adult Comorbidity Evaluation 27 score as a predictor of survival. Strahlenther Onkol 2023;199(2):149–159. https://doi.org/10.1007/s00066-022-01983-6

19. Tiong A., Rischin D., Young RJ., et al. Unilateral radiotherapy treatment for p16/human papillomavirus-positive squamous cell carcinoma of unknown primary in the head and neck. Laryngoscope 2018;128(9):2076–2083. https://doi.org/10.1002/lary.27131

20. Zhou M.J., van Zante A., Lazar A.A., et al. Squamous cell carcinoma of unknown primary of the head and neck: Favorable prognostic factors comparable to those in oropharyngeal cancer. Head Neck 2018;40(5):904–916. https://doi.org/10.1002/hed.25028

21. Hung Y.H., Liu S.A., Wang C.C., et al. Treatment outcomes of unknown primary squamous cell carcinoma of the head and neck. PLoS One 2018;13(10):e0205365. https://doi.org/10.1371/journal.pone.0205365

22. Cho W.K., Roh J.L., Cho K. J, et al. Predictors of survival and recurrence after primary surgery for cervical metastasis of unknown primary. J Cancer Res Clin Oncol 2020;146(4):925–933. https://doi.org/10.1007/s00432-019-03111-x

23. Binder C., Matthes K.L., Korol D., et al. Cancer of unknown primary-Epidemiological trends and relevance of comprehensive genomic profiling. Cancer Med 2018;7(9):4814–4824. https://doi.org/10.1002/cam4.1689

24. Pinkiewicz M., Dorobisz K., Zatoński T. A Systematic Review of Cancer of Unknown Primary in the Head and Neck Region. Cancer Manag Res 2021;13:7235-7241. https://doi.org/10.2147/CMAR.S319179.