Clinical Testing of a New Radiopharmaceutical [^99mТс]-Al₂O₃ for the Diagnosis of Sentinel Lymph Nodes

Introduction. In modern oncology, the identification of sentinel lymph nodes (SLN), the first nodes that stand on the way of malignant tumor metastasis, is of increasing interest. Detection of SLN followed by morphological examination allows personalizing the surgical intervention for early breast cancer, melanoma, head and neck tumors, neoplasms of the cervix and endometrium. Currently, there is an active development of specific radiopharmaceuticals for SLN imaging. Within the framework of the grant from the Federal Target Program "Pharma-2020", an original radiopharmaceutical using gamma aluminum oxide – [^99mТс]-Al₂O₃ was developed. Preclinical studies have been demonstrated its effectiveness and safety. Pharmacokinetic studies of [^99mTc]-Al₂O₃ showed that 24 hours after its subcutaneous administration, about 12 % of the administered dose is accumulated in the SLN, which gives possibility for its detection.

Aim. To study the possibility of clinical [^99mTc]-Al₂O₃ using for visualization of SLN in breast, larynx and laryngopharyngeal cancer.

Materials and methods. The definition of SLN was carried out in 55 patients with breast cancer and 30 patients with malignant tumors of the larynx and laryngopharynx. The study included peritumoral radiopharmaceutical injection, single-photon emission computed tomography with qualitative and quantitative analysis of the images and radioguided surgery detection of lymph nodes with their subsequent morphological examination.

Results and discussion. Clinical studies have shown that radionuclide imaging of SLN using [^99mTc]-Al₂O₃ is characterized by high sensitivity in breast cancer, larynx and laryngopharyngeal cancer patients (94.5 and 90 %, respectively), due to the high-intensity accumulation of this radiopharmaceutical in the lymph nodes. The optimal time point for SPECT and radioguided examination is an interval of 18–20 hours after injection of [^99mTc]-Al₂O₃, which allows visualizing the maximum possible number of lymph nodes with the most optimal level of radioactivity for their detection.

Conclusion. Application of radionuclide imaging of SLN with the use of [^99mTc]-Al₂O₃ as a radiopharmaceutical is useful in planning surgical treatment of patients with tumors of the breast, larynx and laryngopharynx to determine the extent of surgery.

1. Boada A., Tejera-Vaquerizo A., Ribero S., Puig S., Moreno-Ramírez D., Quaglino P., Osella-Abate S., Cassoni P., Malvehy J., Carrera C., Pigem R., Barreiro-Capurro A., Requena C., Traves V., Manrique-Silva E., Fernández-Orland A., Ferrandiz L., García-Senosiain O., Fernández-Figueras M. T., Ferrándiz C., Nagore E. SENTIMEL study group. Factors associated with sentinel lymph node status and prognostic role of completion lymph node dissection for thick melanoma. European Journal of Surgical Oncology. 2020;46(2):263–271. DOI: 10.1016/j.ejso.2019.09.189.

2. Ni J. S., Janz T. A., Nguyen S. A., Lentsch E. J. Predictors of occult lymph node metastasis in cutaneous head and neck melanoma. World Journal of Otorhinolaryngology – Head and Neck Surgery. 2019;5(4):200–206. DOI: 10.1016/j.wjorl.2019.02.003.

3. Tortorella L., Casarin J., Multinu F., Cappuccio S., McGree M. E., Weaver A. L., Langstraat C. L., Keeney G. L., Kumar A., Melis G. B., Angioni S., Scambia G., Mariani A., Glaser G. E. Sentinel lymph node biopsy with cervical injection of indocyanine green in apparent early-stage endometrial cancer: predictors of unsuccessful mapping. Gynecologic Oncology. 2019;155(1):34–38. DOI: 10.1016/j.ygyno.2019.08.008.

4. Cabañas R. M. An approach for the treatment of penile cancer. Cancer. 1977;39:456–466.

5. Krzhivitskii P. I., Novikov S. N., Kanaev S. V., Krivorotko P. V., Popova N. S., Chernaya A. V., Klitcenko O. A. The use of single-photon emission computed tomography-computed tomography in detecting multiple metastatic lymph nodes in patients with breast cancer. Nuclear Medicine Communications. 2019;40(2):169–174. DOI: 10.1097/MNM.0000000000000954.

6. Persico M. G., Marenco M., De Matteis G., Manfrinato G., Cavenaghi G., Sgarella A., Aprile C., Lodola L. ^99mTc-⁶⁸Ga-ICG-Labelled Macroaggregates and Nanocolloids of Human Serum Albumin: Synthesis Procedures of a Trimodal Imaging Agent Using Commercial Kits. Contrast Media & Molecular Imaging. 2020;2020:1–11. DOI: 10.1155/2020/3629705.

7. Chernov V. I., Afanas’ev S. G., Sinilkin A. A., Tickaya A. A., Avgustinovich A. V. Radionuclide research methods in identifying "sentinel" lymph nodes. Sibirskij onkologicheskij zhurnal. 2008;28(4):5–10. (In Russ.)

8. Chernov V. I., Sinilkin I. G., Zel’chan R. V., Tickaya A. A., Kodina G. E., Malysheva A. O., Klement’eva O. E., Taratonenkova N. A., Lishmanov Yu. B. Experimental study of the possibility of using ^99mTc-nanotech for visualization of lymph nodes. Medicinskaya radiologiya i radiacionnaya bezopasnost’. 2011;56(1):36–42. (In Russ.)

9. Sadkin V., Sкuridin V., Nesterov E., Stasyuk E., Rogov A., Varlamova N., Zelchan R. ^99mTc-labeled nanocolloid drugs: development methods. Scientific Reports. 2020;10(1):14013. DOI: 10.1038/s41598-020-70991-2.

10. Skuridin V. S., Stasyuk E. S., Varlamova V. N., Rogov A. S., Sadkin V. L., Nesterov E. A. Obtaining a new nanocolloidal radiopharmaceutical based on aluminum oxide. Izvestiya Tomskogo politekhnicheskogo universiteta. 2013;323(3):33–37. (In Russ.)

11. Varlamova N. V., Skuridin V. S., Nesterov E. A., Larionova L. A., Chernov V. I. Study of the cumulative properties of the radiopharmaceutical "Nanocolloid, ^99mTc-Al₂O₃" on rats. Vestnik Novosibirskogo gosudarstvennogo universiteta. Seriya: Biologiya, klinicheskaya medicina. 2015;13(2):40–44. (In Russ.)

12. Varlamova N. V., Stasyuk E. S., Tickaya A. A., Sinilkin I. G., Larionova L. A., Sherstoboev E. Yu., Trofimova E. S., Ligacheva A. A., Skuridin V. S. Study of the allergenic properties of the radiopharmaceutical "Nanocolloid, ^99mТc-Al₂O₃" in the experiment. Sovremennye tekhnologii v medicine. 2015;4:72–77. (In Russ.) DOI: 10.17691/stm2015.7.4.09.

13. Varlamova N. V., Skuridin V. S., Nesterov E. A., Chernov V. I., Tickaya A. A. Acute toxicity study of a new radiopharmaceutical "Nanocolloid, ^99mTc-Al₂O₃" for diagnostics in oncology. Eksperimental’naya i klinicheskaya farmakologiya. 2015;78(6):26–29. (In Russ.) DOI: 10.30906/0869-2092-2015-78-6-26-29.

14. Skuridin V. S., CHernov V. I., Varlamova N. V., Nesterov E. A., Sinilkin I. G., Zel’chan R. V. Study of the functional suitability of the "Nanocolloid, ^99mTc-Al₂O₃" radiopharmaceutical for scintigraphic and intraoperative detection of sentinel lymph nodes. Diagnosticheskaya i intervencionnaya radiologiya. 2015;3:76–80. (In Russ.)

15. Chernov V., Titskaya A., Sinilkin I., Zelchan R., Varlamova N. Possibility to Use the Radiopharmaceutical Based on the Gamma-Aluminum Oxide Labeled with ^99mTc to Identify Sentinel Lymph Nodes in the Experiment. Advanced Materials Research. 2015;1084:443–446. DOI: 10.4028/www.scientific.net/AMR.1084.443.

16. Uren R. F., Howman-Giles R. B., Chung D., Thompson J. F. Role of lymphoscintigraphy for selective sentinel lymphadenectomy. Cancer Treatment and Research Communications. 2005;127:15–38. DOI: 10.1007/0-387-23604-x_2.

17. Ban E. J., Lee J. S., Koo J. S., Park S., Kim S. I., Park B. W. How many sentinel lymph nodes are enough for accurate axillary staging in T1-2 breast cancer? Journal of Breast Cancer. 2011;14:296–300. DOI: 10.4048/jbc.2011.14.4.296.

18. Schuman S., Walker G., Avisar E. Processing sentinel nodes in breast cancer: when and how many? The Archives of Surgery. 2011;146:389–393. DOI: 10.1001/archsurg.2011.29.

19. Uren R. F., Howman-Giles R., Chung D. K. V., Spillane A. J., Noushi F., Gillett D., Gluch L., Mak C., West R., Briody J., Carmalt H. SPECT/CT scans allow precise anatomical location of sentinel lymph nodes in breast cancer and redefine lymphatic drainage from the breast to the axilla. Breast. 2012;21:480–486. DOI: 10.1016/j.breast.2011.11.007.

20. Brenot-Rossi I., Houvenaeghel G., Jacquemier J., Bardou V. J., Martino M., Hassan-Sebbag N., Pasquier J. Nonvisualization of axillary sentinel node during lymphoscintigraphy: is there a pathologic significance in breast cancer? Journal of Nuclear Medicine. 2003;44:1232–1237.

21. Cheng G., Kurita G., Kurita S., Torigian D. A., Alavi A. Current status of sentinel lymph-node biopsy in patients with breast cancer. European Journal of Nuclear Medicine and Molecular Imaging. 2011;38:562–575. DOI: 10.1007/s00259-010-1577-z.

22. Lawson G., Matar N., Nollevaux M. C., Jamart J., Krug B., Delos M., Remacle M., Borght T. V. Reliability of sentinel node technique in the treatment of N0 supraglottic laryngeal cancer. Laryngoscope. 2010;120:2213–2217. DOI: 10.1002/lary.21131.

23. De Veij Mestdagh P. D., Schreuder W. H., Vogel W. V., Donswijk M. L., van Werkhoven E., van der Wal J. E., Dirven R., Karakullukcu B., Sonke J. J., van den Brekel M. W. M., Marijnen C. A. M., Al-Mamgani A. Mapping of sentinel lymph node drainage using SPECT/CT to tailor elective nodal irradiation in head and neck cancer patients (SUSPECT-2): a single-center prospective trial. BMC Cancer. 2019;19(1):1110. DOI: 10.1186/s12885-019-6331-8.

24. Yoshimoto S., Hasegawa Y., Matsuzuka T., Shiotani A., Takahashi K., Kohno N., Yoshida T., Kitano H. Sentinel node biopsy for oral and laryngopharyngeal squamous cell carcinoma: a retrospective study of 177 patients in Japan. Auris Nasus Larynx. 2012;39(1):65–70. DOI: 10.1016/j.anl.2011.03.002.