Stereotactic Photodynamic Therapy of Recurrent Malignant Gliomas

The aim of the study is to assess the effectiveness and safety of stereotactic photodynamic therapy (sPDT) with 5-aminolevulinic acid (5-ALA) in patients with recurrent malignant supratentorial gliomas in functionally relevant brain areas.

Materials and Methods. In a retrospective single-center study the results of sPDT with 5-ALA in 10 patients (6 of 10 were male), aged 30 to 62 years (median: 51.5 years; 95% CI: 38–59 years) with recurrent malignant brain gliomas after standard therapy who underwent surgery during the period of 2020–2023 were analyzed. sPDT was conducted during 15 min using 5-ALA at a dosage of 20 mg/kg, a diode laser with a wavelength of 635 nm and power of 1 W, and the LFT-02-BIOSPEC unit (BIOSPEC, Russia). Three patients got repeated sPDT after 3, 7, and 15 months due to a relapse. The number of target points and the optimal position for intervention paths were determined according to the data of preoperative stereotactic MRI of the brain with contrast intensification using the CRW Precision stereotactic navigation system (Integra, USA) and intraoperative registration of the area with the highest intensity of protoporphyrin IX fluorescence along the path (according to fluorescence biospectroscopy).

Results. Glioblastoma (grade IV, WHO) was diagnosed in 7 patients, anaplastic astrocytoma (grade III, WHO) — in 3 persons. Genetic studies were performed for 9 patients, 7 of them had tumors without the IDH1 gene mutation. None of the patients had a combined 1p/19q deletion. The median volume of the contrast-enhancing part of the recurrent tumor was 7.95 cm³ (95% CI: 3.3–13.6 cm³). The median time to relapse after sPDT in patients with anaplastic astrocytomas and glioblastomas was 14.5 and 6.5 months, respectively. The median survival time after sPDT in patients with glioblastomas was 15.8 months (95% CI: 0.5–20.1 months), and in patients with anaplastic astrocytomas — 46.3 months (95%, CI not specified). In the early postoperative period, two patients had motor aphasia and hemiparesis, which further regressed.

Conclusion. The results of a small group of patients allow to consider sPDT with 5-ALA as a promising technique to treat patients with recurrent high-grade gliomas in functionally relevant brain areas and require further prospective assessment.

1. Germano I.M., Johnson D.R., Patrick H.H., Goodman A.L., Ziu M., Ormond D.R., Olson J.J. Congress of Neurological Surgeons systematic review and evidence-based guidelines on the management of progressive glioblastoma in adults: update of the 2014 guidelines. Neurosurgery 2022; 90(5): e112–e115, https://doi.org/10.1227/neu.0000000000001903.
2. Ziu M., Goyal S., Olson J.J. Congress of Neurological Surgeons systematic review and evidence-based guidelines update on the role of radiation therapy in the management of progressive and recurrent glioblastoma in adults. J Neurooncol 2022; 158(2): 255–264, https://doi.org/10.1007/s11060-021-03857-w.
3. Seystahl K., Wick W., Weller M. Therapeutic options in recurrent glioblastoma — an update. Crit Rev Oncol Hematol 2016; 99: 389–408, https://doi.org/10.1016/j.critrevonc.2016.01.018.
4. Wick W., Gorlia T., Bendszus M., Taphoorn M., Sahm F., Harting I., Brandes A.A., Taal W., Domont J., Idbaih A., Campone M., Clement P.M., Stupp R., Fabbro M., Le Rhun E., Dubois F., Weller M., von Deimling A., Golfinopoulos V., Bromberg J.C., Platten M., Klein M., van den Bent M.J. Lomustine and bevacizumab in progressive glioblastoma. N Engl J Med 2017; 377(20): 1954–1963, https://doi.org/10.1056/nejmoa1707358.
5. Brandes A.A., Bartolotti M., Franceschi E. Second surgery for recurrent glioblastoma: advantages and pitfalls. Expert Rev Anticancer Ther 2013; 13(5): 583–587, https://doi.org/10.1586/era.13.32.
6. Kamath A.A., Friedman D.D., Akbari S.H.A., Kim A.H., Tao Y., Luo J., Leuthardt E.C. Glioblastoma treated with magnetic resonance imaging-guided laser interstitial thermal therapy: safety, efficacy, and outcomes. Neurosurgery 2019; 84(4): 836–843, https://doi.org/10.1093/neuros/nyy375.
7. Martynov B.V., Kholyavin A.I., Nizkovolos V.B., Parfenov V.E., Trufanov G.E., Svistov D.V. Stereotactic cryodestruction of gliomas. Prog Neurol Surg 2018; 32: 27–38, https://doi.org/10.1159/000469677.
8. Koga H., Mori K., Tokunaga Y. Interstitial radiofrequency hyperthermia for brain tumors-preliminary laboratory studies and clinical application. Neurol Med Chir (Tokyo) 1993; 33(5): 290–294, https://doi.org/10.2176/nmc.33.290.
9. Alkins R.D., Mainprize T.G. High-intensity focused ultrasound ablation therapy of gliomas. Prog Neurol Surg 2018; 32: 39–47, https://doi.org/10.1159/000469678.
10. Bhanja D., Wilding H., Baroz A., Trifoi M., Shenoy G., Slagle-Webb B., Hayes D., Soudagar Y., Connor J., Mansouri A. Photodynamic therapy for glioblastoma: illuminating the path toward clinical applicability. Cancers (Basel) 2023; 15(13): 3427, https://doi.org/10.3390/cancers15133427.
11. Stylli S.S., Kaye A.H., MacGregor L., Howes M., Rajendra P. Photodynamic therapy of high grade glioma — long term survival. J Clin Neurosci 2005; 12(4): 389–398, https://doi.org/10.1016/j.jocn.2005.01.006.
12. Beck T.J., Kreth F.W., Beyer W., Mehrkens J.H., Obermeier A., Stepp H., Stummer W., Baumgartner R. Interstitial photodynamic therapy of nonresectable malignant glioma recurrences using 5-aminolevulinic acid induced protoporphyrin IX. Lasers Surg Med 2007; 39(5): 386–393, https://doi.org/10.1002/lsm.20507.
13. Ponyaev A.I., Glukhova J.S., Chernykh J.S. Photosensitizers for photodynamic therapy (review). Izvestia Sankt-Peterburgskogo gosudarstvennogo tehnologiceskogo instituta (tehniceskogo universiteta) 2017; 41: 71–78.
14. Bartusik-Aebisher D., Woźnicki P., Dynarowicz K., Aebisher D. Photosensitizers for photodynamic therapy of brain cancers — a review. Brain Sci 2023; 13(9): 1299, https://doi.org/10.3390/brainsci13091299.
15. Goryaynov S.A., Okhlopkov V.A., Golbin D.A., Batalov A., Konovalov N.A., Zelenkov P.V., Potapov A.A., Chernyshov K.A., Svistov D.V., Martynov B.V., Kim A.V., Byvaltsev V.A., Pavlova G.V., Loschenov V.B. Fluorescence diagnosis in neurooncology: retrospective analysis of 653 cases. Front Oncol 2019; 9: 830, https://doi.org/10.3389/fonc.2019.00830.
16. Cramer S.W., Chen C.C. Photodynamic therapy for the treatment of glioblastoma. Front Surg 2020; 6: 81, https://doi.org/10.3389/fsurg.2019.00081.
17. Vermandel M., Dupont C., Lecomte F., Leroy H.A., Tuleasca C., Mordon S., Hadjipanayis C.G., Reyns N. Standardized intraoperative 5-ALA photodynamic therapy for newly diagnosed glioblastoma patients: a preliminary analysis of the INDYGO clinical trial. J Neurooncol 2021; 152(3): 501–514, https://doi.org/10.1007/s11060-021-03718-6.
18. Kaneko S., Fujimoto S., Yamaguchi H., Yamauchi T., Yoshimoto T., Tokuda K. Photodynamic therapy of malignant gliomas. Prog Neurol Surg 2018; 32: 1–13, https://doi.org/10.1159/000469675.
19. Louis D.N., Perry A., Reifenberger G., von Deimling A., Figarella-Branger D., Cavenee W.K., Ohgaki H., Wiestler O.D., Kleihues P., Ellison D.W. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol 2016; 131(6): 803–820, https://doi.org/10.1007/s00401-016-1545-1.
20. Wen P.Y., Macdonald D.R., Reardon D.A., Cloughesy T.F., Sorensen A.G., Galanis E., DeGroot J., Wick W., Gilbert M.R., Lassman A.B., Tsien C., Mikkelsen T., Wong E.T., Chamberlain M.C., Stupp R., Lamborn K.R., Vogelbaum M.A., van den Bent M.J., Chang S.M. Updated response assessment criteria for high-grade gliomas: Response Assessment in Neuro-Oncology Working Group. J Clin Oncol 2010; 28(11): 1963–1972, https://doi.org/10.1200/jco.2009.26.3541.
21. Li Y.M., Suki D., Hess K., Sawaya R. The influence of maximum safe resection of glioblastoma on survival in 1229 patients: can we do better than gross-total resection? J Neurosurg 2016; 124(4): 977–988, https://doi.org/10.3171/2015.5.jns142087.
22. Martynov R.S., Gaidar B.V., Parfenov V.E., Martynov B.V., Svistov D.V., Alekseeva N.P. The complications of early postoperative period for treatment of supratentorial recurrent gliomas. Nejrohirurgia 2016; 2: 30–36.
23. Suchorska B., Weller M., Tabatabai G., Senft C., Hau P., Sabel M.C., Herrlinger U., Ketter R., Schlegel U., Marosi C., Reifenberger G., Wick W., Tonn J.C., Wirsching H.G. Complete resection of contrast-enhancing tumor volume is associated with improved survival in recurrent glioblastoma — results from the DIRECTOR trial. Neuro Oncol 2016; 18(4): 549–556, https://doi.org/10.1093/neuonc/nov326.
24. Sastry R.A., Shankar G.M., Gerstner E.R., Curry W.T. The impact of surgery on survival after progression of glioblastoma: a retrospective cohort analysis of a contemporary patient population. J Clin Neurosci 2018; 53: 41–47, https://doi.org/10.1016/j.jocn.2018.04.004.
25. Hou L.C., Veeravagu A., Hsu A.R., Tse V.C. Recurrent glioblastoma multiforme: a review of natural history and management options. Neurosurg Focus 2006; 20(4): E5, https://doi.org/10.3171/foc.2006.20.4.2.
26. Duffau H. Awake surgery for left posterior insular low-grade glioma through the parietorolandic operculum: the need to preserve the functional connectivity. A case series. Front Surg 2022; 8: 824003, https://doi.org/10.3389/fsurg.2021.824003.
27. Kawaguchi T., Kumabe T., Saito R., Kanamori M., Iwasaki M., Yamashita Y., Sonoda Y., Tominaga T. Practical surgical indicators to identify candidates for radical resection of insulo-opercular gliomas. J Neurosurg 2014; 121(5): 1124–1132, https://doi.org/10.3171/2014.7.jns13899.
28. Suchorska B., Ruge M., Treuer H., Sturm V., Voges J. Stereotactic brachytherapy of low-grade cerebral glioma after tumor resection. Neuro Oncol 2011; 13(10): 1133–1142, https://doi.org/10.1093/neuonc/nor100.
29. Shah A.H., Burks J.D., Buttrick S.S., Debs L., Ivan M.E., Komotar R.J. Laser interstitial thermal therapy as a primary treatment for deep inaccessible gliomas. Neurosurgery 2019; 84(3): 768–777, https://doi.org/10.1093/neuros/nyy238.
30. Watson J., Romagna A., Ballhausen H., Niyazi M., Lietke S., Siller S., Belka C., Thon N., Nachbichler S.B. Long-term outcome of stereotactic brachytherapy with temporary iodine-125 seeds in patients with WHO grade II gliomas. Radiat Oncol 2020; 15(1): 275, https://doi.org/10.1186/s13014-020-01719-9.
31. Rafaelyan A.A., Alekseev D.E., Martynov B.V., Kholyavin A.I., Papayan G.V., Lytkin M.V., Svistov D.V., Zheleznyak I.S., Imyanitov E.N. Stereotactic photodynamic therapy for recurrent glioblastoma. Case report and literature review. Voprosy neirokhirurgii im. N.N. Burdenko 2020; 84(5): 81–88, https://doi.org/10.17116/neiro20208405181.
32. Lietke S., Schmutzer M., Schwartz C., Weller J., Siller S., Aumiller M., Heckl C., Forbrig R., Niyazi M., Egensperger R., Stepp H., Sroka R., Tonn J.C., Rühm A., Thon N. Interstitial photodynamic therapy using 5-ALA for malignant glioma recurrences. Cancers (Basel) 2021; 13(8): 1767, https://doi.org/10.3390/cancers13081767.
33. Schipmann S., Müther M., Stögbauer L., Zimmer S., Brokinkel B., Holling M., Grauer O., Molina E.S., Warneke N., Stummer W. Combination of ALA-induced fluorescence-guided resection and intraoperative open photodynamic therapy for recurrent glioblastoma: case series on a promising dual strategy for local tumor control. J Neurosurg 2020; 134(2): 426–436, https://doi.org/10.3171/2019.11.jns192443.
34. Birzu C., French P., Caccese M., Cerretti G., Idbaih A., Zagonel V., Lombardi G. Recurrent glioblastoma: from molecular landscape to new treatment perspectives. Cancers (Basel) 2020; 13(1): 47, https://doi.org/10.3390/cancers13010047.
35. Dalle Ore C.L., Chandra A., Rick J., Lau D., Shahin M., Nguyen A.T., McDermott M., Berger M.S., Aghi M.K. Presence of histopathological treatment effects at resection of recurrent glioblastoma: incidence and effect on outcome. Neurosurgery 2019; 85(6): 793–800, https://doi.org/10.1093/neuros/nyy501.
36. Tully P.A., Gogos A.J., Love C., Liew D., Drummond K.J., Morokoff A.P. Reoperation for recurrent glioblastoma and its association with survival benefit. Neurosurgery 2016; 79(5): 678–689, https://doi.org/10.1227/neu.0000000000001338.
37. Sloan A.E., Ahluwalia M.S., Valerio-Pascua J., Manjila S., Torchia M.G., Jones S.E., Sunshine J.L., Phillips M., Griswold M.A., Clampitt M., Brewer C., Jochum J., McGraw M.V., Diorio D., Ditz G., Barnett G.H. Results of the NeuroBlate system first-in-humans phase I clinical trial for recurrent glioblastoma. J Neurosurg 2013; 118(6): 1202–1219, https://doi.org/10.3171/2013.1.jns1291.
38. de Groot J.F., Kim A.H., Prabhu S., Rao G., Laxton A.W., Fecci P.E., O’Brien B.J., Sloan A., Chiang V., Tatter S.B., Mohammadi A.M., Placantonakis D.G., Strowd R.E., Chen C., Hadjipanayis C., Khasraw M., Sun D., Piccioni D., Sinicrope K.D., Campian J.L., Kurz S.C., Williams B., Smith K., Tovar-Spinoza Z., Leuthardt E.C. Efficacy of laser interstitial thermal therapy (LITT) for newly diagnosed and recurrent IDH wild-type glioblastoma. Neurooncol Adv 2022; 4(1): vdac040, https://doi.org/10.1093/noajnl/vdac040.
39. Johansson A., Faber F., Kniebühler G., Stepp H., Sroka R., Egensperger R., Beyer W., Kreth F.W. Protoporphyrin IX fluorescence and photobleaching during interstitial photodynamic therapy of malignant gliomas for early treatment prognosis. Lasers Surg Med 2013; 45(4): 225–234, https://doi.org/10.1002/lsm.22126.
40. Niranjan A., Kano H., Iyer A., Kondziolka D., Flickinger J.C., Lunsford L.D. Role of adjuvant or salvage radiosurgery in the management of unresected residual or progressive glioblastoma multiforme in the pre-bevacizumab era. J Neurosurg 2015; 122(4): 757–765, https://doi.org/10.3171/2014.11.jns13295.

Rafaelian A.A., Martynov B.V., Chemodakova K.A., Kholyavin A.I., Martynov R.S., Klimenkova E.Yu., Prokudin M.Yu., Papayan G.V., Boykov I.V., Svistov D.V. Stereotactic Photodynamic Therapy of Recurrent Malignant Gliomas. Sovremennye tehnologii v medicine 2024; 16(2): 58, https://doi.org/10.17691/stm2024.16.2.06