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Standardized intraoperative 5-ALA photodynamic therapy for newly diagnosed glioblastoma patients: a preliminary analysis of the INDYGO clinical trial

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Abstract

Purpose

Glioblastoma (GBM) is the most aggressive malignant primary brain tumor. The unfavorable prognosis despite maximal therapy relates to high propensity for recurrence. Thus, overall survival (OS) is quite limited and local failure remains the fundamental problem. Here, we present a safety and feasibility trial after treating GBM intraoperatively by photodynamic therapy (PDT) after 5-aminolevulinic acid (5-ALA) administration and maximal resection.

Methods

Ten patients with newly diagnosed GBM were enrolled and treated between May 2017 and June 2018. The standardized therapeutic approach included maximal resection (near total or gross total tumor resection (GTR)) guided by 5-ALA fluorescence-guided surgery (FGS), followed by intraoperative PDT. Postoperatively, patients underwent adjuvant therapy (Stupp protocol). Follow-up included clinical examinations and brain MR imaging was performed every 3 months until tumor progression and/or death.

Results

There were no unacceptable or unexpected toxicities or serious adverse effects. At the time of the interim analysis, the actuarial 12-months progression-free survival (PFS) rate was 60% (median 17.1 months), and the actuarial 12-months OS rate was 80% (median 23.1 months).

Conclusions

This trial assessed the feasibility and the safety of intraoperative 5-ALA PDT as a novel approach for treating GBM after maximal tumor resection. The current standard of care remains microsurgical resection whenever feasible, followed by adjuvant therapy (Stupp protocol). We postulate that PDT delivered immediately after resection as an add-on therapy of this primary brain cancer is safe and may help to decrease the recurrence risk by targeting residual tumor cells in the resection cavity. Trial registration NCT number: NCT03048240. EudraCT number: 2016-002706-39.

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Availability of data and material

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Code availability

Not applicable for that section.

References

  1. Grill J (2007) Glioblastoma. http://www.orpha.net/consor4.01/www/cgi-bin/Disease_Search.php?lng=EN&data_id=3752&Disease_Disease_Search_diseaseGroup=glioblastome&Disease_Disease_Search_diseaseType=Pat&Maladie(s)/groupes%20de%20maladies=Glioblastome&title=Glioblastome&search=Disease_Search_Simple

  2. Fisher JL, Schwartzbaum JA, Wrensch M, Wiemels JL (2007) Epidemiology of brain tumors. Neurol Clin 25(4):867–890. https://doi.org/10.1016/j.ncl.2007.07.002

    Article  PubMed  Google Scholar 

  3. Iacob G, Dinca EB (2009) Current data and strategy in glioblastoma multiforme. J Med Life 2(4):386–393

    PubMed  PubMed Central  Google Scholar 

  4. Ostrom QT, Bauchet L, Davis FG, Deltour I, Fisher JL, Langer CE, Pekmezci M, Schwartzbaum JA, Turner MC, Walsh KM, Wrensch MR, Barnholtz-Sloan JS (2014) The epidemiology of glioma in adults: a “state of the science” review. Neuro-Oncology 16(7):896–913. https://doi.org/10.1093/neuonc/nou087

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO, European Organisation for R, Treatment of Cancer Brain T, Radiotherapy G, National Cancer Institute of Canada Clinical Trials G (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352(10):987–996. https://doi.org/10.1056/NEJMoa043330

    Article  CAS  PubMed  Google Scholar 

  6. Brown TJ, Brennan MC, Li M, Church EW, Brandmeir NJ, Rakszawski KL, Patel AS, Rizk EB, Suki D, Sawaya R, Glantz M (2016) Association of the extent of resection with survival in glioblastoma: a systematic review and meta-analysis. JAMA Oncol 2(11):1460–1469. https://doi.org/10.1001/jamaoncol.2016.1373

    Article  PubMed  PubMed Central  Google Scholar 

  7. Stummer W, Reulen HJ, Meinel T, Pichlmeier U, Schumacher W, Tonn JC, Rohde V, Oppel F, Turowski B, Woiciechowsky C, Franz K, Pietsch T (2008) Extent of resection and survival in glioblastoma multiforme: identification of and adjustment for bias. Neurosurgery 62(3):564–576. https://doi.org/10.1227/01.neu.0000317304.31579.17 (discussion 564-576)

    Article  PubMed  Google Scholar 

  8. Stummer W, Pichlmeier U, Meinel T, Wiestler OD, Zanella F, Reulen HJ (2006) Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol 7(5):392–401

    Article  CAS  Google Scholar 

  9. Hadjipanayis CG, Stummer W, Sheehan JP (2019) 5-ALA fluorescence-guided surgery of CNS tumors. J Neurooncol 141(3):477–478. https://doi.org/10.1007/s11060-019-03109-y

    Article  PubMed  Google Scholar 

  10. Hadjipanayis CG, Stummer W (2019) 5-ALA and FDA approval for glioma surgery. J Neurooncol 141(3):479–486. https://doi.org/10.1007/s11060-019-03098-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Petrecca K, Guiot MC, Panet-Raymond V, Souhami L (2013) Failure pattern following complete resection plus radiotherapy and temozolomide is at the resection margin in patients with glioblastoma. J Neurooncol 111(1):19–23. https://doi.org/10.1007/s11060-012-0983-4

    Article  PubMed  Google Scholar 

  12. Bacellar IO, Tsubone TM, Pavani C, Baptista MS (2015) Photodynamic efficiency: from molecular photochemistry to cell death. Int J Mol Sci 16(9):20523–20559. https://doi.org/10.3390/ijms160920523

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Valdes PA, Kim A, Brantsch M, Niu C, Moses ZB, Tosteson TD, Wilson BC, Paulsen KD, Roberts DW, Harris BT (2011) delta-Aminolevulinic acid-induced protoporphyrin IX concentration correlates with histopathologic markers of malignancy in human gliomas: the need for quantitative fluorescence-guided resection to identify regions of increasing malignancy. Neuro-Oncology 13(8):846–856. https://doi.org/10.1093/neuonc/nor086

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Johansson A, Faber F, Kniebuhler G, Stepp H, Sroka R, Egensperger R, Beyer W, Kreth FW (2013) Protoporphyrin IX fluorescence and photobleaching during interstitial photodynamic therapy of malignant gliomas for early treatment prognosis. Lasers Surg Med 45(4):225–234. https://doi.org/10.1002/lsm.22126

    Article  PubMed  Google Scholar 

  15. Johansson A, Palte G, Schnell O, Tonn JC, Herms J, Stepp H (2010) 5-Aminolevulinic acid-induced protoporphyrin IX levels in tissue of human malignant brain tumors. Photochem Photobiol 86(6):1373–1378. https://doi.org/10.1111/j.1751-1097.2010.00799.x

    Article  CAS  PubMed  Google Scholar 

  16. Vermandel M, Quidet M, Vignion-Dewalle A-S, Leroy H-A, Leroux B, Mordon S, Reyns N (2019) Comparison of different treatment schemes in 5-ALA interstitial photodynamic therapy for high-grade glioma in a preclinical model: an MRI study. Photodiagn Photodyn Ther 25:166–176. https://doi.org/10.1016/j.pdpdt.2018.12.003

    Article  CAS  Google Scholar 

  17. Leroy HA, Vermandel M, Leroux B, Duhamel A, Lejeune JP, Mordon S, Reyns N (2018) MRI assessment of treatment delivery for interstitial photodynamic therapy of high-grade glioma in a preclinical model. Lasers Surg Med 50(5):460–468. https://doi.org/10.1002/lsm.22744

    Article  PubMed  Google Scholar 

  18. Leroy HA, Vermandel M, Vignion-Dewalle AS, Leroux B, Maurage CA, Duhamel A, Mordon S, Reyns N (2017) Interstitial photodynamic therapy and glioblastoma: light fractionation in a preclinical model. Lasers Surg Med 49(5):506–515. https://doi.org/10.1002/lsm.22620

    Article  PubMed  Google Scholar 

  19. Beck TJ, Kreth FW, Beyer W, Mehrkens JH, Obermeier A, Stepp H, Stummer W, Baumgartner R (2007) Interstitial photodynamic therapy of nonresectable malignant glioma recurrences using 5-aminolevulinic acid induced protoporphyrin IX. Lasers Surg Med 39(5):386–393. https://doi.org/10.1002/lsm.20507

    Article  PubMed  Google Scholar 

  20. Schipmann S, Muther M, Stogbauer L, Zimmer S, Brokinkel B, Holling M, Grauer O, Suero Molina E, Warneke N, Stummer W (2020) 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. https://doi.org/10.3171/2019.11.JNS192443

    Article  PubMed  Google Scholar 

  21. Stummer W, Beck T, Beyer W, Mehrkens JH, Obermeier A, Etminan N, Stepp H, Tonn JC, Baumgartner R, Herms J, Kreth FW (2008) Long-sustaining response in a patient with non-resectable, distant recurrence of glioblastoma multiforme treated by interstitial photodynamic therapy using 5-ALA: case report. J Neurooncol 87(1):103–109. https://doi.org/10.1007/s11060-007-9497-x

    Article  CAS  PubMed  Google Scholar 

  22. Stupp R, Taillibert S, Kanner A, Read W, Steinberg D, Lhermitte B, Toms S, Idbaih A, Ahluwalia MS, Fink K, Di Meco F, Lieberman F, Zhu JJ, Stragliotto G, Tran D, Brem S, Hottinger A, Kirson ED, Lavy-Shahaf G, Weinberg U, Kim CY, Paek SH, Nicholas G, Bruna J, Hirte H, Weller M, Palti Y, Hegi ME, Ram Z (2017) Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma: a randomized clinical trial. JAMA 318(23):2306–2316. https://doi.org/10.1001/jama.2017.18718

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Stupp R, Taillibert S, Kanner AA, Kesari S, Steinberg DM, Toms SA, Taylor LP, Lieberman F, Silvani A, Fink KL, Barnett GH, Zhu JJ, Henson JW, Engelhard HH, Chen TC, Tran DD, Sroubek J, Tran ND, Hottinger AF, Landolfi J, Desai R, Caroli M, Kew Y, Honnorat J, Idbaih A, Kirson ED, Weinberg U, Palti Y, Hegi ME, Ram Z (2015) Maintenance therapy with tumor-treating fields plus temozolomide vs temozolomide alone for glioblastoma: a randomized clinical trial. JAMA 314(23):2535–2543. https://doi.org/10.1001/jama.2015.16669

    Article  CAS  PubMed  Google Scholar 

  24. Gandhi S, Tayebi Meybodi A, Belykh E, Cavallo C, Zhao X, Syed MP, Borba Moreira L, Lawton MT, Nakaji P, Preul MC (2019) Survival outcomes among patients with high-grade glioma treated with 5-aminolevulinic acid-guided surgery: a systematic review and meta-analysis. Front Oncol 9:620. https://doi.org/10.3389/fonc.2019.00620

    Article  PubMed  PubMed Central  Google Scholar 

  25. Dupont C, Vermandel M, Leroy HA, Quidet M, Lecomte F, Delhem N, Mordon S, Reyns N (2019) INtraoperative photoDYnamic Therapy for GliOblastomas (INDYGO): study protocol for a phase I clinical trial. Neurosurgery 84(6):E414–E419. https://doi.org/10.1093/neuros/nyy324

    Article  PubMed  Google Scholar 

  26. Dupont C, Mordon S, Deleporte P, Reyns N, Vermandel M (2017) A novel device for intraoperative photodynamic therapy dedicated to glioblastoma treatment. Future Oncol. https://doi.org/10.2217/fon-2017-0261

    Article  PubMed  Google Scholar 

  27. Curnow A, MacRobert AJ, Bown SG (2006) Comparing and combining light dose fractionation and iron chelation to enhance experimental photodynamic therapy with aminolevulinic acid. Lasers Surg Med 38(4):325–331. https://doi.org/10.1002/lsm.20328

    Article  PubMed  Google Scholar 

  28. Iinuma S, Schomacker KT, Wagnieres G, Rajadhyaksha M, Bamberg M, Momma T, Hasan T (1999) In vivo fluence rate and fractionation effects on tumor response and photobleaching: photodynamic therapy with two photosensitizers in an orthotopic rat tumor model. Cancer Res 59(24):6164–6170

    CAS  PubMed  Google Scholar 

  29. Tudge SH, Kaye AH, Hill JS (1999) Modulation of light delivery in photodynamic therapy of brain tumours. J Clin Neurosci 6(3):227–232. https://doi.org/10.1016/s0967-5868(99)90508-8

    Article  CAS  PubMed  Google Scholar 

  30. Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JE, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352(10):997–1003. https://doi.org/10.1056/NEJMoa043331

    Article  CAS  PubMed  Google Scholar 

  31. Stupp R, Brada M, van den Bent MJ, Tonn JC, Pentheroudakis G, Group EGW (2014) High-grade glioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 25(Suppl 3):iii93–iii101. https://doi.org/10.1093/annonc/mdu050

    Article  PubMed  Google Scholar 

  32. Weller M, van den Bent M, Hopkins K, Tonn JC, Stupp R, Falini A, Cohen-Jonathan-Moyal E, Frappaz D, Henriksson R, Balana C, Chinot O, Ram Z, Reifenberger G, Soffietti R, Wick W, European Association for Neuro-Oncology Task Force on Malignant G (2014) EANO guideline for the diagnosis and treatment of anaplastic gliomas and glioblastoma. Lancet Oncol 15(9):e395-403. https://doi.org/10.1016/S1470-2045(14)70011-7

    Article  PubMed  Google Scholar 

  33. Wen PY, Chang SM, Van den Bent MJ, Vogelbaum MA, Macdonald DR, Lee EQ (2017) Response assessment in neuro-oncology clinical trials. J Clin Oncol 35(21):2439–2449. https://doi.org/10.1200/JCO.2017.72.7511

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Brown EG (2004) Using MedDRA: implications for risk management. Drug Saf 27(8):591–602. https://doi.org/10.2165/00002018-200427080-00010

    Article  PubMed  Google Scholar 

  35. Kreth FW, Thon N, Simon M, Westphal M, Schackert G, Nikkhah G, Hentschel B, Reifenberger G, Pietsch T, Weller M, Tonn JC, German Glioma N (2013) Gross total but not incomplete resection of glioblastoma prolongs survival in the era of radiochemotherapy. Ann Oncol 24(12):3117–3123. https://doi.org/10.1093/annonc/mdt388

    Article  PubMed  Google Scholar 

  36. Delgado-Lopez PD, Corrales-Garcia EM (2016) Survival in glioblastoma: a review on the impact of treatment modalities. Clin Transl Oncol 18(11):1062–1071. https://doi.org/10.1007/s12094-016-1497-x

    Article  CAS  PubMed  Google Scholar 

  37. Senft C, Bink A, Franz K, Vatter H, Gasser T, Seifert V (2011) Intraoperative MRI guidance and extent of resection in glioma surgery: a randomised, controlled trial. Lancet Oncol 12(11):997–1003. https://doi.org/10.1016/S1470-2045(11)70196-6

    Article  PubMed  Google Scholar 

  38. Kostron H, Weiser G, Fritsch E, Grunert V (1987) Photodynamic therapy of malignant brain tumors: clinical and neuropathological results. Photochem Photobiol 46(5):937–943. https://doi.org/10.1111/j.1751-1097.1987.tb04872.x

    Article  CAS  PubMed  Google Scholar 

  39. Kostron H, Fritsch E, Grunert V (1988) Photodynamic therapy of malignant brain tumours: a phase I/II trial. Br J Neurosurg 2(2):241–248. https://doi.org/10.3109/02688698808992675

    Article  CAS  PubMed  Google Scholar 

  40. Kostron H, Hochleitner B, Obwegeser A, Seiwald M (1995) Clinical and experimental results of photodynamic therapy in neurosurgery, vol 2371. Fifth international photodynamic association biennial meeting. SPIE

  41. Mansouri A, Hachem LD, Mansouri S, Nassiri F, Laperriere NJ, Xia D, Lindeman NI, Wen PY, Chakravarti A, Mehta MP, Hegi ME, Stupp R, Aldape KD, Zadeh G (2019) MGMT promoter methylation status testing to guide therapy for glioblastoma: refining the approach based on emerging evidence and current challenges. Neuro-Oncology 21(2):167–178. https://doi.org/10.1093/neuonc/noy132

    Article  CAS  PubMed  Google Scholar 

  42. Brem H, Piantadosi S, Burger PC, Walker M, Selker R, Vick NA, Black K, Sisti M, Brem S, Mohr G et al (1995) Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. Polym Brain Tumor Treat Gr Lancet 345(8956):1008–1012. https://doi.org/10.1016/s0140-6736(95)90755-6

    Article  CAS  Google Scholar 

  43. Brem H, Ewend MG, Piantadosi S, Greenhoot J, Burger PC, Sisti M (1995) The safety of interstitial chemotherapy with BCNU-loaded polymer followed by radiation therapy in the treatment of newly diagnosed malignant gliomas: phase I trial. J Neurooncol 26(2):111–123. https://doi.org/10.1007/BF01060217

    Article  CAS  PubMed  Google Scholar 

  44. Zhou J, Patel TR, Sirianni RW, Strohbehn G, Zheng MQ, Duong N, Schafbauer T, Huttner AJ, Huang Y, Carson RE, Zhang Y, Sullivan DJ Jr, Piepmeier JM, Saltzman WM (2013) Highly penetrative, drug-loaded nanocarriers improve treatment of glioblastoma. Proc Natl Acad Sci USA 110(29):11751–11756. https://doi.org/10.1073/pnas.1304504110

    Article  PubMed  Google Scholar 

  45. Dupont C, Mordon S, Deleporte P, Reyns N, Vermandel M (2017) A novel device for intraoperative photodynamic therapy dedicated to glioblastoma treatment. Future Oncol 13(27):2441–2454. https://doi.org/10.2217/fon-2017-0261

    Article  CAS  PubMed  Google Scholar 

  46. Mathews MS, Chighvinadze D, Gach HM, Uzal FA, Madsen SJ, Hirschberg H (2011) Cerebral edema following photodynamic therapy using endogenous and exogenous photosensitizers in normal brain. Lasers Surg Med 43(9):892–900. https://doi.org/10.1002/lsm.21135

    Article  PubMed  PubMed Central  Google Scholar 

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Funding

The authors of this publication received research support from INSERM, University of Lille, University Hospital of Lille, American Society for Laser Medicine and Surgery, Ligue contre le Cancer and Agence Nationale pour la Recherche.

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Correspondence to Nicolas Reyns.

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Conflicts of interest

M. Vermandel, C. Dupont, S. Mordon and N. Reyns are co-founders of Hemerion Therapeutics SAS, Lille, France. Constantinos Hadjipanayis is a consultant for NX Development Corporation (NXDC) and Synaptive Medical Inc. He receives royalties from the sale of Gleolan® (5-ALA) which is marketed by NXDC. Gleolan® is an optical imaging agent approved in the United States for the visualization of malignant tissue during glioma surgery.

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All procedures performed in studies were in accordance with the ethical standards of the National Research Committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The French National Agency for Medicine and Health Product Safety (ANSM) as well as the French National Ethics Committee approved this study.

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Vermandel, M., Dupont, C., Lecomte, F. et al. Standardized intraoperative 5-ALA photodynamic therapy for newly diagnosed glioblastoma patients: a preliminary analysis of the INDYGO clinical trial. J Neurooncol 152, 501–514 (2021). https://doi.org/10.1007/s11060-021-03718-6

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