Microscopic images of the tumor vasculature in a window chamber by Chen et al, (4) showing the tumor blood vessels before a 1hr treatment with LTSL-Dox + heat, and 24hrs after the treatment. The dramatic result is that all the blood vessels had been shut down and all that was left was a small thrombosis.

As we were discussing the LTSL-Dox technology and what we had done over the years, Kate asked the question, "Could LTSL-Dox work with LITT?" i.e., could LTSL-Dox plus LITT provide additional advantages beyond LITT alone? That is, could intravenous LTSL-Dox release its drug triggered by LITT-warming in the impossible-to-remove peripheral regions, that are known to be highly invasive and where recurrence almost inevitably occurs. 

As we show in the MRI-brain image below, in the core of the irradiated area, there is virtually instantaneous irreversible cell destruction at temperatures > 60 °C, Then, there is a dynamic thermal reaction (48–60 °C) that can still kill cancer cells.  But it is the tissue margins that may suffer none or only reversible cell damage and it is this periphery that becomes a region with a high rate of relapses.  

With LTSL-Dox + LITT, while central and medium zones can still have their therapeutic effects, the goals of the new procedure shift to optimal warming of the tumor to 42°C, especially at the periphery. For the right sized tumor (up to 3 cm), LTSL-Dox could, in principle, 'clean up' the remaining tumor cells when the margins are warmed by LITT. We think that this where LTSL-Dox could help eradicate this all-important peripheral cell zone.

(1) Wood, B.J., et al., Phase I study of heat-deployed liposomal doxorubicin during radiofrequency ablation for hepatic malignancies. J Vasc Interv Radiol, 2012. 23(2): p. 248-55.e7.

While surgical resection does provide some enhancement of Overall Survival (OS), not all tumors are amenable to conventional surgical resection.  Even with resection, recurrence is the norm. Data above shows, GBM median survival times as a function of age (3).

According to the Central Brain Tumor Registry of the United States (CBTRUS) (1), the most commonly occurring malignant brain and other CNS histopathology was glioblastoma (14.2% of all tumors and 50.1% of all malignant tumors).  Unfortunately, even with the best available treatments, patients inevitably progress and die from the disease.  As reported by Mohamed et al, (2) and references therein, "Despite the initiation of aggressive treatment along with extensive surgery, concurrent radiation and adjuvant temozolomide, the median survival time of adult patients remains around 10 months and up to 14 months in patients receiving combined treatment with radiotherapy" And... "Only 3% to 5% of patients survive more than three years, and reports of survival exceeding five years are sporadic".

See also the edited 21-chapter book by Steven De Vleeschouwer, entitled "Glioblastoma" (4).

(1) Ostrom, Q.T., et al., CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2015–2019. Neuro-Oncology, 2022. 24(Supplement_5): p. v1-v95.

(2) Mohammed, S., M. Dinesan, and T. Ajayakumar, Survival and quality of life analysis in glioblastoma multiforme with adjuvant chemoradiotherapy: a retrospective study. Rep Pract Oncol Radiother, 2022. 27(6): p. 1026-1036.

(3) Gorlia, T., et al., New prognostic factors and calculators for outcome prediction in patients with recurrent glioblastoma: a pooled analysis of EORTC Brain Tumour Group phase I and II clinical trials. Eur J Cancer, 2012. 48(8): p. 1176-84.

(4) De Vleeschouwer, S., ed. Glioblastoma [Internet]. 2017, Codon Publications: Brisbane (AU).

Thermal Damage Threshold (TDT) lines. Image from Kamath et al 2019, (7) , during laser ablation, demonstrating tumor volume (constructed manually on Monteris® [Plymouth, Minnesota] proprietary software at the time of surgery) and yellow and blue thermal damage threshold (TDT) lines (derived from real-time MR thermometry).

As also reported in the paper by de Groot et al (1), while studies have demonstrated strong safety data for LITT there is variable efficacy in subgroups of patients.  "In 29 new and 60 recurrent grade 4 glioblastoma patients the median overall survival (OS) was 9.73 months for newly diagnosed patients and median post-procedure survival was 8.97 months for recurrent patients".

Despite median physician-estimated extent of ablation of 91%-99%, tumors still progressed. The infiltrated cancer cells for GBM tumors make it difficult for surgeons to surgically and completely resect the whole tumor or to fully ablate with LITT. In the picture shown to the left from Kamath et al, (2) in their phase 1 trial testing times and temperatures, there are areas outside of the yellow Thermal Damage Threshold (TDT) line that miss the pink border outlining the tumor. It’s these external margins that cause the GBM tumors to grow back so consistently in patients. 

(1) de Groot, J.F., et al., Efficacy of laser interstitial thermal therapy (LITT) for newly diagnosed and recurrent IDH wild-type glioblastoma. Neuro-Oncology Advances, 2022. 4(1).

(2) Kamath, A.A., et al., Glioblastoma Treated With Magnetic Resonance Imaging-Guided Laser Interstitial Thermal Therapy: Safety, Efficacy, and Outcomes. Neurosurgery, 2019. 84(4): p. 836-843.