Review Article
Sono-Photodynamic Therapy for Glioblastoma- A New and Promising Area of Research in Clinical Neurooncology
Tzerkovsky DA* and Borychevsky FF
Corresponding Author: Tzerkovsky Dmitry, Laboratory of photodynamic therapy and hyperthermia with chemotherapy group, Republic of Belarus
Received: September 12, 2017; Revised: October 24, 2017 ; Accepted: October 5, 2017
Citation: Tzerkovsky DA & Borychevsky FF. (2017) Sono-Photodynamic Therapy for Glioblastoma- A New and Promising Area of Research in Clinical Neurooncology. J Neurosurg Imaging Techniques, 2(2): 145-149
Copyrights: ©2017 Tzerkovsky DA & Borychevsky FF. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
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The aim of this study is to evaluate the antitumor efficacy and safety of intraoperative sono-photodynamic (iSPDT) therapy with photosensitizer photolon in patients with recurrent glioblastoma. The study included 25 patients with histologically verified recurrence of glioblastoma (grade IV). The main group included 15 patients who received treatment under the scheme «surgery + iSPDT + chemotherapy»; in the control group-10 patients receiving treatment under the scheme «surgery + chemotherapy». The  first  stage of the treatment was total/subtotal tumor resection followed by intravenous administration of photolon; then tumor  bed  was  consecutively exposed  to  ultrasound  (1.04  MHz; 1  W/cm2; 10  min.) and photoirradiation (50-100 J/cm2) 0.5 h. after  the start of photolon infusion. Within 3-4 weeks after discharge from hospital all patients underwent chemotherapy. The toxicity of anticancer therapies was evaluated on the basis of frequency and severity of adverse reactions accounted in accordance with CTCAE (Version 4.0). The criteria for assessing antitumor efficacy were: MRI images at 3 and 6 months after iSPDT treatment, median OS and post-iSPDT median times. The revealed adverse reactions (headache n=6, 40%; convulsions n=2, 13%) corresponded to I/II degrees and did not affect the terms of hospitalization. The median OS of died patients from first diagnosis was 23.9 months in iSPDT and 14.1 months in control group, respective (p=0.004). The post-iSPDT median survival was 8.2 month, while in the control group (without iSPDT) it was 5.8 month (p=0.012). iSDDT is a well-tolerated and potentially effective option in the treatment of glioblastoma. However, to evaluate the antitumor efficacy of this method of treatment, randomized trials are necessary.

 

Key words: Sono-photodynamic therapy, Photosensitizer, Photolon, Glioblastoma

INTRODUCTION

 

Glioblastoma is a serious health and social problem and is one of the most malignant types of central nervous system tumors. The main treatment for this nosologic form of tumor  is  surgery  in  combination  with  external  beam radiation  therapy and  chemotherapy  with  temozolomide [1, 2]. Despite advances in treatment modalities it remains largely incurable. According  to epidemiological  studies,  5-year  survival  in  patients with this pathology is an average of 3-5%, and the median overall survival  from  the  time  of  histological  verification  varies  from 12  to  17  month  [3].  In many countries there is an intensive search and development of new methods of treatment of malignant gliomas allowing to increase the overall survival of patients with this disease.

One  of  these  is  sono-photodynamic  therapy  (SPDT),  which is  a  treatment  method  based  on  the  significant  increase  of the  cytotoxicity  of  drugs  (photosensitizers, PS) combined  with  ultrasound  (US)  and photoirradiation  of  the  tumor  tissue.  According  to  numerous studies  of  sono-photochemical  reactions  include  a  direct interaction  of  excited  molecules  with  the  help  of  ultrasonic radiation, the PS on the substrate and forming transient radicals that react with oxygen. Interaction  initiates  a  complex  cascade  of  free  radicals,  such as singlet oxygen,  hydroxyl  radical,  hydrogen peroxide and superoxide anion radical, causing the development  of  oxidative  stress syndrome.  As a result, SPDT effectively induced glioma-cell apoptosis and necrosis. The two possible mechanisms might be: 

  • promoting  mitochondria  to release Cyto-C and activate Caspase-3, then to initiate apoptosis;
  • the destroying of microvessels, inhibition of angiogenesis and the induction of ischemia and anoxia of glioma cells, resulting in ischemic necrosis [4,5].

At the moment, this area in experimental and clinical neurooncology is actively developing in Japan, South Korea, China and Republic of Belarus. Scientists from a number of scientific centers have published the results of experimental studies (in vivo) that indicate a high antitumor efficacy of SPDT in the treatment of various glioma cell lines (glioma C6, glioma F98, etc.) [6-9]. Approbation of the SPDT in clinical conditions in patients with malignant gliomas within I/II phases of clinical trials is a very relevant and necessary option.

The aim of our study was to evaluate the results of phase I clinical testing method intraoperative SPDT (iSPDT) with PS photolon in patients with recurrent glioblastoma.

MATERIALS AND METHODS

The work is based on the analysis of treatment results of 25 patients with recurrent forms of malignant gliomas (glioblastoma grade IV, GBM) who received treatment in Department of Neurooncology and Neurosurgery of N.N. Alexandrov National Cancer Centre (Lesnoy, Republic Belarus).

Ethical aspects: The study was started after approval by the local ethics committee. All patients were informed of treatment methods, follow-up and possible adverse reactions, and signed informed consent to participate in the study. All studies were conducted in accordance with the requirements of the Helsinki Declaration of the World Medical Association, which was adopted at the 18th General Assembly of the World Medical Association (1964) and Law of the Republic of Belarus № 2435-XII (June 18, 1993) «On Health Care» as amended by the Law of the Republic of Belarus № 433-3 (October 21, 2016).

Inclusion сriteria: All patients who were included in the study met the following criteria:

  • histologically verified diagnosisglioblastoma grade IV (according to the three-degree system in the modification of St. Anne-Mayo);
  • physical status by the Karnovsky index > 50%;
  • the expected life expectancy is not less than 6 months;
  • the age of patients is from 18 to 70 years;
  • absence during the last 3 weeks of chemotherapy sessions and during the last 4 weeks radiotherapy sessions;
  • complete recovery of patients from acute toxic effects of all previous chemotherapeutic interventions.

The control group (retrospective control) included 10 patients with recurrent GBM grade IV with mean age 55.4 ± 9.9 years. All  patients  included  in  the  control groups had  previously  undergone surgical intervention in the volume of total/subtotal resection of the tumor focus with courses of adjuvant chemotherapy with  carmustine (2  mg, intravenously)  and/or lomustine (40 mg,  orally)  3-4  weeks  after  completion  of  surgical  intervention (number of chemotherapy courses: 3-7).

The main group included 15 patients with recurrent GBM grade IV with mean age 49.5 ± 9.7 years. Patients included in main group were performed (Table 1):

·          total or subtotal removal of tumor recurrence;

·          0.5 hours before the end of the operational phase the PS photolon (RUE «Belmedpreparaty», Minsk, Republic of Belarus) was intravenously administrated in a dose of 2 mg/kg;

·          local ultrasonic treatment of the bed and walls of the removed tumor was performed on ultrasound therapy unit «Phyaction USTH 91» (Gymna Uniphy N.V., Bilzen, Belgium)» at a frequency of 1.04 MHz, intensity of radiation 1 W/сm2 and power 3  W for 10 minutes;

·          photoirradiation of the bed and walls of the removed tumor was performed on semiconductor laser «UPL PDT» (LEMT, Republic Belarus, λ=660±5 nm) at the exposure doses 50 J/cm2 (n = 5), 75 J/cm2  (n = 5), 100 J/cm2 (n = 5) with power density – 0.17 W/cm2 and time of photoirradiation of 10-30 minutes.

·          3-4 weeks after treatment (surgical intervention + iSPDT), patients received chemotherapy as patients of control group.

Follow-up and evaluation of treatment effects: all patients were performed brain MRI with contrast enhancement to monitor the effectiveness of the treatment and after 3 and 6 months. Assessment of tolerability and safety of the treatment was carried out for 1 month after the treatment on the basis of data on adverse events and reactions revealed in the course of treatment, their nature, frequency and severity. Given the specific characteristics of the disease and the treatment, the following side effects were assessed (CTCAE, Version 4.0, http://www.meddramsso.com).

Statistical analysis: to estimate the patients’ survival rates, Kaplan-Meier method was used. The comparative survival analysis was performed with non-parametric log-rank test. Differences were considered statistically significant at a significance level of p<0.05. The following parameters were studied: frequency and severity of complications and adverse reactions after treatment (%); median overall survival (OS; month); post-iSPDT median survival (month); indicators of 6-, 12-, 18- and 24-month survival rate after diagnosis verification (%). The calculation of statistical indicators was performed with «STATISTICA 8.0» software.

RESULTS

Assessment of safety and tolerability of iSPDT: PS administration was not accompanied by violations of vital functions in any case. In all patients, the postoperative period was favorable, no serious complications were found. 3 out of 5 patients from group 100 J/cm2 has been noted moderately severe  headache  (CTCAE,  version  4.0;  grade  II)  in  the  early postoperative  period.  According  to multi-slice  computed  tomography 24 hours  after  treatment,  no  signs  of  intracranial  bleeding  in  the postoperative  cavity  were  identified.  No manifestations of cutaneous phototoxicity (itching, pasty skin) were noted.

Assessment of antitumor efficacy of iSPDT: Frequency evaluation of tumor stabilization based on MRI data. In order to evaluate the immediate results after exposure in patients in the study group, intravenous contrast MRI was performed in 3 and 6 months after the treatment. In MRI studies at 3 and 6 months after iSPDT no signs of local recurrence were found in 60% of cases (in 9 of 15 patients). The most effective treatment regimen included surgery, photolon administration at a dose 2 mg/kg, local ultrasound (1.04 MHz; 1 W/сm2; 3 W) and photoirradiation at an exposure dose of 75 J/cm2. In MRI studies at 3 and 6 months after iSPDT with this parameters no signs of local recurrence were found in 100% of cases (in 5 of 5 patients) and there was a regression of residual tumor lesions in 2 patients (Table 1).

Overall survival: The median OS for main group patients amounted to 23.9 month [95% CI=12-35 month], it being 14.1 month in the control group (without iSPDT) [95% CI=5.5-21 month] (p=0.004) (Figure 1).


The post-iSPDT median survival was 8.2 month [95% CI=5.5-23 month]; it being 5.8 month [95% CI=1.5-12 month] in the control group (without iSPDT) (p=0.012) (Figure 2). Survival rates are presented in Table 2.

CONCLUSION

In  our  opinion,  the  combination  of  different  technological solutions  allows practitioners  to  choose  an  adequate  scheme of laser and ultrasonic irradiation of the resected tumor bed of any location and, in the long term, to make the developed method an integral part of the scheme of complex treatment of patients with primary and recurrent forms of malignant gliomas.

Despite a small number of observations in our study, we can draw a preliminary conclusion about good tolerability and antitumor efficacy of iSPDT in the treatment of recurrent forms of GBM. In our opinion, the inclusion of the method of treatment developed by us into combined and complex treatment regimens will improve the results of treatment of this severe pathology. And further study of the mechanisms underlying the antitumor response of the SPDT, will allow to find the optimal regimens of exposure to cells of glial tumors.

In order to determine the antitumor efficacy and SPDT in the near future, we plan to continue our studies within the framework of a randomized study.                                

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