**3. Photodiagnosis and photodynamic therapy in neurosurgery**

Currently, standard treatment of glioblastoma is based on microsurgical tumour resection, radiation and chemotherapy. Overall prognosis of glioblastoma patients remains poor; therefore, new therapeutical options are necessary. Glioblastomas are diffuse infiltrating tumors, with growth patterns according to Scherer as follows: (i)perineuronal growth (perineuronal satellitosis); (ii) surface (subpial) growth; (iii) perivascular growth and (iv) intrafascicular growth.(Peiffer & Kleihues 1999) Due to the fact that tumor recurrence occurs most frequently at the resection margins, PDT of malignant glioma might be a promising treatment option as a local therapy. Additionally PDT might be able to reach the so called Guerilla cells(Claes, Idema, & Wesseling 2007), tumor cells localized in the brain adjacent to tumor region (BAT region) by local therapy at the end of the resection and perhaps by PDT stimulated anti-tumor immunity. Stimulation of anti-tumor immunity by PDT is off increasing relevance, an opportunity for PDT to become quite more than another local glioma treatment method. This topic will be discussed later in the chapter.

In the 1970s, when lasers and optical light delivery systems became available, the therapeutic use of Hp maintained interest also in neurosurgery. In 1972, Diamond et al. studied the photodynamic effects of Hp in glioma cell cultures where addition of 10*-*5 M Hp and exposure to light caused cell death.(Diamond et al. 1972) In 1975 the same group investigated the photodynamic effect of Hp *in vivo* in Fisher rats and subcutaneous implanted glioma cells; the authors demonstrated a time dependent cell death of glioma cells increasing by time of light exposure. For clinical use of PDT in Neurosurgery mainly HpD and mTHPC are currently in use.

#### **3.1 Photodiagnosis (PD) and PDT with 5-ALA PpIX**

Introduction of 5-ALA fluorescence guided resection was a milestone in neurosurgery in the last fifteen years. Great contribution was done by Stummer and coworkers. 5-ALA is orally applied about 4 hours before surgery. Surgery is performed under operating

Visualization and Photodynamic Therapy in Malignant Glioma - An Overview and Perspectives 187

Table 1. Summary of the randomised controlled multicentre phase III trial, fluorescence-

Stratification by postoperative MRI findings showed that patients without residual contrastenhancing tumor had higher overall median survival than did those with residualenhancing tumour (**17.9** months [CI 14.3-19.4] vs **12.9** months [CI 10.6-14.0]). Although *in vivo* experience demonstrated the feasibility to perform 5-ALA PDT, 5-ALA PDT is not established up to now in clinical practice without exceptions of some groups. Beck et al. 2007 treated 10 patients with small and circumscribed recurrent malignant gliomas by implantation of up to six light diffusers with a distance of 9mm.(Beck et al. 2007) By this method a mean tumor volume of 5.9 cm3 could be treated. The median survival was 15

Currently Kostron (2010) reviewed clinical investigations of PDT in a meta analysis, median survival of primary GBM with PDT was 22 months vs 15, in recurrent GBM 9 months vs. 3 months.(Kostron 2010) A brief overview about the relevant clinical investigations in the last decade is given by table 2. For PDT the PSs Hpd (Photofrin®) and mTHPC (Foscan) were

**patients** 

500 J/cm2 27, 13 study

group 14 control group

70-260 J/cm2 145 Mean survival 14.3

20 J/cm2 26 Median survival 9

**Results** 

mon.

GBM

mon.

96 Survival time 7.5

22%

2-year survival 28% for newly diagnosed

Control 3.5 mon.

mon., 1-year survival 44%, 2-year survival

Tumor progression 8.6 mon. vs. 4.8 mon.

**Photosensitizer Light dose Number of** 

PFS (median) 5.1 mon. 3.6 mon. PFS-6 months 41.0 % 21.1 % SR age > 55 years 14.1 mon. 11.5 mon. SR age < 55 years 18 mon. 17.5 mon. SR 5-ALA vs. whitelight 17,9 mon. 12,9 mon

guided surgery with 5-ALA versus white light surgery. Stummer et al. 2006

PFS: progression free survival; SR: survival rate

months, without side effects in the treated patients.

HpD 5 mg/kg bw

mTHPC 0.15 mg/kg bw

HpD 2 mg/kg bw

ALA and Photofrin (HpD)

Table 2. Short overview - clinical investigations with PDT

**Author,** 

Stylli 2005 (Stylli et al. 2005)

Kostron 2006(Kostron, Fiegele, & Akatuna 2006)

Muller

2006(Muller & Wilson 2006)

Eljamel 2008 (Eljamel 2008)

**Publication year** 

**3.2 PDT in neurosurosurgery clinical studies – an overview** 

**5-ALA White light** 

microscope, during resection the surgeon is able to switch between the white light mode and the fluorescent mode (blue light), where the tumour appears red fluorescent, see also figure 1.

Fig. 1. Glioblastoma WHO IV at the beginning of resection in white light mode (upper row left) and under fluorescence mode (upper row right) after opening of the dura. Note the red shining PpIX fluorescence. During resection under white light conditions residual tumor (bottom row left) can be clearly detected under fluorescence mode (bottom row right).

The first results of improvement of the radicality of resection by 5-ALA fluorescence guided surgery were published in the nineties. The results of a randomised controlled multicentre phase III trial performed are summerized. The German study group investigated 322 patients enrolled by 32 investigators at 17 study centres. 161 patients were treated by fluorescence-guided surgery with 5-ALA, (20 mg/kg bodyweight; medac, Wedel, Germany), 161 were resected under conventional white light mode. In the fluorescence guided resection group tumor was resected completely in 65%, in the white light group complete tumor resection was achieved only in 36% of patients, as investigated by early postsurgical MRI. The difference between the groups was 29% [95% Confidence interval (CI) 17-40], p<0.0001. Table 1 gives a short overview about the results depending to surgery (5- ALA fluorescence guided vs. resection under white light mode).(Stummer, Pichlmeier, Meinel, Wiestler, Zanella, & Reulen 2006)


Table 1. Summary of the randomised controlled multicentre phase III trial, fluorescenceguided surgery with 5-ALA versus white light surgery. Stummer et al. 2006

Stratification by postoperative MRI findings showed that patients without residual contrastenhancing tumor had higher overall median survival than did those with residualenhancing tumour (**17.9** months [CI 14.3-19.4] vs **12.9** months [CI 10.6-14.0]). Although *in vivo* experience demonstrated the feasibility to perform 5-ALA PDT, 5-ALA PDT is not established up to now in clinical practice without exceptions of some groups. Beck et al. 2007 treated 10 patients with small and circumscribed recurrent malignant gliomas by implantation of up to six light diffusers with a distance of 9mm.(Beck et al. 2007) By this method a mean tumor volume of 5.9 cm3 could be treated. The median survival was 15 months, without side effects in the treated patients.
