Photodynamic Treatment of Neurooncologic Patients with a New Photosensitizer of the E6 Chlorin Group: The First Experience

G.S. Tigliev,

V.E. Olyushin, E.A. Chesnokova, A.Yu. Ulitin, A.V. Komfort, M.L. Gelfondt, D.V. Vasilyev

Polenov Research Neurosurgical Institute, Saint Petersburg,
Petrov Research Institute of Oncology, Saint Petersburg, Russia

 

Introduction

Photodynamic therapy (PDT) is one of the methods, causing a local effect on tumor cells. It is based on administration of a photosensitizer, its selective accumulation in tumor tissue and subsequent interaction with light, having a certain wavelength and ensuring adequate penetration through biologic tissues. This leads to photochemically mediated destruction of cells in oxygen presence.

There is a rather profound experience of applying PDT, gained in our country and abroad. It concerns treatment of such systemic oncologic diseases, as malignant dermal neoplasms, tumors of the lung and gastrointenstinal tract. According to existing data, there are grounds for supposition, that PDT is most effective, when used for prevention of local spread of a pathologic process [17]. Neuroectodermal neoplasms are known to have an ability for local expansion into cerebral tissue and infiltrative growth, while metastatic spreading beyond the limits of the CNS is not characteristic of them. Thus, duration of a relapse-free period and life of patients with gliomas is dependent on a speed of local spread of a pathologic process. PDT, as a method of treatment, possesses a local effect and is aimed at gaining a greater zone of destruction of tumor cells during surgical intervention. In its turn, the latter should improve prognosis in this group of patients [1, 2, 4, 6, 9, 11, 13].

Clinical studies of a fluorescence effect, watched during metabolism of a photosensitizer's molecules, have been carried out [19, 20, 21, 22]. This effect can be used as a means of intraoperative control in removal of glial tumors.

The main goal of our research is to estimate safety and efficacy of photodynamic therapy in applying a new preparation of the E6 chlorin group for combined antineoplastic treatment of patients with cerebral gliomas.

Materials and Methods

Population

The present series includes 15 patients (7 females and 8 males) with glial tumors of the cerebrum hemispheres, which were characterized by a different degree of malignancy. There were primary tumors and neoplasms with prolonged growth. According to histostructure, distribution of patients with primary tumors was as follows: differentiated astrocytomas - 1, anaplastic gliomas - 3, glioblastomas -7. As for 7 reoperated cases with prolonged growth of malignant gliomas, histologic findings were indicative of glioblastoma in 6 and oligoastrocytoma in 1 of them.

Administration of a Photosensitizer

We used photoditazin, being a home photosensitizer of the E6 chlorin group (the second generation). The drug was administered intravenously during intubation. An expected maximum therapeutic effect was watched during 3-4 hours after administration, i.e. the photosensitizer concentration achieved its maximum level by the end of tumor removal. A dose was equal to 50 mg.

Surgical Treatment and Irradiation of the Tumor Bed

The maximum possible removal of neoplastic tissue was made. It depended on tumor localization and a character of its growth. Then a tumor bed was irradiated by a scattered laser beam. It was done with a prototype of Atkus-2, a semiconductive laser with a wavelength of 660 nm. Output power at a butt end of a quartz monofiber was 2 W; irradiation time was 1200-1800 sec (a dose of 160-230 J/cm2 and 400-600 J/cm2). Irradiation methods were different. In case of a regular form of resection cavity and anticipated total removal, irradiation of a tumor bed was carried out at a distance of 1 cm from the walls of this cavity with scanning movements of a light guide. If the cavity under discussion had an irregular and asymmetric form with "pockets" and excavations, an irradiation zone was divided into several segments and a light guide was applied to several equidistant points in turn. Such an approach allowed to obtain uniform distribution of an irradiation dose against a background of reducing total time of the procedure.

Considerable perivascular growth of tumor cells and marked infiltration of the cortex zones, located at some distance from the main node (Figure), made neurosurgeons give up an idea of resecting areas of neoplastic infiltration due to a high risk of invalidism.

A new method of treatment of malignant cerebral tumors with multi-focal growth was elaborated and tested in the Department of Surgery of Cerebral and Spinal Tumors of the Polenov Research Institute (Priority Certificate N 2002131368 of November 11, 2002). Its essence is as follows: a tumor bed is irradiated by a scattered laser beam, then it is focused and staged irradiation of small cortical neoplastic areas (including perivascular ones), located at some distance from the main node, is carried out. It allows to achieve greater reduction of neoplastic cells and to avoid additional operative damage of the brain substance.

A Postoperative Period

A subsequent stage of treatment in a group of patients with primary differentiated and anaplastic glial tumors included remote gamma-therapy with a total dose of 50-60 Grey, which started on the 15-25th day after operation. Irradiation was not used in cases with prolonged growth of gliomas, who had already undergone a course of radiation therapy after the first operation.

All patients were subject to polychemotherapy with nitrozourea derivatives in compliance with a scheme of combined treatment, adopted in the above Department.

MRI or CT examination with use of a contrast substance was carried out on the 10-17th postoperative day and 2 months after radiation therapy.

A course of the nearest postoperative period was estimated with taking into account dynamics of cerebral and focal neurologic symptoms, complication development, side effects. Remote results were analyzed with assessment of duration of a relapse-free period and a patient's state on the basis of Karnofski's scale.

Results

A Postoperative Period

A postoperative period was favorable in all 14 cases. There were no complications. Persistent augmentation of neurologic symptoms, which started on the 4th day of operation, was observed in 1 patient with primary glioblastoma. It was caused by hemorrhage into residual neoplastic tissue. Transitory increase of temperature up to 38-38.8o was watched in 7 patients on the 3-7th postoperative day. Infectious complications were absent. One should take into account, that a photosensitizer is prone to selective accumulation not only in neoplastic tissue, but also in dermal and retinal cells, persisting there for a long time; thus, skin photosensitization in an early postoperative period, leading to development of dermal erythema and thermal injury of retina can become one of the possible side effects of photodynamic treatment. We did not observe such complications, as well as a response of parenchymal organs to PDT in our study. However, all our patients were recommended to avoid direct sunlight during 3-4 days.

Remote Results

As for patients with primary gliomas, duration of a long-term follow-up in 2 male and 1 female patients with anaplastic astrocytomas was equal to 27 and 20 months respectively. Today they have no prolonged growth of tumor. A relapse-free period in a patient with fibrillar astrocytoma lasted 24 months. Three out of four patients with primary glioblastomas are alive (a follow-up of 7 months). They are in a compensated state and there are no symptoms of prolonged growth. Total removal of multiform glioblastoma was performed in 1 female; she underwent a course of PDT and polychemotherapy. However, we observed prolonged growth in a month after operation and PDT. Data on cases with primary gliomas are given in Table 1.

Table 1

Photodynamic Treatment of Patients with Primary Glial Tumors: Results

Results ®
Histo-Structure ¯

A relapse-free period
(months)

Fibrillar astrocytoma

23

Anaplastic astrocytoma

20 *

Anaplastic astrocytoma

27 *

Anaplastic astrocytoma

27 *

Glioblastoma

7 *

Glioblastoma

7 *

Glioblastoma

7 *

Glioblastoma

1

* - At present there are no data, indicative of prolonged growth.

Results of surgical interventions and PDT in patients with prolonged growth of glial tumors are presented in Table 2. It is known, that every new recurrence of malignant glioma shortens duration of a relapse-free period. PDT allowed to extend it in 3 out of 7 cases with prolonged growth of malignant gliomas (Table 2).

Table 2

Photodynamic Treatment of Patients with Prolonged Growth of Glial Tumors: Results

Results ®
Histo-Structure ¯

A relapse-free period
(months)

Oligoastrocytoma

13

Glioblastoma

18

Glioblastoma

2

Glioblastoma

3

Glioblastoma

5

Glioblastoma

4 *

Glioblastoma

1 *

* - At present there are no data, indicative of prolonged growth.

One patient with prolonged growth of glioblastoma was admitted to our Department in 2 months after its repeated removal and use of PDT. A multifocal growth and nodes, located at some distance from a primary focus, were revealed. Our follow-up of 2 patients with prolonged growth is still being continued. At present its duration is equal to 1 and 4 months respectively.

Discussion

Today there are many articles, which describe results of clinical trials, devoted to use and efficacy of PDT in neurooncology [4, 5, 6, 7, 8, 9, 11, 15, 16, 18 27]. However, comparative analysis is a difficult task due to heterogeneity and scantiness of groups of patients, use of different photosensitizers, variety of prescribed doses of both drugs and light. Table 3 reflects the results of PDT use in neurooncology, which have been obtained in foreign clinics and research centers.

Table 3

Remote Results (Data of Literature)

Authors

Histostructure

Results

Perria et al.
1980

3 glioblastomas;
1 sarcoma.

Life duration of 6-44 weeks. One fatal outcome at an early stage, caused by pneumonia.

Kaye et al.
1987

19 glioblastomas;
3 astrocytomas.

Life duration of 1-16 months (13 patients). No signs of prolonged growth.

Muller and Wilson
1987

16 glioblastomas;
13 astrocytomas.

A relapse-free period of more than 26 months (36% of cases).

Kostron et al.
1987

16 glioblastomas.

Life duration of up to 12 months (6 cases).

Perria et al.
1988

1 metastasis;
2 glioblastomas;
3 astrocytomas;
2 oligodendrogliomas.

No signs of prolonged growth in CT examination, carried out in 9 months (6 cases).

Kostron et al.
1988

1 metastasis;
18 glioblastomas.

Life duration of 22 months in 6 cases with glioblastomas.

Pouer et al.
1991

1 metastasis;
4 anapl. astrocytomas;
1 gliosarcoma;
1 glioblastoma (prolonged growth).

A relapse-free period: 45, 35, 8 and 6 weeks in 4 cases with anapl. astrocytoma; 27 weeks in a patient with glioblastoma; 2 weeks in a patient with gliosarcoma.

Muller and Wilson
1995

56 gliomas (prolonged growth).

Mean life duration in cases with prolonged growth of glioblastomas and anaplastic astrocytomas - 30 weeks and 44 weeks respectively.

Popovic et al.
1995

78 glioblastomas;
24 anapl. astrocytomas;
7 astrocytomas.

Mean life duration in 38cases with glioblastomas and 40 cases with their prolonged growth - 24 months (105 weeks) and 9 months respectively, in 24 cases with anaplastic astrocytomas - more than 20 months, 7 patients with astrocytomas are alive.

Muller and Wilson
2000

32 glioblastomas;
14 anapl. astrocytomas;
6 mixed malig. gliomas;
4 ependymomas.

Mean life duration: glioblastomas - 31 weeks, anaplastic astrocytomas - 50 weeks, mixed malignant gliomas - more than 64 weeks, enedymomas - more than 61 weeks.

The research in the above medical establishments was based on use of hematoporphirin derivative (HpD) and its own derivative, known as photofrin. A complex and heterogeneous composition of HpD, presence of a great number of active components in it hamper identification of specific molecules from the point of view of their individual activity and effect zone. Besides, it impedes correction of necessary doses. Other important shortcomings of HpD and photofrin include insufficient selectivity, long-term persistence (in particular, it concerns skin) and maximum absorption of light with a wavelength of 400 nm by them, whereas adequate penetration through biological tissues is possible only in irradiation within the range of 650-800 nm [2, 3, 11, 12, 17, 23, 24].

An ideal photosensitizer for PDT of intracerebral tumors is to meet the following demands:

  1. it should be a single fraction, capable of selective accumulation within neoplastic tissue;
  2. it should have an ability to penetrate through the intact blood-brain barrier and to reside in infiltrative neoplastic tissue without accumulation in normal brain;
  3. it should have a maximum cytotoxic effect on tumor cells and a minimum effect on adjacent intact cerebral tissue;
  4. it should be characterized by maximum absorption of light within the range of 650-800 nm;
  5. it should have no toxic effect and be excreted from tissues and especially from the skin very quickly.

Development of new and more perfect photosensitizers has been carried out since 1980. The main groups are respresented by modified porphyrins, chlorins and phthalocyanins [12, 17]. It should be noted, that the preparation of the E6 chlorin group, used by us, has several advantages. First of all, it possesses maximum absorption of light at a wavelength of 660 nm. Besides, the preparation is retained within the body during not more than 2 days. As it has been mentioned above, this allowed to reduce a number of complications, caused by the preparation persistence.

The majority of our patients took corticosteroids during several days. It was done with the purpose of reducing intracranial pressure and stabilizing a neurologic state before operation. There is a theoretical supposition, according to which steroid drugs can decrease an ability of neoplastic cerebral cells to capture a photosensitizer because of their effect on tumor microcirculation [11, 14]. However, Kaye A.H. [4, 5], who measured uptake of a certain preparation with the help of fluorescence methods, failed to reveal a marked effect of steroids on intracellular concentration of the photosensitizer. Today we are engaged in analyzing efficacy of photodynamic treatment in different groups of patients and its dependence on peculiarities of preoperative drug therapy.

In spite of numerous experimental and clinical studies, a mechanism of PDT action and potentialities of its clinical use are still unclear. The future of the method is closely connected with new achievements of physics and pharmacology, use of improved photosensitizers and laser devices, development of new modifications of PDT, which will be able to effect a regional vascular bed in a tumor zone and to be combined with neutron therapy.

Conclusion

The present article is devoted to description of our first experience of using photodynamic treatment, carried out with a new photosensitizer of the E6 chlorin group. Scantiness of the group of patients does not allow to come to a final conclusion about efficacy of our method. Nevertheless, the obtained results demonstrate, that PDT, characterized by an admissible risk, can be used in neurooncologic patients.

Expediency of wider introduction and further development of methods of photodynamic therapy are conditioned by a principal difference between a photodynamic mechanism of destruction of neoplastic cells and mechanisms of radiation and chemotherapy [13]. Thus, PDT can supplement a standard complex scheme of glioma treatment and raise its efficacy.

At present employees of the Department of Surgery of Cerebral and Spinal Tumors continue their work at studying the preparation pharmacodynamics in the brain, selection of appropriate doses and correction of radiation methods, estimation of both local and systemic effects of PDT on the body's immunological status.

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