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11. Photodynamic Therapy for Skin Cancer with Minimized Light Doses and
Minimized Doses of Chlorin Derivatives Photosensitizers


A.A.Radaev, E.Ph.Stranadko


Introduction

Skin cancer is the most wide-spread type of malignant neoplasm among the world population with high and increasing incidence rates. Photodynamic therapy (PDT) is a relatively new and quick-developing medical technology. At present PDT is one of the alternative methods of skin cancer treatment which provides a high degree recovery and excellent cosmetic results. However sometimes for the advanced skin cancer patients even PDT doesnt yield a 100 % therapeutic effect. The big variability is a distinguishing particularity of PDT. This particularity proved to be a very useful, because it allows to use PDT effectively in oncology for various localizations, stages, and histological structure of malignant tumors.


Aim of the work

For reduction of the undesirable PDT side effects, prevention of complications and reduction of the treatment cost, we pursued a goal to develop the optimized PDT protocol with minimized doses of chlorin e6 derivatives and minimized light doses.


Materials and methods

The analysis of PDT efficacy for skin cancer patients has been carried out concerning traditional and minimized doses of photosensitizers and light. For the work we used the second generation photosensitizers, namely chlorin e6 derivatives Radachlorin (the Rada-Pharma Co. Ltd., Russia) and Photolon (the firm Belmedpreparaty, Belorussia). By comparison with the first generation photosensitizers (Photofrin II, Photohem, Photosun, HpD) they have a variety of advantages, namely greater absorption peak (662 nm vs 630 nm), greater tumor/normal tissue ratio (10-15 vs 1.5-2.0) that defines a tumor-targeting accumulation, and greater quantum yield of singlet oxygen production. As a standard dose of Radachlorin we considered the doses in the range of 0.7 1.0 mg/kg, as regards Photolon the standard dose was 2.0 mg/kg. The standard values of energy density were 200 300 J/cm2 under power density in the range of 100 400 mW/cm2.

The work is based on the data for 104 skin cancer patients with basal-cell carcinoma, metatypical and squamous-cell carcinoma. Age of the patients was in the range of 41 85 years old. Middle age of the patients was 69.4 years old. There were 104 patients (200 lesions) in total. Among them the Radachlorin based PDT has been carried out for 83 patients (159 lesions), the Photolon based PDT has been carried out for 21 patients (51 lesions). The minimized doses of Photolon (Table 1) and Radachlorin (Table 2) have been used for 13 patients.


Table 1. Patient distribution depending on minimized dose of Photolon

Minimized dose (mg/kg)

Total

1.5

1.3

1.2

1

3

4

8


Table 2. Patient distribution depending on minimized dose of Radachlorin

Minimized dose (mg/kg)

Total

0.6

0.5

2

3

5


For these patients we used minimized values of power density (Table 3) and energy density (Table 4).


Table 3. Patient distribution depending on value of minimized power density


Photosensitizer


Power density (W/cm2)

Total

0.017

0.035

0.048

0.054

Photolon

2

1

3

2

8

Radachlorin

-

1

3

1

5

TOTAL

2

2

6

3

13


Table 4. Patient distribution depending on value of minimized energy density


Photosensitizer


Energy density (J/cm2)

Total

40

50

65

85

100

150

Photolon

3

3

-

-

1

1

8

Radachlorin

-

1

1

2

1

-

5

TOTAL

3

4

1

2

2

1

13


Duration of the patient observation for the both groups is represented in Table 5 and Table 6.


Table 5. Patient distribution depending on duration of the observation after PDT
with power density of 0.2
0.4 W/cm2 and energy density of 200300 J/cm2

Photosensitizer

Duration of the observation (months)

Total

23

36

69

912

1218

1824

Photolon

1

2

2

1

6

1

13

Radachlorin

8

26

11

11

22

-

78

TOTAL

9

28

13

12

28

1

91


Table 6. Patient distribution depending on duration of the observation after PDT with minimized power density and energy density

Photosensitizer

Duration of the observation (months)

Total

2 3

3 - 6

6 - 9

Photolon

2

6

-

8

Radachlorin

-

3

2

5

TOTAL

2

9

2

13


Results

Results of the treatment were assessed according to the following parameters:

  1. COMPLETE RESORPTION (CR) was stated when there was no visual and palpated lesion confirmed by negative results of the hystological or cytological examination.
  2. PARTIAL RESORPTION (PR) was stated when reduction of maximal size of the malignant node was by 50 %, as well as when there was visual absence of a tumor, but malignant cells were revealed by morphological investigations (in such a way some recurrences after PDT were found).
  3. Tumor reduction by less than half size or tumor status without changes was considered as NO RESPONSE (NR).

PDT efficacy with standard values of power density and energy density is represented in Table 7 and PDT efficacy with minimized doses of photosensitizers, power and energy density is represented in Table 8.


Table 7. PDT results with power density of 0.20.4 W/cm2 and energy density of 200300 J/cm2

Photosensitizer

PDT results

CR

PR

Total

Photolon

12 (92.3 %)

1 (7.7 %)

13 (100 %)

Radachlorin

75 (96.2 %)

3 (3.8 %)

78 (100 %)

TOTAL

87 (95.6 %)

4 (4.4 %)

91 (100 %)

CR - complete resorption; PR - partial resorption


Table 8. PDT results with minimized values of power density and energy density

Photosensitizer

PDT results

CR

PR

Total

Photolon

7 (87.5 %)

1 (12.5 %)

8 (100 %)

Radachlorin

5 (100 %)

-

5 (100 %)

TOTAL

12 (92.3 %)

1 (7.7 %)

13 (100 %)

CR - complete resorption; PR - partial resorption


It follows from these tables that CR frequencies almost coincide for the both groups in spite of significant reduction for doses of photosensitizers, power and energy density for the second group.


Discussion

In Russia during the last 10 years the second generation photosensitizers, namely chlorin e6 derivatives Photoditazine, Radachlorin, and Photolon are used for PDT. By comparison with the first generation photosensitizers (Photofrin II, Photohem, Photosun, HpD) they have a variety of advantages, namely greater absorption peak (662 nm vs 630 nm), greater tumor/normal tissue ratio (10-15 vs 1.5-2.0) that defines a tumor-targeting accumulation, and greater quantum yield of singlet oxygen production.

The big variability is a distinguishing particularity of PDT. This particularity proved to be a very useful, because it allows to use PDT effectively in oncology for various localizations, stages, and histological structure of malignant tumors. Changing physicochemical parameters of PDT (drug type, drug dose, drug-light interval, power density, power energy) we have developed the optimized PDT protocol.

In the work we used the standard doses of Radachlorin in the range of 0.7 1.0 mg/kg and Photolon of 2.0 mg/kg in combination with the standard values of energy density in the range of 200 300 J/cm2 and power density in the range of 100 400 mW/cm2. These PDT parameters allow to destroy a tumor, but in consequence of PDT a significant reactions of surrounding healthy tissues are going on. This process is being accompanied by a long period of the defect tissue healing in a tumor necrosis area.

Chlorin derivatives photosensitizers have a high tumor/normal tissue ratio and are accumulated mainly in tumor tissue by comparison with surrounding normal tissues, therefore these reduced drug doses are fully sufficient for tumor destruction. Significant reduction of their concentration in normal tissues allows to prevent changes of healthy tissues, up to hardly noticeable residual reactions and reversible changes. Reducing simultaneously light power density up to 0.02 - 0.05 W/cm2 and light dose up to 50 J/cm2, owing to a high tumor-targeting accumulation we have been able to keep a high efficiency of PDT for skin cancer.

The PDT protocol with minimized doses of photosensitizers, power and energy density allowed: to keep a high treatment efficacy; to avoid side effects and complications; and to short time for the healing of soft tissue defect after PDT.




Conclusion

PDT for skin cancer is a comfortable and effective method which provides good functional and cosmetic results. Usage of the optimized PDT protocol with photosensitizers from the group of chlorin e6 derivatives provides high efficacy of PDT and allows to avoid side effects. Minimized doses of chlorin e6  derivatives photosensitizers and minimized light doses allow to avoid rough destructive changes of tissues because of PDT. It allows to destroy skin tumor completely and to keep surrounding normal tissues as non-damaged ones in irradiation area. As a result, in 92.3 % cases one has been registered out a complete tumor resorption and time reduction for the healing of soft tissue defect after tumor destruction.



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