Continuous Low-Dose-Rate Radiation of Radionuclide Phosphorus-32 for Hemangiomas

Abstract

The study goal was to clarify the therapeutic effect and the absorbed dose of radionuclide phosphorus-32 for skin hemangiomas and the consequent risk of side effects in these patients. Phosphorus-32 is an β emitter and is used for skin hemangioma treatment. In comparison with the few Gy per minute of the linear accelerators, the dose rate of phosphorus-32 for hemangiomas is much <1 Gy/hour; so, the latter is called low-dose-rate radiation. To achieve the therapeutic dose, continuous hours or days of radiation is necessary. For strawberry hemangiomas, the phosphorus-32 applicator was tightly placed on the lesion site for several hours until reaching therapeutic dose. The absorbed dose was estimated by radiochromic films. The absorbed dose of phosphorus-32 irradiation declined exponentially with a depth from 0 to 2.5 mm. Of the 316 patients with strawberry hemangiomas, the lesion disappeared completely within 3 months after one-time treatment in 259 cases (82%). For cavernous hemangiomas, 370KBq phosphorus-32 colloid was injected into the hemangioma each square centimeter, and the absorbed radiation was estimated by theoretical calculation. Forty-two of the 58 patients with cavernous hemangiomas (72%) had lesions that completely disappeared within 3 months after receiving one to six treatments. Thus, the phosphorus-32 for strawberry hemangiomas and the chromium phosphate-32 colloid for cavernous hemangiomas were clearly efficacious.

Introduction

The hemangioma is the most common benign, vascular proliferative tumor.^1,2 Most hemangiomas have natural phases of proliferation (growth) and involution (dissolution) and are frequently left untreated.³ However, problematic hemangiomas occur when they ulcerate, have massive growth, cause disfigurement, or impact normal function or cosmetic development.⁴ The treatment of these problematic hemangiomas should be considered.

Current treatment options for problematic hemangiomas include systemic or intralesional corticosteroids, chemotherapeutic agents (vincristine, pingyangmycin, and α-interferon),^5,6 laser surgery,^7,8 surgery,^9,10 cryosurgery,¹¹ retaining copper needles, high-frequency electrocoagulation, and superficial X-ray. Each treatment method has its advantages and disadvantages.

The applied radiation of the radionuclide phosphorus-32 is an effective and convenient method for hemangioma treatment,¹² especially with the radiation applicator of phosphorus-32 for strawberry hemangiomas and Colloid Chromium Phosphate (phosphorus-32) internal irradiation for cavernous hemangiomas.^12
–14 Since the therapeutic effects of skin application and consequently adverse events are closely related to absorbed dose of phosphorus-32, quantitative analyses of absorbed dose of phosphorus-32 for hemangioma treatment should be required.

Materials and Methods

Preparation of the simply phosphorus-32 applicator

For radiation dose verification, the filter paper (WHATMAN GRADE 589/1) was cut 1.1×1.2 cm², and 4.14 MBq radionuclide phosphorus-32 solution (Beijing Atom HighTech Co., Ltd.) was dripped on. After drying, the filter was sealed by plastic tape (thickness of plastic tape is 0.08 mm).

For strawberry hemangioma, the filter paper was cut into the shape of the lesions. According to 3.7 MBq phosphorus-32 solution/cm², the phosphorus-32 was dripped on. After drying, the filter was sealed by plastic tape.^14,15

The activity of phosphorus-32 on filter was determined on intensity of radioactivity by the manufacturers (Beijing Atom HighTech Co., Ltd.), and the dose calibrator was used as a reference.

The radiochromic films verification of phosphorus-32 applicator external irradiation

GAFCHROMIC^® EBT (external beam therapy) dosimetry film has been used in this radiotherapy study. The dose range of ISP (International Specialty Products) radiochromic film is 1–800 cGy and energy independent from the keV range into the MeV range. It is made by laminating two film coatings, each having an active layer ∼17 μm thick and a surface layer ∼3 μm thick. Transmission densitometers measuring are suitable for measuring EBT film, which can be read using a film scanner.

The radiochromic films (GAFCHROMIC EBT) were exposed to a linear accelerator (ELEKTA 1239) by a 4 MV electron beam every 25 cGy from 25 to 575 cGy. Each film was scanned by a film scanner (EPSON EXPRESSION 1680). The standard curve for the radiation dose and gray scale film was established using dose analysis software (PROCHECK).

There were 20 pieces of overlapping radiochromic films. The film thickness was 0.225 mm, measured using a vernier caliper. The total thickness of all 20 pieces of film was 4.5 mm. The radiation applicator of P-32 was placed on the top, irradiation occurred for 30 minutes, and the radiation dose of the 20-films were determined by a standard curve. According to the thickness of the film and radiation dose, the relationship between radiation dose and distance was obtained.

The calculation of absorbed dose of phosphorus-32 for hemangiomas

Samei et al. (1996) gave the phosphorus-32 depth-dose distributions in lithium fluoride and soft tissue by EGS4. The dose percent (%) was reduced in depth (mm) by exponential decay. The dose was reduced ∼1/10 from 0.5 mm to 2.5 mm in lithium fluoride and from 0.5 mm to 5 mm in soft tissue.¹⁵

Park et al. (2008) gave the phosphorus-32 depth-dose distributions for reducing the recurrence rate after pterygium excision by MCNP5. The surface absorbed dose of phosphorus-32 applicator was 0.025 Gy/MBq/hour with aluminum foils encased and 0.315 Gy/MBq/hour with medical plastic encased, and the dose rate was reduced into ∼1/10 in 2 mm depth.¹⁶

There were three steps required for estimation of the absorbed dose of the internal radiation after phosphorus-32 colloid hemangioma-injections. First, the source and target regions of a representative dosimetric model should be defined. Second, the activity as a function of time in source regions was quantified. Third, calculations of phosphorus-32 were made for the source-target region. The calculation was considered by direct Monte–Carlo radiation transport, dose point-kernel methods, or precalculated voxel S-values.¹⁷

It is assumed that all energy of phosphorus-32 is deposited in hemangiomas, the absorbed dose rate is 0.417 Gy/MBq/g/hour, and the total absorbed dose is 197 Gy/MBq/g.¹⁷

The Committee on Medical Internal Radiation Dose (MIRD) has developed many standard methods, models, and assumptions for assessing internal radiation dose for administered radiopharmaceuticals. In 1999, the method of S value (absorbed fractions) for phosphorus-32 within cubical voxels of 3 mm and 6 mm edge were used to construct three-dimensional dose calculations. The voxels model of anatomical structure is based on computer tomography (CT), and the voxels model of accumulated activity is based on single photon emission computer tomography (SPECT). Thus, the absorbed dose of the region of interest is estimated based on the phosphorus-32 S values (absorbed fractions). The voxels is defined as the calculation of radiation absorbed dose to tissue regions with dimensions of 6 mm edge. Thus, the absorbed dose for the source voxel itself is 1.14 Gy/MBq/hour, and the voxels irradiating its nearest neighboring voxel (center-to-center distance of 6 mm) are 0.09 Gy/MBq/hour.¹⁷

The application of phosphorus-32 for hemangiomas

The protocol was approved by the Ethics Committee of the Shaanxi Cancer Hospital.

For dose verification, the phosphorus-32 applicator (activity of 4.14 MBq and area of 1.1×1.2 cm²) was placed tightly on radiochromic film for 0.5 hour.

For strawberry hemangiomas, the phosphorus-32 applicator (activity according to 3.7 MBq/cm² and shape according to the lesion shape) was placed tightly on the lesion for 10 hours. The treatment and side effects were evaluated following one-time treatment within a month.

For cavernous hemangiomas, the phosphorus-32 colloid was injected into hemangiomas according to 0.37 MBq/cm². Type-B ultrasonic examination was used to evaluate treatment effects after 1 month. If the hemangiomas shrank but did not disappear completely, another treatment was chosen. The largest number of treatments in this study was six.

Characteristics of patients and the therapeutic effect and side effect

All of the 316 strawberry hemangioma outpatients from January 2000 to January 2007 were included in the study. All of their parents were informed of the radiation therapy, including the uncertainty risk of cancer development in the future. Each voluntarily accepted the therapy. The characteristics of patients and the therapeutic effects are shown in Table 1, which were classified into the following two categories: cured and improved. The characteristics of patients and side effects are shown in Table 2. The side effects included pigmentation, pigment loss, and radiation burning. The relationship between the characteristics of hemangiomas and treatment effects was statistically analyzed. The relationship between the characteristics of hemangiomas and side effects was also statistically analyzed.

Table 1.

Effects of Phosphorus-32 Treatment in 316 Strawberry Hemangioma Patients

		Treatment effect
Parameter Demographics		Cured		Improved
Age (years)	n	n	%	n	%
<6 month	186	154	82.8	32	17.2
6–12 month	112	91	81.3	21	18.7
>1 year	18	14	77.8	4	22.2
Gender
Male	93	75	80.6	18	19.4
Female	223	184	82.5	39	17.5
Hemangioma characteristics
Location
Head and neck	209	169	80.9	40	19.1
Chest and back	75	64	85.3	11	14.7
Limbs	32	26	81.3	6	18.7
Size
<4 cm²	83	77	92.8	6	7.2
4–16 cm²	171	148	86.5	23	13.5
>16 cm²	62	35	56.5	27	43.5

Table 2.

Adverse Events Manifested in 58 Strawberry Hemangioma Patients

		Side effect
Parameter Demographics		Pigmentation		Pigment loss		Burning
Age (years)	n	n	%	n	%	n	%
<6 month	186	29	15.6	14	7.5	5	2.7
6–12 month	112	17	15.2	7	6.3	4	3.6
>1 year	18	4	22	2	11.1	0	0
Gender
Male	93	13	14	9	69.2	2	2.2
Female	223	37	16.6	14	37.8	7	3.1
Hemangioma characteristics
Location
Head and neck	209	32	15.3	11	5.3	6	2.9
Chest and back	75	12	16	9	12	3	4
Limbs	32	6	18.8	3	9.4	0	0
Size
<4 cm²	83	6	7.2	1	1.2	0	0
4–16 cm²	171	28	16.4	12	7	4	2.3
>16 cm²	62	16	25.8	10	16.1	5	8.1

All of the 58 cavernous hemangioma outpatients from January 2000 to January 2007 were included in the study. Each of them or their parents was informed about the radiation therapy, including the uncertainty risk of cancer development in the future. All of the patients voluntarily accepted the therapy. The characteristics of the patients and the therapeutic effect are shown in Table 3. The characteristics of patients and side effects are shown in Table 4.

Table 3.

Effects of Phosphorus-32 Treatment in Cavernous Hemangioma Patients

		Treatment effect
Parameter Demographics		Cured		Improved
Age (years)	n	n	%	n	%
<1 year	15	11	73.3	4	26.7
1–8 years	12	8	66.7	4	33.3
9–20 years	18	13	72.2	5	27.8
>20 years	13	10	76.9	3	23.1
Gender
Male	21	16	76.2	5	23.8
Female	37	26	70.3	11	29.7
Hemangioma characteristics
Location
Head and neck	29	21	72.4	8	27.6
Chest and back	15	11	73.3	4	26.7
Limbs	14	10	71.4	4	28.6
Size
<4 cm²	8	8	100	0	0
4–16 cm²	43	30	69.8	13	30.2
>16 cm²	7	4	57.1	3	42.9

Table 4.

Adverse Events Manifested in Cavernous Hemangioma Patients

		Side effect
Parameter Demographics		Pigmentation		Pigment loss		Burning
Age (years)	n	n	%	n	%	n	%
<1 year	15	3	20	2	13.3	1	6.7
1–8 years	12	2	16.7	2	16.7	2	17
9–20 years	18	5	27.8	3	16.7	2	11
>20 years	13	3	23.1	2	15.4	1	7.7
Gender
Male	21	5	23.8	4	19	2	9.5
Female	37	9	24.3	5	13.5	4	11
Hemangioma characteristics
Location
Head and neck	29	6	20.7	5	17.2	2	6.9
Chest and back	15	3	20	2	13.3	3	20
Limbs	14	4	28.6	2	14.3	1	7.1
Size
<4 cm²	8	1	12.5	0	0	0	0
4–16 cm²	43	8	18.6	6	14	4	9.3
>16 cm²	7	4	57.1	3	42.9	2	29

Statistical analyses was performed using chi-square tests for differences in age, gender, hemangioma location, hemangioma size on treatment effect, and side effect (pigmentation, pigment loss, and burning). All statistical analyses were performed using SPSS software, version 13.0 (SPSS, Inc.). Statistical significance was defined as p<0.05.

Results

The radiochromic films verification of phosphorus-32 external irradiation

The 4.14 MBq phosphorus-32 applicator of the 1.1×1.2 cm² area irradiated a stack of 20 stack of radiochromic films for 0.5 hours. The absorbed dose of every film was measured using dose analysis software (PROCHECK). The absorbed dose of the No. 1 film, the nearest film to the radiation applicator that reflects the surface absorbed dose of applicator, was 2.65 Gy. The absorbed dose rate of the No. 1 film was 0.969 Gy/hour/MBq/cm² according to the area and time. After the radiation was counted in each film of sheets, the absorbed dose rate was determined as shown in Table 5. The dose rate decreased with depth from the surface (Table 5).

Table 5.

Depth Distribution for Absorbed Dose of the Phosphorus-32 Radiation

No. films ^a	Distance (mm)	Absorbed dose (Gy)	Dose rate (Gy/hour/MBq/cm²)	Percent change (%)
1	0	2.65	0.969	100
2	0.225	1.75	0.640	66
3	0.45	1.20	0.439	45.3
4	0.675	0.98	0.358	37
5	0.9	0.68	0.248	25.7
6	1.125	0.55	0.201	20.8
7	1.35	0.39	0.142	14.7
8	1.575	0.25	0.091	9.4
9	1.8	0.19	0.069	7.2
10	2.025	0.16	0.058	6
11	2.25	0.12	0.043	4.5
12	2.475	0.05	0.018	1.9

Radiochromic films were overlapped, and the radiation applicator of P-32 was placed on the top. No. 1 is the nearest film to the radiation applicator, and No. 2–12 films were placed in the order of depth.

The treatment for strawberry hemangiomas by phosphorus-32 external irradiation

Of the 316 patients, there were 259 cases (82%) whose strawberry hemangiomas disappeared completely in 3 months after treatment, while the rest of the 57 cases (18%) showed that the hemangioma size was reduced. No cases were found where strawberry hemangiomas continued to grow after treatment.

The chi-square values were 0.339, 0.168, 0.758, and 36.769 in strawberry hemangioma treatment effects of different age (<6 month, 6–12 month, >1 year), gender (male, female), hemangioma location (head and neck, chest and back, limbs), and hemangioma size (<4 cm², 4–16 cm², >16 cm²) (Table 1). There were no statistical differences in treatment effects by age, gender, and hemangioma location (p>0.05). There were statistically significant differences in the treatment effects of hemangioma size (p<0.05).

The status of strawberry hemangiomas with pigmentation, pigment loss, and burning as adverse events was examined and statistically analyzed with regard to ages of the patients, gender, site/location of lesion, and size of lesion. Chi-square values of pigmentation, pigment loss, and burning were 0.595, 0.584, and 0.651, respectively, in strawberry hemangiomas after phosphorus-32 applicator treatment of various age groups, and there were no statistically significant differences (p>0.05). Chi-square values were 0.336, 1.123, and 0.442 of different genders and were 0.248, 3.943, and1.239 of different locations, with no significant differences (p>0.05). Chi-square values were 9.281, 11.751, and 7.602 of side effects in different groups of the size of hemangioma area, and there were statistically significant differences (p<0.05).

The treatment for cavernous hemangiomas by P-32 colloid internal irradiation

Of the 58 patients, there were 42 cases (72%) whose cavernous hemangiomas disappeared completely within 3 months after treatment. Significant reductions in hemangiomas were found in 16 cases (28%). Figure 1A shows a 6-month-old girl with a 5×6 cm cavernous hemangioma on the head that disappeared after four treatments as shown in Figure 1B.

FIG. 1.

(A) A 6-month-old girl with a 5×6 cm cavernous hemangioma on the head. (B) The hemangioma disappeared after four treatments.

The chi-square values were 0.075, 0.235, 0.013, and 4.015 in cavernous hemangioma treatment effects of different ages (<1 year, 1–8 years, 9–20 years, >20 years), gender (male, female), hemangioma location (head and neck, chest and back, limbs), and hemangioma size (<4 cm², 4–16 cm², >16 cm²) (Table 3). There were no significant differences of treatment effects between age, gender, and hemangioma location (p>0.05). There were statistically significant differences between treatment effects and hemangioma size (p<0.05).

The chi-square values of pigmentation, pigment loss, and burning were 0.579, 0.084, and 0.845, respectively, in cavernous hemangiomas after phosphorus-32 colloid interstitial injection of various ages; were 0.001, 0.312, and 0.023 of various genders; were 0.405, 0.136, and 2.034 of different locations; and were 5.665, 5.541, and 3.481 of different sizes. There were no significant differences (p>0.05).

Discussion

Although phosphorus-32 has been used for hemangiomas for decades, calculating the radiation absorbed dose was still based on clinical experience. The Monte–Carlo calculation is an available tool in clinical practice that evaluates radiation absorbed dose.¹⁸ Since the direct Monte-–Carlo calculation is computationally intensive, the dose point-kernel methods and pre-calculated voxel S-values are applied. Phosphorus-32 is a 100% β emitter for which the maximum β energy is 1.71 MeV and the maximum range in water or tissue is 7.5 mm.¹⁹ Since the dose rate was reduced to ∼1/10 as phosphorus-32 β penetrate every 2 mm depth in water or tissue,^15,16 it is hard to describe the change in phosphorus-32 dose rate in water using mini-ionization chambers. Usually, the dose rate referred point is measured by films such as the surface or 1 mm depth in water.^20,21 This study explored to describe a continued dose rate changing with depth. In the study, the surface absorbed dose of 4.14 MBq phosphorus-32 applicator of 1.32 cm² was 2.65 Gy in half hour, and the dose rate was 0.696 Gy/hour/MBq/cm². The penetration depth decayed exponentially, and the depth that reduced the dose rate ∼1/10 was 1.575 mm (Table 5).

There are three layers of skin—the epidermis, dermis, and subcutaneous tissue. The thickness of the epidermis varies with different types of skin from different areas, and is generally about 0.07–0.12 mm in thickness. The thickness of the dermis is also dependent on the location of the skin and is generally 1–2 mm thick. Capillaries are abundant in the dermis, leaving much room for strawberry hemangiomas to be formed. These parameters indicate that radiation should be exposed to the skin tissue at roughly 0.1–2 mm in depth. The films showed that the radiation depth was no >2.5 mm deep (Table 5). Therefore, the character for phosphorus-32 radiation is ideally fit for strawberry hemangiomas of 0.1–2 mm in depth of skin tissue.

In 316 patients, strawberry hemangiomas displayed no further growth after one treatment in all the cases, and the hemangiomas disappeared completely after treatment 259 cases (82%) (Table 1). Thus, the curative effect of localized radiation was affirmed.¹⁴ Adverse events manifested in 50 (15.8%), 23 (7.3%), and 9 (2.8%) patients with pigmentation, pigment loss, and burning, respectively. Both therapeutic effects and adverse events in response to localized radiation did not significantly differ in the various groups based on age, gender, and hemangioma location. However, there were significant differences in adverse events in various groups of hemangioma size. Therefore, patients with a large area of hemangioma should be considered for less radiation.

Cavernous hemangiomas cannot remain untreated. Although they are benign tumors, some patients with the disease can develop serious consequences, and necessary treatment should be conducted as soon as possible.

Phosphorus-32 colloid injection interstitial radiation is used as a method for cavernous hemangiomas.^{22

–29} The chromium phosphate colloid with a particle size between 20 and 50 nm is an inert material that could not be used in cellular metabolism. It cannot be absorbed by a vascular system directly and can be eliminated by lymphatic system slowly. After an interstitial injection, 60%–80% would stay in injection sites for a long time after radiation, and the others would be eliminated by the lymphatic system.²⁵ Thus, it was clearly demonstrated that phosphorus-32 and chromium phosphate-32 colloid were considerably efficacious for problematic strawberry hemangiomas (massive growth or disfigurement) and cavernous hemangiomas, respectively. In this study, we attempted to determine the absorbed dose rate of phosphorus-32 applicator in space and the absorbed dose calculation of phosphorus-32 colloid in tissues.

Footnotes

Acknowledgments

The authors would like to thank Medjaden Bioscience Limited for helpful review of the article.

Disclosure Statement

No competing financial conflicts exist.

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