Vloten WA van, Willemze R, Lange Vejlsgaard G, Thomsen K (eds): Cutaneous Lymphoma. CUIT Probl Dermatol. Basel, Karger, 1990, vol 19, pp 238-251
Electron Beam Irradiation for Cutaneous Lymphoma Theodore CM.
L01
Department of Radiotherapy, Lahey Clinic Medical Center, Burlington, Mass., USA
1 The author wishes to thank Dr. Ferdinand A. Salzman and Mr. Kenneth A. Wright for reviewing the manuscript and especially Mrs. Patricia L. Cronin for the data management for this paper.
Downloaded by: Université de Paris 193.51.85.197 - 1/24/2020 11:45:00 PM
Like lymphoma elsewhere in the body, cutaneous lymphoma is sensitive to ionization radiation. For the half century since the discovery of x-rays, superficial photon irradiation was the most effective palliative therapy for this disease. Scholtz [1] in 1902 was the first to describe the use of radiation in the treatment of cutaneous lymphoma. Limiting factors, however, included the unavailability of large field size, low dose rates, and the intolerance of deeper structures. In 1940, Trump et al. [2] first suggested electron beam irradiation in the treatment of superficial cutaneous malignancies. A major advance in radiotherapy for cutaneous lymphoma was the introduction of low megavolt electron beam therapy by our group in 1951 with the capability of wide-field irradiation, including whole body surface or total skin electron irradiation (TSEI) [3-6]. Today, TSEI remains one of the most effective treatment modalities for this disease [7]. The penetration of electron beam radiation can be restricted to the involved cutaneous tissue, minimizing radiation effects to underlying normal tissue. The biologic effects of megavolt electron beam irradiation are similar to those of x-ray irradiation [8].
Electron Beam Irradiation for Cutaneous Lymphoma
Well·collimated electron beam
monoenergetic
-ll _ ;
_
239
Tube extension from Van de Graaff accelerator
Aluminum cone
0.5-10 Gy/s
Fig. 1. TSEI technique using a Van de Graaff generator.
In cooperation with the Massachusetts Institute of Technology, we have used a Van de Graaff generator producing monoenergetic electron beam energies ranging from 1.5 to 3.5 MeV for wide-field therapy or TSEI in patients with widespread cutaneous disease since 1951 (fig. 1). The electron beam is directed vertically downward and collimated by a cone with a long narrow slit at the bottom, using low atomic number material and scattering foils at the exit window to improve uniformity across the width of the field. Patients are treated while in a horizontal position on a motorized couch, which is passed under the downward-directed electron beam for the treatment. Electron beam current is adjusted to deliver the specified dose with a single traverse of the couch for each treatment position. Treatment time for a traverse from head to foot is approximately 1 min. A modification of this treatment technique was later used at the National Institutes of Health (9]. Williams et aL (10] reported in 1979 a similar technique through adaptation of an established MEL SL75/10 accelerator. Several years after we began treating patients with TSEI, the Stanford group adapted their linear accelerator to TSEI therapy (11, 12]. During the past three decades, this
Downloaded by: Université de Paris 193.51.85.197 - 1/24/2020 11:45:00 PM
Methods and Techniques
240
Lo
•I
3m
2
I
Day 1
Day 3 R latlL fat '-----:::=::::-----
AP/PA
~
Day 2
lAOIRPO
\
I
\
I
~
te -
Day 4 RAO/ LPO
I
Fig. 2. TSEI technique using a linear accelerator. Fig. 3. Eight-field technique in TSEI.
Downloaded by: Université de Paris 193.51.85.197 - 1/24/2020 11:45:00 PM
3
Electron Beam Irradiation for Cutaneous Lymphoma
241
technique, or a modification of it, has become the most common technique used in radiotherapy for generalized cutaneous lymphoma [13-18]. The most important differences are that, with a standard linear accelerator, patients must be treated in an upright position and treatment time is long. The entire setup, however, is rather complex, limiting the availability of TSEI to only a few centers. A single horizontally directed beam does not produce adequate dose uniformity over the patient's skin surface, and most commonly, a combination of two angled beams is used (fig. 2) [9, 19-22]. Sewchand et al. [23] suggested a multiple-field pendulum-arc technique. In centers where only higher energy linear accelerators are available, an energy degrader is usually necessary. This degrader could be a Lucite or polyester screen [9]. Two other points need to be mentioned regarding improvement of dose uniformity over irradiated skin surface. First, TSEI in general has evolved from treating two fields (anterior and posterior) to treating four fields (adding two lateral fields) to treating six fields per cycle. The six fields are single anterior and two posterior oblique fields alternating with single posterior and two anterior oblique fields. We currently use the eightfield technique, treating two opposed fields per day, taking 4 treatment days to complete one cycle; our daily dose per field is 1.5 Gy (fig. 3,4) [24, 25]. A rotational technique has been suggested to optimize dose homogeneity [18, 26]. Second, for areas of the body not exposed to direct electron beam radiation, 'boosting' becomes necessary to ensure total skin therapy. With our technique using the Van de Graaff generator with the patient treated while lying down, these areas include the vertex of the scalp, axillae, and perineum. In patients treated in the standing position with a linear accelerator, the soles of the feet and inframammary regions also need to be boosted. The most common mode of boosting is by using soft x-rays from an orthovoltage machine, but many radiotherapists
Downloaded by: Université de Paris 193.51.85.197 - 1/24/2020 11:45:00 PM
Fig. 4. Film dosimetry in phantom with eight-field technique in TSEI.
Lo
242
today also use low megavolt electron beam radiation. The most common dose level is 20 Gy in 10 fractions. Decreased doses are given on purpose because of possible field overlap with TSEI. During TSEI, it is important to shield the lens of the eye to avoid development of radiation-induced cataracts. If uninvolved by tumor, eyebrows and nails are also protected.
Unlike with Hodgkin's disease, our experience revealed that, although a direct relationship exists between total radiation dose and tumor response or rate of induction of remission in TSEI for generalized cutaneous lymphoma, the correlation between radiation dose and probability of relapse-free survival was not seen. Prognosis is directly related to extent of skin and visceral involvement or stage of disease. For staging of cutaneous lymphoma, we modified the classification suggested by Bunn et al. [27] (table 1). Between 1951 and 1985, more than 1,000 patients were treated at the Lahey Clinic with TSEI. Our records show that 801 patients treated with electron beam therapy on the Van de Graaff generator had pathologically diagnosed cutaneous lymphoma. All positive pathologic reports read either 'mycosis fungoides' or 'lymphoma cutis', but we have no knowledge of how many of these patients had T-cell lymphoma. For analysis, 51 patients were excluded because of no follow-up or inadequate follow-up. Of the 750 patients evaluated, 692 had generalized cutaneous disease, and 58 had limited disease (stage I). There were 477 male patients with a median age of 59 years (range 17-93 years) and 273 female patients with a median age of 57 years (range 19-89 years). Minimum follow-up was 3 years. Almost all patients (90%) had topical treatment, such as steroid therapy, before electron beam irradiation. Of 692 patients who had generalized cutaneous disease, 57 patients had documented visceral metastases at presentation. Table 2 shows the distribution of types of lesions. Patients who had mixed lesions were grouped into the more advanced lesion stage. Six hundred seventy-three patients received TSEI, and 19 patients received only spot treatments for various reasons. Lymphoma ofthe skin is radiosensitive, and our initial treatment philosophy was to use the visual disappearance of cutaneous disease as a determinant for total dose. Most of our early patients were treated with
Downloaded by: Université de Paris 193.51.85.197 - 1/24/2020 11:45:00 PM
The Lahey Clinic Experience
Electron Beam Irradiation for Cutaneous Lymphoma
243
Table 1. Staging classification Stage II II III IV
Description limited cutaneous disease « 25 % of total body surface) generalized cutaneous disease lymph node involvement with any skin stage visceral involvement with any skin stage
Table 2. Cutaneous lymphoma treated (1951-1985) Disease
Patients, n
Limited disease (stage I) Generalized cutaneous disease Erythema Plaque Tumor
58 692
Total
750
this intention to a total dose of not more than 10 Gy, using TSEI mainly as a palliative measure. More recently, total dose has been increased to 24-30 Gy, depending on extent of disease and age of the patient. However, as doses approached 30 Gy, we found increasing severity of acute skin reactions, requiring interruption in the course of treatment in many of these patients. Tables 3 and 4 show the disease-free survival rates in terms of total dose and stage of disease, respectively. Although higher total dose appears to attain better disease-free survival initially, we did not see flattening of the survival curves after 5 years. Patients continued to show recurrence of disease, and at 10 years, disease-free survival was essentially the same: around 10% across the board. For different TSEI dose ranges, overall survival rates were virtually identical (fig. 5). Sixty-six patients died from intercurrent disease, and 18 patients had secondary visceral malignancies. Tables 5 and 6 show the number and percentage of patients who required a repeat course of electron beam therapy with either TSEI or spot treatment after an initial course of TSEI. At least half of the patients who
Downloaded by: Université de Paris 193.51.85.197 - 1/24/2020 11:45:00 PM
198 276 218
Lo
244
Table 3. Disease-free survival in terms of total skin electron irradiation dose
< 10 Gy (n At 5 years At 10 years
=
510)
77(15%) 41 (8%)
10-20 Gy (n
=
106) 20-30 Gy (n
21 (20%) 10 (9%)
=
38)
8 (21 %) 1 (3%)
Table 4. Disease-free survival after total skin electron irradiation
Plaque (n At 5 years At 10 years
=
270)
51 (19%) 25 (9%)
Erythema (n
=
193) Tumor (n
34 (18%) 18 (9%)
=
2 I 0)
22 (10%) 9 (4%)
Table 5. Further electron beam therapy given in terms of initial total skin electron irradiation dose
Initial dose, Gy
30
Patients, n
510 106 38 11
Treatment TSEI
Spot
271 (53%) 33 (31 %) 10 (26%)
46 (9%) 15 (14%) 10 (26%) 5(45%)
o
Table 6. Further electron beam therapy given after total skin electron irradiation in terms of initial stage of disease
Plaque Tumor Erythema
Patients, n
270 210 193
Treatment TSEI
Spot
145 (54%) 104 (50%) 73 (38%)
33 (12%) 31 (15%) 12 (6%) Downloaded by: Université de Paris 193.51.85.197 - 1/24/2020 11:45:00 PM
Stage of disease
245
Electron Beam Irradiation for Cutaneous Lymphoma
100 90
80 70
60 50 'iii 40 >
'2::s
30
§
20
I/)
E
~ 10L--r-,r-.--r-.--.--r--r-,--.--r-.--.--r-o
o
1
Years
2
3
4
5
6
7
8
--0-
Electron Beam Irradiation for Cutaneous Lymphoma Theodore CM.
L01
Department of Radiotherapy, Lahey Clinic Medical Center, Burlington, Mass., USA
1 The author wishes to thank Dr. Ferdinand A. Salzman and Mr. Kenneth A. Wright for reviewing the manuscript and especially Mrs. Patricia L. Cronin for the data management for this paper.
Downloaded by: Université de Paris 193.51.85.197 - 1/24/2020 11:45:00 PM
Like lymphoma elsewhere in the body, cutaneous lymphoma is sensitive to ionization radiation. For the half century since the discovery of x-rays, superficial photon irradiation was the most effective palliative therapy for this disease. Scholtz [1] in 1902 was the first to describe the use of radiation in the treatment of cutaneous lymphoma. Limiting factors, however, included the unavailability of large field size, low dose rates, and the intolerance of deeper structures. In 1940, Trump et al. [2] first suggested electron beam irradiation in the treatment of superficial cutaneous malignancies. A major advance in radiotherapy for cutaneous lymphoma was the introduction of low megavolt electron beam therapy by our group in 1951 with the capability of wide-field irradiation, including whole body surface or total skin electron irradiation (TSEI) [3-6]. Today, TSEI remains one of the most effective treatment modalities for this disease [7]. The penetration of electron beam radiation can be restricted to the involved cutaneous tissue, minimizing radiation effects to underlying normal tissue. The biologic effects of megavolt electron beam irradiation are similar to those of x-ray irradiation [8].
Electron Beam Irradiation for Cutaneous Lymphoma
Well·collimated electron beam
monoenergetic
-ll _ ;
_
239
Tube extension from Van de Graaff accelerator
Aluminum cone
0.5-10 Gy/s
Fig. 1. TSEI technique using a Van de Graaff generator.
In cooperation with the Massachusetts Institute of Technology, we have used a Van de Graaff generator producing monoenergetic electron beam energies ranging from 1.5 to 3.5 MeV for wide-field therapy or TSEI in patients with widespread cutaneous disease since 1951 (fig. 1). The electron beam is directed vertically downward and collimated by a cone with a long narrow slit at the bottom, using low atomic number material and scattering foils at the exit window to improve uniformity across the width of the field. Patients are treated while in a horizontal position on a motorized couch, which is passed under the downward-directed electron beam for the treatment. Electron beam current is adjusted to deliver the specified dose with a single traverse of the couch for each treatment position. Treatment time for a traverse from head to foot is approximately 1 min. A modification of this treatment technique was later used at the National Institutes of Health (9]. Williams et aL (10] reported in 1979 a similar technique through adaptation of an established MEL SL75/10 accelerator. Several years after we began treating patients with TSEI, the Stanford group adapted their linear accelerator to TSEI therapy (11, 12]. During the past three decades, this
Downloaded by: Université de Paris 193.51.85.197 - 1/24/2020 11:45:00 PM
Methods and Techniques
240
Lo
•I
3m
2
I
Day 1
Day 3 R latlL fat '-----:::=::::-----
AP/PA
~
Day 2
lAOIRPO
\
I
\
I
~
te -
Day 4 RAO/ LPO
I
Fig. 2. TSEI technique using a linear accelerator. Fig. 3. Eight-field technique in TSEI.
Downloaded by: Université de Paris 193.51.85.197 - 1/24/2020 11:45:00 PM
3
Electron Beam Irradiation for Cutaneous Lymphoma
241
technique, or a modification of it, has become the most common technique used in radiotherapy for generalized cutaneous lymphoma [13-18]. The most important differences are that, with a standard linear accelerator, patients must be treated in an upright position and treatment time is long. The entire setup, however, is rather complex, limiting the availability of TSEI to only a few centers. A single horizontally directed beam does not produce adequate dose uniformity over the patient's skin surface, and most commonly, a combination of two angled beams is used (fig. 2) [9, 19-22]. Sewchand et al. [23] suggested a multiple-field pendulum-arc technique. In centers where only higher energy linear accelerators are available, an energy degrader is usually necessary. This degrader could be a Lucite or polyester screen [9]. Two other points need to be mentioned regarding improvement of dose uniformity over irradiated skin surface. First, TSEI in general has evolved from treating two fields (anterior and posterior) to treating four fields (adding two lateral fields) to treating six fields per cycle. The six fields are single anterior and two posterior oblique fields alternating with single posterior and two anterior oblique fields. We currently use the eightfield technique, treating two opposed fields per day, taking 4 treatment days to complete one cycle; our daily dose per field is 1.5 Gy (fig. 3,4) [24, 25]. A rotational technique has been suggested to optimize dose homogeneity [18, 26]. Second, for areas of the body not exposed to direct electron beam radiation, 'boosting' becomes necessary to ensure total skin therapy. With our technique using the Van de Graaff generator with the patient treated while lying down, these areas include the vertex of the scalp, axillae, and perineum. In patients treated in the standing position with a linear accelerator, the soles of the feet and inframammary regions also need to be boosted. The most common mode of boosting is by using soft x-rays from an orthovoltage machine, but many radiotherapists
Downloaded by: Université de Paris 193.51.85.197 - 1/24/2020 11:45:00 PM
Fig. 4. Film dosimetry in phantom with eight-field technique in TSEI.
Lo
242
today also use low megavolt electron beam radiation. The most common dose level is 20 Gy in 10 fractions. Decreased doses are given on purpose because of possible field overlap with TSEI. During TSEI, it is important to shield the lens of the eye to avoid development of radiation-induced cataracts. If uninvolved by tumor, eyebrows and nails are also protected.
Unlike with Hodgkin's disease, our experience revealed that, although a direct relationship exists between total radiation dose and tumor response or rate of induction of remission in TSEI for generalized cutaneous lymphoma, the correlation between radiation dose and probability of relapse-free survival was not seen. Prognosis is directly related to extent of skin and visceral involvement or stage of disease. For staging of cutaneous lymphoma, we modified the classification suggested by Bunn et al. [27] (table 1). Between 1951 and 1985, more than 1,000 patients were treated at the Lahey Clinic with TSEI. Our records show that 801 patients treated with electron beam therapy on the Van de Graaff generator had pathologically diagnosed cutaneous lymphoma. All positive pathologic reports read either 'mycosis fungoides' or 'lymphoma cutis', but we have no knowledge of how many of these patients had T-cell lymphoma. For analysis, 51 patients were excluded because of no follow-up or inadequate follow-up. Of the 750 patients evaluated, 692 had generalized cutaneous disease, and 58 had limited disease (stage I). There were 477 male patients with a median age of 59 years (range 17-93 years) and 273 female patients with a median age of 57 years (range 19-89 years). Minimum follow-up was 3 years. Almost all patients (90%) had topical treatment, such as steroid therapy, before electron beam irradiation. Of 692 patients who had generalized cutaneous disease, 57 patients had documented visceral metastases at presentation. Table 2 shows the distribution of types of lesions. Patients who had mixed lesions were grouped into the more advanced lesion stage. Six hundred seventy-three patients received TSEI, and 19 patients received only spot treatments for various reasons. Lymphoma ofthe skin is radiosensitive, and our initial treatment philosophy was to use the visual disappearance of cutaneous disease as a determinant for total dose. Most of our early patients were treated with
Downloaded by: Université de Paris 193.51.85.197 - 1/24/2020 11:45:00 PM
The Lahey Clinic Experience
Electron Beam Irradiation for Cutaneous Lymphoma
243
Table 1. Staging classification Stage II II III IV
Description limited cutaneous disease « 25 % of total body surface) generalized cutaneous disease lymph node involvement with any skin stage visceral involvement with any skin stage
Table 2. Cutaneous lymphoma treated (1951-1985) Disease
Patients, n
Limited disease (stage I) Generalized cutaneous disease Erythema Plaque Tumor
58 692
Total
750
this intention to a total dose of not more than 10 Gy, using TSEI mainly as a palliative measure. More recently, total dose has been increased to 24-30 Gy, depending on extent of disease and age of the patient. However, as doses approached 30 Gy, we found increasing severity of acute skin reactions, requiring interruption in the course of treatment in many of these patients. Tables 3 and 4 show the disease-free survival rates in terms of total dose and stage of disease, respectively. Although higher total dose appears to attain better disease-free survival initially, we did not see flattening of the survival curves after 5 years. Patients continued to show recurrence of disease, and at 10 years, disease-free survival was essentially the same: around 10% across the board. For different TSEI dose ranges, overall survival rates were virtually identical (fig. 5). Sixty-six patients died from intercurrent disease, and 18 patients had secondary visceral malignancies. Tables 5 and 6 show the number and percentage of patients who required a repeat course of electron beam therapy with either TSEI or spot treatment after an initial course of TSEI. At least half of the patients who
Downloaded by: Université de Paris 193.51.85.197 - 1/24/2020 11:45:00 PM
198 276 218
Lo
244
Table 3. Disease-free survival in terms of total skin electron irradiation dose
< 10 Gy (n At 5 years At 10 years
=
510)
77(15%) 41 (8%)
10-20 Gy (n
=
106) 20-30 Gy (n
21 (20%) 10 (9%)
=
38)
8 (21 %) 1 (3%)
Table 4. Disease-free survival after total skin electron irradiation
Plaque (n At 5 years At 10 years
=
270)
51 (19%) 25 (9%)
Erythema (n
=
193) Tumor (n
34 (18%) 18 (9%)
=
2 I 0)
22 (10%) 9 (4%)
Table 5. Further electron beam therapy given in terms of initial total skin electron irradiation dose
Initial dose, Gy
30
Patients, n
510 106 38 11
Treatment TSEI
Spot
271 (53%) 33 (31 %) 10 (26%)
46 (9%) 15 (14%) 10 (26%) 5(45%)
o
Table 6. Further electron beam therapy given after total skin electron irradiation in terms of initial stage of disease
Plaque Tumor Erythema
Patients, n
270 210 193
Treatment TSEI
Spot
145 (54%) 104 (50%) 73 (38%)
33 (12%) 31 (15%) 12 (6%) Downloaded by: Université de Paris 193.51.85.197 - 1/24/2020 11:45:00 PM
Stage of disease
245
Electron Beam Irradiation for Cutaneous Lymphoma
100 90
80 70
60 50 'iii 40 >
'2::s
30
§
20
I/)
E
~ 10L--r-,r-.--r-.--.--r--r-,--.--r-.--.--r-o
o
1
Years
2
3
4
5
6
7
8
--0-
