INT. J .
HYPERTHERMIA, 1992, VOL. 8,
NO.
6, 733-745
Persistent and/or late complications of combined radiation therapy and hyperthermia R. BEN-YOSEF and D. S. KAPP* Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA
Int J Hyperthermia Downloaded from informahealthcare.com by TIB/UB Hannover on 01/10/15 For personal use only.
(Received I I February I992; revised I8 May 1992; accepted 22 May I992) Persistent and/or late complications were analysed in 64 patients (183 fields) that were treated with combined hyperthermia and radiation therapy for advanced, recurrent or metastatic cancer. The incidence and type of complications were evaluated over a minimum follow-up period of 2 years from the onset of treatment (mean 38.7 months; range 24-82.5 months). The primary malignancies included: breast (39), melanomas (6). adenoid cystic carcinomas of salivary glands (4),prostate (4),soft tissue sarcomas (3), squamous cell carcinoma of head and neck (3), lymphomas (3). transitional cell carcinoma of bladder (1) and basal cell carcinoma of the skin (1). The persistent complications noted included induration and fibrosis (39 hyperthermia fields, 22 patients), ulceration at the site of prior tumour (three patients, three fields), and ulceration in normal tissue (one patient, one field). Brachial plexopathy developed in one patient treated for recurrent breast cancer, but she had active disease at that time. A squamous cell carcinoma of the skin developed within the treatment field in a breast cancer patient. Radionecrosis of the mandible was seen in one patient treated for a floor of the mouth cancer, and osteomyelitis with septic arthritis developed in one patient treated for a soft tissue sarcoma of the thigh. Univariate logistic regression analyses of pretreatment and radiation-hyperthermia treatment parameters revealed that maximal tumour temperature had a borderline significant correlation with the development of complications @ =0.07). Multivariate analyses of the pretreatment and treatment parameters revealed the best-two-covariate model to predict complications included mean maximal tumour temperature and tumour type (macroscopic tumours had greater incidence of complications than for microscopic residual disease). The rate and type of persistent and/or late complications seen following combined radiation and hyperthermia did not appear to dramatically differ from those that would be anticipated from irradiation alone in this patient population, with the exception of an increased incidence of areas of induration and tumour necrosis. Key words: Hyperthermia, radiation therapy, combined modality treatment, late
complications
1. Introduction In the past decade, hyperthermia (HT) combined with radiation therapy (XRT) has gained increasing acceptance in the treatment of locally advanced or recurrent cancer (Anderson and Kapp 1990). Acute and subacute toxicities, as well as complications following combined XRT-HT, have been reported (Howard et al. 1987, Kapp et al. 1988, Scott et al. 1988, Meyer and Kapp 1989) and parameters predictive for the development of complications have been noted (Kapp et al. 1992). However, persistent and latedeveloping complications ( B 2 years post-treatment) have not been well documented (Sharma et al. 1990, Hall and Roizin-Towle 1984) and a need for this information has been recently emphasized (Perez 1990). This retrospective study was therefore undertaken to delineate the persistent and/or late complications, as well as those that required surgical *To whom correspondence should be addressed. 0265-6736/92 $3.00 01992 Taylor & Francis Ltd
734
R. Ben-Yosef and D. S. Kapp
or medical intervention, in patients treated at Stanford with combined XRT-HT, and to identify pretreatment and treatment factors associated with the development of complications.
Int J Hyperthermia Downloaded from informahealthcare.com by TIB/UB Hannover on 01/10/15 For personal use only.
2. Methods and materials A total of 322 patients were treated with XRT-HT at Stanford University Medical Center from September 1981 to March 1989. The patients had clinically locally advanced, recurrent, or metastatic disease with a low probability of local control by conventional therapies. A total of 64 out of the 322 patients treated in this period were available for follow-up evaluation at least 24 months after the initiation of XRT-HT, and these form the cohort for this study. All had histological proof of malignancy. Their tumour and prior treatment parameters are summarized in Table 1. All patients were seen for routine followup evaluation every 3-4 weeks for the first 3 months after completion of treatment, every 3 months for the following 2 years, and every 6 months beyond 2 years. For patients who could not return to our facility for follow-up, overall medical status and specific findings in relation to the treatment fields were evaluated by their community physicians, and full records were obtained. Complications were documented by physical examination and/or laboratory findings. 2.1. Radiation therapy treatment Radiation treatments were delivered with electron beam or megavoltage beam techniques as previously described (Kapp et al. 1990). The treatment regimen was dependent on tumour location, prior radiation to the tumour site, and adjacent normal tissues. Multiple-field electron and photon beam techniques were frequently used to minimize additional dose to the treatment-limiting adjacent normal tissues (Kapp and Meyer 1991). Radiation field size was chosen to include the tumour with generous margins (2-3 cm minimum). For patients with recurrences of breast cancer on the chest wall, the entire chest wall and adjacent supraclavicular area were included whenever possible (Kapp et al. 1991, Kapp and Meyer 1991). For most tumours a dose of 180 or 200 cGy per fraction was utilized four or five times per week. However, for the treatment of melanoma a dose per fraction of 350 cGy was delivered twice per week for a total dose of 4200 cGy. 2.2. Hyperthermia treatments The goal of each HT treatment was to obtain a minimum intratumoral temperature of 43°C for 45 min while limiting temperatures in normal tissues to 43-43.5"C. Power was adjusted to prevent any monitored intratumoral temperatures from exceeding 50"C, and to avoid excessive pain. In general, additional analgesics were not employed during the treatment, and power was adjusted to maintain steady-state temperatures at the desired level. HT was initiated within 30-60 min following the XRT, and successive HT treatments were separated by at least 3 days to minimize thermotolerance (Kapp et al. 1990). A treatment field was defined as a discrete region that could be treated with a single HT applicator or applicator array (Kapp et al. 1988). The selection of hyperthermia applicator was based on tumour site, size and nature of the surrounding normal tissues. Detailed descriptions of the microwave, ultrasound and radiofrequency devices employed have been previously reported (Kapp et al. 1988, Samulski et al. 1990, Lee et al. 1992). Mean number of HT fields per patient was 2-85 (range 1-10), and the mean number of HT treatments per field was 2.54 (range 1-8). Most of the patients were treated with microwave devices for superficially located tumours. The radiation and HT treatment parameters are summarized in Table 2.
61 -0
6
4
4
3
3
3
1 1
Malignant melanoma
Adenoid cystic carcinoma, salivary glands Adenocarcinoma of prostate
Soft tissue sarcoma
Squamous cell carcinoma of head and neck Lymphoma
Transitional cell carcinoma of bladder Basal cell carcinoma of skin
XRT, Radiation therapy: HT, hyperthermia.
54-6 (32.0-82.3) 60-4 (29 '7-76 * 8) 54.8 (27.7-70.7)
39
Adenocarcinoma of breast
66.8
(55 -9-63.6) 64.3 (47.5-85.8) 63.9 (36.4-74.2) 46.2 (25-5-59.1) 66- 1
Age mean (range) (years)
Number of patients
Tumour histology
41
(27.2-62.8) 27.7 (24.0-33 -4) 35.3 (26 * 8-44.5) 25-9 (24.5-27.4) 36-0 (25 .6-50.2) 24
44.8
36.3 (24.0-78.6) 49-8 (26-1-82.5)
Follow-up time mean (range) (months)
0 1
3
3
2
2
4
1
30
No. of patients with prior XRT
1 1
1
2
3
0
2
6
No. of patients with prior surgery 38
1 0
3
1
1
0
3
2
24
No. of patients with prior chemotherapy
Table 1. Characteristics and prior treatment parameters of patients with persistent and/or late complications and follow-up for 24 months or more after initiation of XRT-HT.
Int J Hyperthermia Downloaded from informahealthcare.com by TIB/UB Hannover on 01/10/15 For personal use only.
2
0
2.
0
zsB
P
F
B 3
n 3
t
2 -. 4 n,
b n,
Number of fields No. of HT treatments per field: mean (range)
Adenocarcinoma of breast 144 2.2 (1-7) Malignant melanoma 16 4.4 (2-8) Adenoid cystic carcinoma 5 2 (2) of salivary glands Adenocarcinoma of prostate 4 2.25 (1-4) Soft tissue sarcoma 3 3.3 (2-5) Squamous cell carcinoma of 4 2.25 (2-3) head and neck Lymphoma 5 2.8 (2-4) Transitional cell carcinoma of 1 2 bladder Basal cell carcinoma of skin 1 5 HT, hyperthermia: XRT, radiation therapy; Ex, external; I, interstitial; S, ?Included implant dose.
Tumour histology
3418 (1947-4400)
1 (Ex) 6Ooo 1 (Ex) 3960 superficial; Ec, eccentric; D, deep.
3 (Ex)
10 710
6Ooo
6698 (4400-8200)
7892 (7610-8000)t 6920 (4520-9340) 8842 (8230-9340)
Concurrent XRT dose Total XRT dose per field: per field: mean (range) mean (range) (CGY) (cGy) 3921 (1400-7560) 7347 (3000-11900) 4396 (3600-6400) 4729 (3600-9000) 2318 (2000-3420) 8222 (7013-10420)
1 (EX), 2 (I) 5490 (2960-8000)t 3 (Ex) 3420 (24004520) 2 (EX), 1 (I) 3623 (3420-4270)
39 (Ex) 6 (Ex) 3 (EX), 2 (I)
Type of HT
Table 2. Hyperthermia-radiation therapy treatment parameters of patients with long term follow-up.
Int J Hyperthermia Downloaded from informahealthcare.com by TIB/UB Hannover on 01/10/15 For personal use only.
1 (Ec) 1 (S)
3 (S)
4 (D) 1 (S), 2 (D) 2 (S), 1 (D)
39 (S) 3 (D), 3 (S) 3 (S), 2 (D)
Tumour location
3 %
9
p
!5
a
%
s
P
2
3
Int J Hyperthermia Downloaded from informahealthcare.com by TIB/UB Hannover on 01/10/15 For personal use only.
Persistent and/or late complications
737
2.3. 7hermometry Intratumoral and adjacent subcutaneous normal tissue temperatures were measured manually or automatically by moving the sensor probes at 0.5 or 1.0 cm intervals along the subcutaneously placed catheters, at least twice during treatments. Multiple sensors were also placed on the surface as previously described (Kapp et al. 1988, 1990) and were monitored continuously during treatment. Adjustments in power were made during treatment in an attempt to obtain more uniform tumour and surface temperatures, to minimize pain and to achieve the desired intratumoral and normal tissue temperature goals. Individual HT treatments were characterized by the average (T,,,), maximum (T,,,), and minimum ('Ill,,) of the mapped intratumoral or normal tissue temperatures. Averages of these parameters were calculated over all treatments for a given treatment field (e.g. mean 'Illdx indicating the mean of the maximal measured intratumoral temperatures for all treatments within a given field) as previously described (Kapp er al. 1988). Hyperthermia treatments were also characterized by the maximum recorded intratumoral temperature in the field for all treatments given to that field (e.g. maximum tumour temperature or max TmaX). In addition, the percentage of the intratumoral temperatures measured in a treatment field that were >43.5"C or
HYPERTHERMIA, 1992, VOL. 8,
NO.
6, 733-745
Persistent and/or late complications of combined radiation therapy and hyperthermia R. BEN-YOSEF and D. S. KAPP* Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA
Int J Hyperthermia Downloaded from informahealthcare.com by TIB/UB Hannover on 01/10/15 For personal use only.
(Received I I February I992; revised I8 May 1992; accepted 22 May I992) Persistent and/or late complications were analysed in 64 patients (183 fields) that were treated with combined hyperthermia and radiation therapy for advanced, recurrent or metastatic cancer. The incidence and type of complications were evaluated over a minimum follow-up period of 2 years from the onset of treatment (mean 38.7 months; range 24-82.5 months). The primary malignancies included: breast (39), melanomas (6). adenoid cystic carcinomas of salivary glands (4),prostate (4),soft tissue sarcomas (3), squamous cell carcinoma of head and neck (3), lymphomas (3). transitional cell carcinoma of bladder (1) and basal cell carcinoma of the skin (1). The persistent complications noted included induration and fibrosis (39 hyperthermia fields, 22 patients), ulceration at the site of prior tumour (three patients, three fields), and ulceration in normal tissue (one patient, one field). Brachial plexopathy developed in one patient treated for recurrent breast cancer, but she had active disease at that time. A squamous cell carcinoma of the skin developed within the treatment field in a breast cancer patient. Radionecrosis of the mandible was seen in one patient treated for a floor of the mouth cancer, and osteomyelitis with septic arthritis developed in one patient treated for a soft tissue sarcoma of the thigh. Univariate logistic regression analyses of pretreatment and radiation-hyperthermia treatment parameters revealed that maximal tumour temperature had a borderline significant correlation with the development of complications @ =0.07). Multivariate analyses of the pretreatment and treatment parameters revealed the best-two-covariate model to predict complications included mean maximal tumour temperature and tumour type (macroscopic tumours had greater incidence of complications than for microscopic residual disease). The rate and type of persistent and/or late complications seen following combined radiation and hyperthermia did not appear to dramatically differ from those that would be anticipated from irradiation alone in this patient population, with the exception of an increased incidence of areas of induration and tumour necrosis. Key words: Hyperthermia, radiation therapy, combined modality treatment, late
complications
1. Introduction In the past decade, hyperthermia (HT) combined with radiation therapy (XRT) has gained increasing acceptance in the treatment of locally advanced or recurrent cancer (Anderson and Kapp 1990). Acute and subacute toxicities, as well as complications following combined XRT-HT, have been reported (Howard et al. 1987, Kapp et al. 1988, Scott et al. 1988, Meyer and Kapp 1989) and parameters predictive for the development of complications have been noted (Kapp et al. 1992). However, persistent and latedeveloping complications ( B 2 years post-treatment) have not been well documented (Sharma et al. 1990, Hall and Roizin-Towle 1984) and a need for this information has been recently emphasized (Perez 1990). This retrospective study was therefore undertaken to delineate the persistent and/or late complications, as well as those that required surgical *To whom correspondence should be addressed. 0265-6736/92 $3.00 01992 Taylor & Francis Ltd
734
R. Ben-Yosef and D. S. Kapp
or medical intervention, in patients treated at Stanford with combined XRT-HT, and to identify pretreatment and treatment factors associated with the development of complications.
Int J Hyperthermia Downloaded from informahealthcare.com by TIB/UB Hannover on 01/10/15 For personal use only.
2. Methods and materials A total of 322 patients were treated with XRT-HT at Stanford University Medical Center from September 1981 to March 1989. The patients had clinically locally advanced, recurrent, or metastatic disease with a low probability of local control by conventional therapies. A total of 64 out of the 322 patients treated in this period were available for follow-up evaluation at least 24 months after the initiation of XRT-HT, and these form the cohort for this study. All had histological proof of malignancy. Their tumour and prior treatment parameters are summarized in Table 1. All patients were seen for routine followup evaluation every 3-4 weeks for the first 3 months after completion of treatment, every 3 months for the following 2 years, and every 6 months beyond 2 years. For patients who could not return to our facility for follow-up, overall medical status and specific findings in relation to the treatment fields were evaluated by their community physicians, and full records were obtained. Complications were documented by physical examination and/or laboratory findings. 2.1. Radiation therapy treatment Radiation treatments were delivered with electron beam or megavoltage beam techniques as previously described (Kapp et al. 1990). The treatment regimen was dependent on tumour location, prior radiation to the tumour site, and adjacent normal tissues. Multiple-field electron and photon beam techniques were frequently used to minimize additional dose to the treatment-limiting adjacent normal tissues (Kapp and Meyer 1991). Radiation field size was chosen to include the tumour with generous margins (2-3 cm minimum). For patients with recurrences of breast cancer on the chest wall, the entire chest wall and adjacent supraclavicular area were included whenever possible (Kapp et al. 1991, Kapp and Meyer 1991). For most tumours a dose of 180 or 200 cGy per fraction was utilized four or five times per week. However, for the treatment of melanoma a dose per fraction of 350 cGy was delivered twice per week for a total dose of 4200 cGy. 2.2. Hyperthermia treatments The goal of each HT treatment was to obtain a minimum intratumoral temperature of 43°C for 45 min while limiting temperatures in normal tissues to 43-43.5"C. Power was adjusted to prevent any monitored intratumoral temperatures from exceeding 50"C, and to avoid excessive pain. In general, additional analgesics were not employed during the treatment, and power was adjusted to maintain steady-state temperatures at the desired level. HT was initiated within 30-60 min following the XRT, and successive HT treatments were separated by at least 3 days to minimize thermotolerance (Kapp et al. 1990). A treatment field was defined as a discrete region that could be treated with a single HT applicator or applicator array (Kapp et al. 1988). The selection of hyperthermia applicator was based on tumour site, size and nature of the surrounding normal tissues. Detailed descriptions of the microwave, ultrasound and radiofrequency devices employed have been previously reported (Kapp et al. 1988, Samulski et al. 1990, Lee et al. 1992). Mean number of HT fields per patient was 2-85 (range 1-10), and the mean number of HT treatments per field was 2.54 (range 1-8). Most of the patients were treated with microwave devices for superficially located tumours. The radiation and HT treatment parameters are summarized in Table 2.
61 -0
6
4
4
3
3
3
1 1
Malignant melanoma
Adenoid cystic carcinoma, salivary glands Adenocarcinoma of prostate
Soft tissue sarcoma
Squamous cell carcinoma of head and neck Lymphoma
Transitional cell carcinoma of bladder Basal cell carcinoma of skin
XRT, Radiation therapy: HT, hyperthermia.
54-6 (32.0-82.3) 60-4 (29 '7-76 * 8) 54.8 (27.7-70.7)
39
Adenocarcinoma of breast
66.8
(55 -9-63.6) 64.3 (47.5-85.8) 63.9 (36.4-74.2) 46.2 (25-5-59.1) 66- 1
Age mean (range) (years)
Number of patients
Tumour histology
41
(27.2-62.8) 27.7 (24.0-33 -4) 35.3 (26 * 8-44.5) 25-9 (24.5-27.4) 36-0 (25 .6-50.2) 24
44.8
36.3 (24.0-78.6) 49-8 (26-1-82.5)
Follow-up time mean (range) (months)
0 1
3
3
2
2
4
1
30
No. of patients with prior XRT
1 1
1
2
3
0
2
6
No. of patients with prior surgery 38
1 0
3
1
1
0
3
2
24
No. of patients with prior chemotherapy
Table 1. Characteristics and prior treatment parameters of patients with persistent and/or late complications and follow-up for 24 months or more after initiation of XRT-HT.
Int J Hyperthermia Downloaded from informahealthcare.com by TIB/UB Hannover on 01/10/15 For personal use only.
2
0
2.
0
zsB
P
F
B 3
n 3
t
2 -. 4 n,
b n,
Number of fields No. of HT treatments per field: mean (range)
Adenocarcinoma of breast 144 2.2 (1-7) Malignant melanoma 16 4.4 (2-8) Adenoid cystic carcinoma 5 2 (2) of salivary glands Adenocarcinoma of prostate 4 2.25 (1-4) Soft tissue sarcoma 3 3.3 (2-5) Squamous cell carcinoma of 4 2.25 (2-3) head and neck Lymphoma 5 2.8 (2-4) Transitional cell carcinoma of 1 2 bladder Basal cell carcinoma of skin 1 5 HT, hyperthermia: XRT, radiation therapy; Ex, external; I, interstitial; S, ?Included implant dose.
Tumour histology
3418 (1947-4400)
1 (Ex) 6Ooo 1 (Ex) 3960 superficial; Ec, eccentric; D, deep.
3 (Ex)
10 710
6Ooo
6698 (4400-8200)
7892 (7610-8000)t 6920 (4520-9340) 8842 (8230-9340)
Concurrent XRT dose Total XRT dose per field: per field: mean (range) mean (range) (CGY) (cGy) 3921 (1400-7560) 7347 (3000-11900) 4396 (3600-6400) 4729 (3600-9000) 2318 (2000-3420) 8222 (7013-10420)
1 (EX), 2 (I) 5490 (2960-8000)t 3 (Ex) 3420 (24004520) 2 (EX), 1 (I) 3623 (3420-4270)
39 (Ex) 6 (Ex) 3 (EX), 2 (I)
Type of HT
Table 2. Hyperthermia-radiation therapy treatment parameters of patients with long term follow-up.
Int J Hyperthermia Downloaded from informahealthcare.com by TIB/UB Hannover on 01/10/15 For personal use only.
1 (Ec) 1 (S)
3 (S)
4 (D) 1 (S), 2 (D) 2 (S), 1 (D)
39 (S) 3 (D), 3 (S) 3 (S), 2 (D)
Tumour location
3 %
9
p
!5
a
%
s
P
2
3
Int J Hyperthermia Downloaded from informahealthcare.com by TIB/UB Hannover on 01/10/15 For personal use only.
Persistent and/or late complications
737
2.3. 7hermometry Intratumoral and adjacent subcutaneous normal tissue temperatures were measured manually or automatically by moving the sensor probes at 0.5 or 1.0 cm intervals along the subcutaneously placed catheters, at least twice during treatments. Multiple sensors were also placed on the surface as previously described (Kapp et al. 1988, 1990) and were monitored continuously during treatment. Adjustments in power were made during treatment in an attempt to obtain more uniform tumour and surface temperatures, to minimize pain and to achieve the desired intratumoral and normal tissue temperature goals. Individual HT treatments were characterized by the average (T,,,), maximum (T,,,), and minimum ('Ill,,) of the mapped intratumoral or normal tissue temperatures. Averages of these parameters were calculated over all treatments for a given treatment field (e.g. mean 'Illdx indicating the mean of the maximal measured intratumoral temperatures for all treatments within a given field) as previously described (Kapp er al. 1988). Hyperthermia treatments were also characterized by the maximum recorded intratumoral temperature in the field for all treatments given to that field (e.g. maximum tumour temperature or max TmaX). In addition, the percentage of the intratumoral temperatures measured in a treatment field that were >43.5"C or
