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Second primary malignancies after radiotherapy including HDR 252Cf brachytherapy for cervical cancer
Brachytherapy
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(2015)
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Second primary malignancies after radiotherapy including HDR 252Cf brachytherapy for cervical cancer Vitalija Samerdokiene1,*, Konstantinas Povilas Valuckas2, Ernestas Janulionis2, Vydmantas Atkocius1, Mark J. Rivard3 2
1 Scientific Research Center, National Cancer Institute, Vilnius University, Vilnius, Lithuania Radiation and Medical Oncology Center, National Cancer Institute, Vilnius University, Vilnius, Lithuania 3 Department of Radiation Oncology, Tufts University School of Medicine, Boston, MA
ABSTRACT
PURPOSE: Second primary malignancies (SPMs) are among the most serious late adverse effects after radiotherapy experienced over time by the increasing population of cancer survivors worldwide. The study aim was to determine the rate and distribution of SPMs for neutron- and photon-emitting brachytherapy (BT) sources for patients treated for cervical cancer. METHODS AND MATERIALS: The cohort comprised 662 patients with invasive cervical cancer (Stages IIB and IIIB) and contributed 5,224 patient-years (PY) of observation. These patients were treated by radiotherapy during the 1989e1999 year period with cobalt-60 source (60Co) teletherapy. The first group of patients (N 5 375; 3,154 PY) received high-dose-rate (HDR) californium-252 source (252Cf) BT, whereas the second group (N 5 287; 2,070 PY) received HDR 60Co BT. RESULTS: Over a 25-year period, 35 SPMs were observed, amounting to 5.3% of all observed patients: in 16 (2.4%) heavily, 2 (0.3%) moderately, 14 (2.1%) lightly irradiated body sites, and 3 (0.5%) other sites. Of these, 21 cases (5.6%) were observed in the HDR 252Cf BT group, whereas 14 cases (4.9%) were observed in the HDR 60Co BT group. Exposures received during 60Co teletherapy and HDR BT with either 252Cf or 60Co had statistically equivalent ( p 5 0.68) effects on SPM development. CONCLUSIONS: Cure rates are improving, and therefore, there are more long-term survivors from cervical cancer. This study shows no significant difference in rates or distribution of SPMs in women treated with neutron BT compared with photon BT ( p 5 0.68). After reviewing related literature and our research results, it is evident that a detailed investigation of SPM frequency, localization, and dose to adjacent organs is a suitable topic for further research. Ó 2015 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.
Keywords:
Second primary malignancies; Cervical cancer;
252
Cf brachytherapy
Introduction Cervical cancer is the most common female cancers worldwide (1). Radiotherapy is the main treatment option for locally advanced cervical carcinoma. One of the most serious long-term effects after radiotherapy is development of radiation-induced second primary malignancies (SPMs). Received 16 April 2015; received in revised form 28 May 2015; accepted 16 June 2015. Conflict of interest: None. * Corresponding author. Scientific Research Center, National Cancer Institute, Vilnius University, P. Baublio 3B, LT-08406 Vilnius, Lithuania. Tel.: þ370-5-219-0901; fax: þ370-5-272-0164. E-mail address: [email protected] (V. Samerdokiene).
A significant increase in the number of long-term survivors is the good news in our fight against cancer. On the other hand, some patients treated with radiotherapy suffer from adverse effects, including the development of SPMs (2). Although radiation exposure is a well-established risk factor for developing SPMs, the estimation of the true incidence of radiation-induced SPMs is difficult. This is due in part to the various confounding factors, that is, genetic abnormalities, lifestyle factors, smoking, and so on. It has previously been shown that SPMs increase in long-term cancer survivors. Because of advances in cancer treatments, the rates of SPMs in cervical cancer may increase over time (3). This is due in part to progress in medical advances in the application of new treatment technologies. SPMs are relatively rare in patients having
1538-4721/$ - see front matter Ó 2015 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.brachy.2015.06.006
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a shorter survival rates (i.e., !10 years). In women surviving $15 years after radiotherapy, there is a significant increase in SPMs. Since 2000, high-dose-rate (HDR) californium-252 source (252Cf) brachytherapy (BT) has been used widely for the treatment of locally advanced cervical cancer (4, 5). More recently, outcomes have been reported on 952 patients treated for esophageal cancer (6). Those who investigated this treatment option have discussed at length the risk of SPMs after neutron irradiation (7). However, results on SPMs from 252Cf BT have not been previously reported. When compared with photon exposure, neutron exposure causes higher damage to human cells (8, 9). On the other hand, high dose rates and high fraction doses may decrease the relative biologic effectiveness of neutrons for tumoricidal effects and late radiation responses, including SPMs (10). The pattern of SPMs after treatment of cervical cancer provides important information on the risk of radiationinduced malignancies. A large number of women survive many years after treatment and can be studied for late effects such as SPMs. These studies present different data on SPMs
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after irradiation using photons. In a multinational study, Kleinerman et al. (11) reported that radiotherapy for cervical cancer was associated with statistically significantly increased risks of SPMs, particularly in pelvic organs that are adjacent to the cervix and receive large doses of photon radiation (O30 Gy). Knowledge of such SPMs after the radiotherapy of cervical cancer provides important information about the origin of radiation-induced cancer. Because most of the patients become long-term survivors after radiotherapy of primary cervical cancer, this model is well suited for studying late effects, including SPMs, although most clinical evidence concerns older external beam radiotherapy techniques. In terms of other techniques (BT, intensitymodulated radiotherapy, protons, and so on), clinical studies examining SPMs often have relatively low patient numbers and short followup. Until further clinical information is available, studies provide theoretical SPMs risk estimates. Given lack of published data on SPMs for differing radiation qualities, the aim of the present study was to determine the rate and distribution of SPMs with neutron- and photon-emitting BT sources.
Table 1 Demographic and clinical characteristics of the evaluated Stage IIB and IIIB cervical cancer survivors according to types of radiotherapy, either high-dose-rate (HDR) 252Cf brachytherapy (BT) or HDR 60Co BT (both in conjunction with 60Co teletherapy) Characteristics
HDR
252
Cf BT
HDR
375 Patients
N
Overall survival 5y 10 y 15 y 20 y 25 y Age at diagnosis, years Median (range) Followup, months Median (range) Patient-years of followup Histopathology Squamous cell carcinoma Adenocarcinoma Other Histopathologic grade G1: well differentiated G2: moderately differentiated G3: poorly or undifferentiated Unknown Cumulative point A dose, Gy Median (range) !75 $75 Cumulative point B dose, Gy Median (range) !60 $60 Length of radiotherapy course, days Median (range) Second primary malignancies Cf 5 californium-252 source;
252
60
Co BT
287 %
N
%
52.27 42.92 35.92 28.05 28.05 53.5 (23.3e90.4)
50.8 (24.6e86.4)
72.9 (3.23e299.4) 3,156
47.57 (1.40e293.2) 2,083
338 14 23
90.13 3.73 6.13
251 18 18
87.46 6.27 6.27
6 23 206 101
1.60 6.13 54.93 26.93
7 31 156 30
2.44 10.80 54.36 10.45
77 (40e102) 117 258
31.20 68.80
77 (24e112) 68 219
23.69 76.31
60 (30e87) 141 234
37.60 62.40
60 (34.5e80) 126 161
43.90 56.10
67 (6e358) 21
5.60
63 (9-1,023) 14
4.88
Co 5 cobalt-60 source.
60
45.80 36.01 29.24 23.20 19.28
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Table 2 Baseline characteristics of the second primary malignancies of the evaluated Stage IIB and IIIB cervical cancer survivors according to types of radiotherapy, either high-dose-rate (HDR) 252Cf neutron brachytherapy (BT) or HDR 60Co photon BT (both in conjunction with 60Co teletherapy) HDR
HDR
60
Co BT
14
N
Age at diagnosis, years Median (range) Followup, months Median (range) Histopathology Squamous cell carcinoma Adenocarcinoma Other Histopathologic grade G1: well differentiated G2: moderately differentiated G3: poorly or undifferentiated Unknown Cumulative point A dose, Gy Median (range) !75 $75 Cumulative point B dose, Gy Median (range) !60 $60 Length of radiotherapy course, days Median (range) Cf 5 californium-252 source;
Cf BT
21
Second primary malignancies
252
252
%
N
%
56.6 (29.0e75.4)
52.7 (30.5e67.6)
165.9 (62.3e234.6)
142.3 (61.5e289.6)
20 0 1
95.24 0.00 4.76
12 1 1
85.71 7.14 7.14
1 1 10 6
4.76 4.76 47.62 28.57
0 0 6 3
0.00 0.00 42.86 21.43
75 (64e80) 10 11
47.62 52.38
76 (65e89) 4 10
28.57 71.43
60 (43e65) 10 11
47.62 52.38
56.8 (50e63) 11 3
78.57 21.43
58 (11e83)
44.5 (21e79)
Co 5 cobalt-60 source.
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Table 3 Frequency of second primary malignancies according to types of radiotherapy, either high-dose-rate (HDR) 252Cf neutron brachytherapy (BT) or HDR 60Co photon BT (both in conjunction with 60Co teletherapy) and the magnitude of irradiated sites Total
HDR
252
Cf BT
HDR
60
Co BT
SPMs
ICD-10 (12)
Mean dose Gy (11)
N
N
%
N
%
All sites Heavily irradiated sites Small intestine Colon Rectum, rectosigmoid junction Vulva Corpus uteri Ovary Urinary tract Moderately irradiated sites Stomach Pancreas Liver Lightly irradiated sites Lung Skin Breast Brain and other parts of CNS Thyroid Other sites Hodgkins lymphoma Non-Hodgkins lymphoma Myeloid leukemia
C16-92
0.1e165
C17 C18 C19-20 C51 C54-55 C56 C66-67
10e20 24 30e60 66 165 32 30e60
35 16 1 2 3 2 3 3 2 2 1 0 1 14 8 2 2 1 1 3 1 1 1
21 8 1 2 1 1 0 1 2 2 1 0 1 8 3 2 1 1 1 3 1 1 1
5.60 2.13 0.27 0.53 0.27 0.27 0.00 0.27 0.53 0.53 0.27 0.00 0.27 2.13 0.80 0.53 0.27 0.27 0.27 0.80 0.27 0.27 0.27
14 8 0 0 2 1 3 2 0 0 0 0 0 6 5 0 1 0 0 0 0 0 0
4.88 2.79 0.00 0.00 0.70 0.35 1.05 0.70 0.00 0.00 0.00 0.00 0.00 2.09 1.74 0.00 0.35 0.00 0.00 0.00 0.00 0.00 0.00
C16 C25 C22
2 2 2
C34 C44 C50 C70 C73
0.3 0.1 0.1 0.1 0.1
C84 C85 C92
7 7 7
Cf 5 californium-252 source; 60Co 5 cobalt-60 source; CNS 5 central nervous system. Note. All cases of SPMs were coded according to the 10th revision of the International Classification of Diseases (ICD-10) (12).
252
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Methods and materials The study cohort comprised 662 women diagnosed with a primary cancer of the cervix uteri with Stage IIB or IIIB disease based on the International Federation of Gynecology and Obstetrics classification, who reported to hospital-based registry of the Lithuanian National Cancer Institute from 1989 to 1999. From the hospital registry, the following information was collected on SPMs: location, stage, histopathologic grade, histology type, length of radiotherapy, history of doses (e.g., cumulative point A and B dose), and other characteristics. All patients with multiple cervical cancers and all cases of cancer in situ were excluded. The retrospective cohort of women (median age 53.5 and 50.8 years in HDR 252Cf and cobalt-60 source [60Co] groups, respectively) in the present study was nonsmokers. On record review, all cases of SPMs were coded according to the 10th revision of the International Classification of Diseases (12). The institutional authority approved review of the records. Table 1 lists baseline characteristics of the cervical cancer survivors. This study used the ‘‘Cahan criteria’’ to determine whether observed secondary tumors qualify as SPMs (13): The tumor has arisen in a previously irradiated field, the latent period is no less than 4 years, primary and secondary tumors having different histologies, and the tissue being normal before radiation therapy. These criteria would strengthen the case for associating the SPM to radiation therapy as opposed to confounding factors such as lifestyle and smoking as stated in the Introduction.
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In our study, the primary tumor of cervix uteri was classified by histologic type according to the International Classification of Diseases for Oncology (ICD-O) code (14), as squamous cell carcinoma (ICD-O code 80703). SPMs of uterus were classified under histologies of adenocarcinoma (ICD-O codes 84603, 83803, and 81403). This confirms that these tumors are in fact new cancers in the uterus and not just a recurrence of an advanced cervical primary. Radiation-induced SPMs may occur in organs within the high-dose treatment field or distant organs well outside irradiation with moderate or low dose. These cancers are thought to be caused by the dose of scatter radiation reaching organs of the patients (15). Consequently, SPMs were grouped as found at heavily irradiated (organ doses O3 Gy) sites (small intestine, colon, rectum and rectosigmoid junction, urinary tract sites as bladder and ureter, corpus uteri, ovary, and vulva); at moderately irradiated (organ dose from 1 to 3 Gy) sites (liver, stomach, and pancreas); lightly irradiated (organ doses !1 Gy) sites (lung, breast, thyroid, skin, brain, and central nervous system); and other sites (myeloid leukemia, Hodgkin’s lymphoma, and non-Hodgkin lymphoma) according to Kleinerman et al. (11). All doses were estimated based on estimates from the clinical treatment planning system. For SPMs to be included, they had to occur at least 4 years after the start of radiotherapy of the cervical cancer. Followup continued until the diagnosis of a second primary cancer, date of death, or date of last followup, whichever occurred first. Data from both types of treatment totaled
Table 4 Second primary malignancies (SPMs) according to the sites of different irradiation of the body and length of latency period (mean and standard deviation) SPMs
ICD-10
Mean dose, Gy
N
Total time (months) mean SD
All sites Heavily irradiated sites Small intestine Colon Rectum, rectosigmoid junction Vulva Corpus uteri Ovary Urinary tract Moderately irradiated sites Stomach Liver Lightly irradiated sites Lung Skin Breast Brain and other CNS Thyroid Other sites Hodgkin’s lymphoma Non-Hodgkin’s lymphoma Myeloid leukemia
C16-92
0.1e165.0
C17 C18 C19-20 C51 C54-55 C56 C66-67
10e20 24 30e60 66 165 32 30e60
35 16 1 2 3 2 3 3 2 2 1 1 14 8 2 2 1 1 3 1 1 1
127.76 134.61 152.93 124.33 170.53 133.52 112.88 115.38 114.42 115.48 100.83 130.13 110.54 96.09 83.47 139.78 193.93 138.43 179.79 225.97 190.17 123.23
C16 C22
2 2
C34 C44 C50 C70 C73
0.3 0.1 0.1 0.1 0.1
C84 C85 C92
7 7 7
53.48 54.18
87.78 55.02 40.33 34.36 42.95 124.33 20.72
51.15 40.81 0.52 98.88
52.15
N 21 8 1 2 1 1 0 1 2 4 1 1 8 3 2 1 1 1 3 1 1 1
ICD-10 5 10th revision of the International Classification of Diseases; SD 5 standard deviation; source; CNS 5 central nervous system.
252 Cf time (months) mean SD
137.44 55.82 148.79 64.81 152.93 124.33 87.78 213.63 162.03 124.20 144.42 75.48 100.83 130.13 115.69 118.79 83.47 69.87 193.93 138.43 179.79 225.97 190.17 123.23
124.33 48.36 47.63 50.18 0.52
52.15
N 14 8 0 0 2 1 3 2 0 0 0 0 6 5 0 1 0 0 0 0 0 0
60 Co time (months) mean SD
113.26 48.05 120.44 40.39 148.98 57.16 105.00 112.88 34.36 110.97 59.77
103.68 59.39 82.47 32.20 209.70
Cf 5 californium-252 source;
252
60
Co 5 cobalt-60
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5224 patient-years of observational followup. The numbers of observed SPMs followed a Poisson distribution. Categorical variables were compared using the c2 test. The survival time and cumulative incidence were estimated by the KaplaneMeier method and compared with the log-rank test. The result was considered significant at 5% level of significance. Statistical analysis was performed using version 21.0 of the SPSS Statistics software (IBM Corporation, Armonk, NY).
Results The present study showed that among cervical cancer patients treated with combined radiotherapy, 35 SPMs (5.3%) were diagnosed over a period of 25 years. Table 2 lists cases of SPMs according to the various clinical characteristics of primary cervical cancer and the types of radiotherapy. Table 3 lists the frequency of SPMs, according to the irradiation levels and the mean dose at the initial treatment of cervical cancer. Most of the observed SPMs were carcinomas in the lung (N 5 8) or digestive tract (N 5 8). In patients (N 5 375) where HDR 252Cf BT was applied, 21 (5.6%) developed SPMs. SPMs were diagnosed at locations in 8 patients (2.1%) with heavily irradiated sites, 2 patients (0.5%) in moderately irradiated sites, 8 patients (2.1%) in lightly irradiated sites, and 3 patients (0.8%) in other body sites. In patients (N 5 287) where HDR 60Co BT was applied, 14 (4.9%) developed SPMs. SPMs were diagnosed at locations in 8 patients (2.8%) with heavily irradiated sites, 0 patient (0.0%) in a moderately irradiated site, 6 patients (2.1%) in lightly irradiated sites, and 0 patient (0%) in other body sites. The mean of SPMs latency period was about 128 months. SPMs from patients receiving HDR 252Cf BT developed 24 months later compared with the HDR 60Co BT group (Table 4). This trend was observed in all localizations of SPMs with the exception of breast cancer, which had a
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140-month difference. The curves of cumulative incidence of SPMs in both groups of patients are presented in Fig. 1 and did not show any statistically significant differences ( p 5 0.68) between SPM occurrences after 5, 10, 15, 20, and 25 year of the followup period. Analyzing the frequency of SPMs by patient age at the time of the diagnosis revealed that 10 SPMs (3.4%) have been found for younger (!50 years) patients and 25 (6.9) SPMs for older (over 50 years). Sixteen SPMs (7.6%) were diagnosed for older women in group of 252Cf and 9 SPMs (5.9%) in group of 60Co. Five SPMs (3.1%) were diagnosed for younger women in group of 252Cf and 5 SPMs (3.7%) in group of 60Co. Age was found (Table 5) in the present study to be a statistically significant factor in the occurrence of total SPMs among older cervical cancer survivors ( p 5 0.046). However, a less significant result ( p 5 0.061) was observed for cervical cancer survivors treated with HDR 252Cf BT. In Table 6, the frequency of SPMs observed in the present study (in total and for both BT treatment types) is compared with other published data.
Discussion According to the National Council on Radiation Protection and Measurements Report 116, colon, lung, and stomach are the most common sites for developing a fatal SPM after radiation exposure (24). Our results were similar, with colon 2(0), lung 3(5), and stomach 3(0) SPMs among cervical cancer survivors treated with HDR BT using either 252 Cf (or 60Co). Most epidemiologic studies have confirmed the importance of age in predicting SPM risk at the time radiation exposure. However, results of this study do not coincide with the large Boice et al. study (3), which showed higher risks of development of SPMs in younger women. Such differences may have been caused due to differences between monitored patient cohorts. In Lithuania, the patients were nonsmokers, generally ate natural foods, and most had a single sexual partner. Aside from that, there were also Table 5 Second primary malignancies (SPMs) according to patient age at diagnosis
Fig. 1. The cumulative incidence of second primary malignancies for Stage IIB and IIIB cervical cancer survivors according to types of radiotherapy, either high-dose-rate (HDR) 252Cf neutron brachytherapy (BT) or HDR 60Co photon BT (both in conjunction with 60Co teletherapy). 252 Cf 5 californium-252 source; 60Co 5 cobalt-60 source.
Age at diagnosis, years
N
SPMs
%
Total patients !50.00 $50.00 HDR 252Cf BT !50.00 $50.00 HDR 60Co BT !50.00 $50.00
662 297 365 375 163 212 287 134 153
35 10 25 21 5 16 14 5 9
5.29 3.37 6.85 5.60 3.07 7.55 4.88 3.73 5.88
p-Value 0.046
0.061
0.399
HDR 5 high dose rate; 252Cf 5 californium-252 source; BT 5 brachytherapy; 60Co 5 cobalt-60 source. Note. To discern the influence of age cutoffs, a p-Value of !0.05 was considered statistically significant.
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Table 6 Number and rate of SPMs between cervical cancer patients who underwent different types of treatment First author
Treatment technique
Present study Present study Present study Ota et al. (16) Arnold et al. (17) Chaturvedi et al. (18) Ohno et al. (19) Kleinerman et al. (10) Chen et al. (20) Kalliala et al. (21) Brener et al. (22) Dong et al. (23)
EBRT þ HDR BT ( Cf or EBRT þ HDR (252Cf) EBRT þ HDR (60Co) EBRT þ ICBT RT RT RT RT RT þ chemo RT þ chemo Sx þ RT þ Chemo Sx þ RT þ chemo 252
60
Co)
FIGO stages
Patients
Followup
SPMs
%
IIB and IIIB IIB and IIIB IIB and IIIB I, II, III, and IV I, II, III, and IV Invasive cancer I, II, III, and IV I, II, III, and IV Invasive cancer Invasive cancer I, II, III, and IV I, II, III, and IV
662 375 287 1600 13,557 52,613 2167 49,828 52,972 7564 2922 633,964
1989e2014 1989e2014 1989e2014 1971 1989e2008 1980e2008 1961e1986 1935e1990 1979e2008 1974e2003 1968e1987 1958e1996
35 21 14 13 676 6796 210 4820 3061 448 98 27,502
5.29 5.60 4.88 0.81 4.99 12.92 9.69 9.67 5.78 5.92 3.35 4.34
SPM 5 second primary malignancy; EBRT 5 external beam therapy; HDR BT 5 high-dose-rate brachytherapy; 252Cf 5 californium-252 source; Co 5 cobalt-60 source; ICBT 5 intracavitary brachytherapy; RT 5 radiotherapy; chemo 5 chemotherapy; Sx 5 surgery. Note. All disease stages are based on the International Federation of Gynecology and Obstetrics (FIGO) classification.
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differences in patient age when SPMs arose. It may be that younger women who did not lead a healthy lifestyle had a higher likelihood for developing SPMs. These findings confirm the results of other authors, especially in Arnold et al. (17), Chen et al. (20), Kalliala et al. (21), Brener et al. (22), and Dong et al. (23). All the studies determined the minimum frequency of SPMs to occur in moderately irradiated anatomic sites, with the highest frequency of SPMs to occur in heavily and lightly irradiated anatomic sites (Table 7). Comparing the patients receiving 60 Co teletherapy and HDR BT with either 252Cf or 60Co showed similar trends in SPM frequencies in both groups ( p 5 0.68). These results suggest that the carcinogenic effects of 60Co teletherapy with HDR 252Cf BT and 60Co teletherapy with HDR 60Co BT were similar. However, this topic needs further investigation with larger samples of patients to increase the statistical power. Another study limitation was that human papilloma virus (HPV) status was unknown for the patient cohort examined in this study. As this was a retrospective study, it was
Table 7 Rate (%) of SPMs, depending on the degree of irradiation with heavily defined as O3 Gy, moderately between 1 Gy and 3 Gy, and lightly being !1 Gy Estimated dose to target organs (Gy) First author
Heavily
Present study (HDR 252Cf BT) Present study (HDR 60Co BT) Arnold et al. (17) Chaturvedi et al. (18) Kleinerman et al. (11) Chen et al. (20) Kalliala et al. (21)
38.10
Moderately
Lightly
Other sites
9.52
38.10
14.28
57.14
0.00
42.86
0.00
21.68 38.15 38.01 31.95 28.57
13.20 12.28 22.87
32.40 30.87 32.73 42.19
4.58 4.96 5.98
SPM 5 second primary malignancy; HDR 5 high dose rate; BT 5 brachytherapy; 252Cf 5 californium-252 source; 60Co 5 cobalt-60 source.
not a standard practice 25 years ago to test for human papilloma virus and no such tests were performed.
Conclusions As cure rates improve for patients treated with BT for cervical cancer, the number of long-term survivors is also increasing. Consequently, there is concern to determine the rate and distribution of SPMs. This study shows no significant difference in rates or distribution of SPMs in women treated with neutron BT compared with photon BT ( p 5 0.68). After reviewing related literature and our research results, it is evident that a detailed investigation of SPMs frequency, localization, and dose to adjacent organs is a suitable topic for further research. Although the length of followup in this study was sufficient to observed SPMs, no statistically significant differences in rates or distributions of SPMs were observed in the women treated with neutron BT compared with photon BT. The observed rates were similar between the two radiation qualities, and therefore, the patient sample sizes were too low to confidently determine statistically significant differences in SPM incidence between HDR BT using either 252Cf or 60 Co. Over a 25-year period, 35 SPMs were observed in total. These were primarily in heavily and lightly irradiated organs, which amounted to 5.3% of all evaluated (N 5 662) cervical cancer patients. The observed frequency of SPMs was similar to those documented in other investigations of SPMs. In summary, although modern therapies prolong the lives of cancer patients, this success carries a risk of late, adverse health effects such as SPMs.
Acknowledgments The authors wish to express their thanks to Ms. T. Rakovskaja for assistance with statistical methods and
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findings. This research was funded by a grant (no. MIP036/2013) from the Research Council of Lithuania.
References [1] GLOBOCAN 2012. Available at: http://globocan.iarc.fr/Pages/fact_ sheets_population.aspx. Accessed April 15, 2015. [2] Suit H, Goldberg S, Niemierko A, et al. Secondary carcinogenesis in patients treated with radiation: a review of data on radiation-induced cancers in human, non-human primate, canine and rodent subjects. Radiat Res 2007;167:12e42. [3] Boice JD, Engholm G, Kleinerman RA, et al. Radiation dose and second cancer risk in patients treated for cancer of the cervix. Radiat Res 1988;116:3e55. [4] Lei X, Qian Ch-Y, Qing Y, et al. Californium-252 brachytherapy combined with external-beam radiotherapy for cervical cancer: long-term treatment results. Int J Radiat Oncol Biol Phys 2011;81: 1264e1270. [5] Zhang M, Xu H-D, Pan S-D, et al. Low-dose-rate californium-252 neutron intracavitary afterloading radiotherapy combined with conformal radiotherapy for treatment of cervical cancer. Int J Radiat Oncol Biol Phys 2012;83:966e971. [6] Liu H, Wang Q, Wan X, et al. Californium-252 neutron brachytherapy combined with external beam radiotherapy for esophageal cancer: long-term treatment results. Brachytherapy 2014;13:514e521. [7] Maruyama Y, van Nagell JR, Yoneda J, et al. Cf-252 neutron brachytherapy treatment for cure of cervical cancer. Nuc Sci App 1991;4: 181e192. [8] Brenner DJ, Hall EJ. Secondary neutrons in clinical proton radiotherapy: a charged issue. Radiother Oncol 2008;86:165e170. [9] Rivard MJ, Melhus CS, Cinkin HD, et al. A radiobiological model for the relative biological effectiveness of high-dose-rate 252Cf brachytherapy. Radiat Res 2005;164:319e323. [10] Kellerer AM, Ruhm W, Walsh L. Indications of the neutron effect contribution in the solid cancer data of the A-bomb survivors. Health Phys 2006;90:554e564. [11] Kleinerman RA, Boice JD Jr, Storm HH, et al. Second primary cancer after treatment for cervical cancer. Cancer 1995;76:442e452.
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[12] International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10), version 2015. Available at: http:// apps.who.int/classifications/icd10/browse/2015/en. Accessed April 15, 2015. [13] Cahan WG, Woodard HQ, Higinbotham NL, Stewart FW, Coley BL. Sarcoma arising in irradiated bone: report of eleven cases. Cancer 1948;1:3e29. [14] Fritz A, Percy C, Jack A, et al. International classification of diseases for oncology. 3rd ed. Geneva, Switzerland: World Health Organization; 2000. [15] Newhauser WD, Durante M. Assessing the risk of second malignancies after modern radiotherapy. Nat Rev Cancer 2011;11: 438e448. [16] Ota T, Takeshima N, Tabata T, et al. Treatment of squamous cell carcinoma of the uterine cervix with radiation therapy alone: long-term survival, late complications, and incidence of second cancers. Br J Cancer 2007;97:1058e1062. [17] Arnold M, Liu L, Kenter GG, et al. Second primary cancers in survivors of cervical cancer in Netherlands: implications for prevention and surveillance. Radiother Oncol 2014;111:374e381. [18] Chaturvedi AK, Engels EA, Gilbert ES, et al. Second cancers among 104,760 survivors of cervical cancer: evaluation of long-term risk. J Natl Cancer Inst 2007;99:1634e1642. [19] Ohno T, Kato S, Sato S, et al. Long-term survival and risk of second cancers after radiotherapy for cervical cancer. Int J Radiat Oncol Biol Phys 2007;69:740e745. [20] Chen C-Y, Lai C-H, Lee K-D, et al. Risk of second primary malignancies in women with cervical cancer: a population-based study in Taiwan over a 30-year period. Gynecol Oncol 2012;127:625e630. [21] Kalialia I, Antila A, Pukkala E, Nieminen P. Risk of cervical and other cancers after treatment of cervical intraepithelial neoplasia: retrospective cohort study. BMJ 2005;331:1183e1185. [22] Brener H, Siegle S, Stegmaier C, Ziegler H. Second primary malignancies following gynecological tumours in Saarland, Germany, 1968-1987. J Cancer Res Clin Oncol 1993;119:179e183. [23] Dong CH, Hemminki K. Second primary neoplasms in 633,964 cancer patients in Sweden, 1958-1996. Int J Cancer 2001;93:155e161. [24] National Council on Radiation Protection and Measurements. Limitation of exposure to ionizing radiation. Bethesda, MF, USA: National Council on radiation protection and measurements; 1993.
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Second primary malignancies after radiotherapy including HDR 252Cf brachytherapy for cervical cancer Vitalija Samerdokiene1,*, Konstantinas Povilas Valuckas2, Ernestas Janulionis2, Vydmantas Atkocius1, Mark J. Rivard3 2
1 Scientific Research Center, National Cancer Institute, Vilnius University, Vilnius, Lithuania Radiation and Medical Oncology Center, National Cancer Institute, Vilnius University, Vilnius, Lithuania 3 Department of Radiation Oncology, Tufts University School of Medicine, Boston, MA
ABSTRACT
PURPOSE: Second primary malignancies (SPMs) are among the most serious late adverse effects after radiotherapy experienced over time by the increasing population of cancer survivors worldwide. The study aim was to determine the rate and distribution of SPMs for neutron- and photon-emitting brachytherapy (BT) sources for patients treated for cervical cancer. METHODS AND MATERIALS: The cohort comprised 662 patients with invasive cervical cancer (Stages IIB and IIIB) and contributed 5,224 patient-years (PY) of observation. These patients were treated by radiotherapy during the 1989e1999 year period with cobalt-60 source (60Co) teletherapy. The first group of patients (N 5 375; 3,154 PY) received high-dose-rate (HDR) californium-252 source (252Cf) BT, whereas the second group (N 5 287; 2,070 PY) received HDR 60Co BT. RESULTS: Over a 25-year period, 35 SPMs were observed, amounting to 5.3% of all observed patients: in 16 (2.4%) heavily, 2 (0.3%) moderately, 14 (2.1%) lightly irradiated body sites, and 3 (0.5%) other sites. Of these, 21 cases (5.6%) were observed in the HDR 252Cf BT group, whereas 14 cases (4.9%) were observed in the HDR 60Co BT group. Exposures received during 60Co teletherapy and HDR BT with either 252Cf or 60Co had statistically equivalent ( p 5 0.68) effects on SPM development. CONCLUSIONS: Cure rates are improving, and therefore, there are more long-term survivors from cervical cancer. This study shows no significant difference in rates or distribution of SPMs in women treated with neutron BT compared with photon BT ( p 5 0.68). After reviewing related literature and our research results, it is evident that a detailed investigation of SPM frequency, localization, and dose to adjacent organs is a suitable topic for further research. Ó 2015 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.
Keywords:
Second primary malignancies; Cervical cancer;
252
Cf brachytherapy
Introduction Cervical cancer is the most common female cancers worldwide (1). Radiotherapy is the main treatment option for locally advanced cervical carcinoma. One of the most serious long-term effects after radiotherapy is development of radiation-induced second primary malignancies (SPMs). Received 16 April 2015; received in revised form 28 May 2015; accepted 16 June 2015. Conflict of interest: None. * Corresponding author. Scientific Research Center, National Cancer Institute, Vilnius University, P. Baublio 3B, LT-08406 Vilnius, Lithuania. Tel.: þ370-5-219-0901; fax: þ370-5-272-0164. E-mail address: [email protected] (V. Samerdokiene).
A significant increase in the number of long-term survivors is the good news in our fight against cancer. On the other hand, some patients treated with radiotherapy suffer from adverse effects, including the development of SPMs (2). Although radiation exposure is a well-established risk factor for developing SPMs, the estimation of the true incidence of radiation-induced SPMs is difficult. This is due in part to the various confounding factors, that is, genetic abnormalities, lifestyle factors, smoking, and so on. It has previously been shown that SPMs increase in long-term cancer survivors. Because of advances in cancer treatments, the rates of SPMs in cervical cancer may increase over time (3). This is due in part to progress in medical advances in the application of new treatment technologies. SPMs are relatively rare in patients having
1538-4721/$ - see front matter Ó 2015 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.brachy.2015.06.006
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a shorter survival rates (i.e., !10 years). In women surviving $15 years after radiotherapy, there is a significant increase in SPMs. Since 2000, high-dose-rate (HDR) californium-252 source (252Cf) brachytherapy (BT) has been used widely for the treatment of locally advanced cervical cancer (4, 5). More recently, outcomes have been reported on 952 patients treated for esophageal cancer (6). Those who investigated this treatment option have discussed at length the risk of SPMs after neutron irradiation (7). However, results on SPMs from 252Cf BT have not been previously reported. When compared with photon exposure, neutron exposure causes higher damage to human cells (8, 9). On the other hand, high dose rates and high fraction doses may decrease the relative biologic effectiveness of neutrons for tumoricidal effects and late radiation responses, including SPMs (10). The pattern of SPMs after treatment of cervical cancer provides important information on the risk of radiationinduced malignancies. A large number of women survive many years after treatment and can be studied for late effects such as SPMs. These studies present different data on SPMs
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after irradiation using photons. In a multinational study, Kleinerman et al. (11) reported that radiotherapy for cervical cancer was associated with statistically significantly increased risks of SPMs, particularly in pelvic organs that are adjacent to the cervix and receive large doses of photon radiation (O30 Gy). Knowledge of such SPMs after the radiotherapy of cervical cancer provides important information about the origin of radiation-induced cancer. Because most of the patients become long-term survivors after radiotherapy of primary cervical cancer, this model is well suited for studying late effects, including SPMs, although most clinical evidence concerns older external beam radiotherapy techniques. In terms of other techniques (BT, intensitymodulated radiotherapy, protons, and so on), clinical studies examining SPMs often have relatively low patient numbers and short followup. Until further clinical information is available, studies provide theoretical SPMs risk estimates. Given lack of published data on SPMs for differing radiation qualities, the aim of the present study was to determine the rate and distribution of SPMs with neutron- and photon-emitting BT sources.
Table 1 Demographic and clinical characteristics of the evaluated Stage IIB and IIIB cervical cancer survivors according to types of radiotherapy, either high-dose-rate (HDR) 252Cf brachytherapy (BT) or HDR 60Co BT (both in conjunction with 60Co teletherapy) Characteristics
HDR
252
Cf BT
HDR
375 Patients
N
Overall survival 5y 10 y 15 y 20 y 25 y Age at diagnosis, years Median (range) Followup, months Median (range) Patient-years of followup Histopathology Squamous cell carcinoma Adenocarcinoma Other Histopathologic grade G1: well differentiated G2: moderately differentiated G3: poorly or undifferentiated Unknown Cumulative point A dose, Gy Median (range) !75 $75 Cumulative point B dose, Gy Median (range) !60 $60 Length of radiotherapy course, days Median (range) Second primary malignancies Cf 5 californium-252 source;
252
60
Co BT
287 %
N
%
52.27 42.92 35.92 28.05 28.05 53.5 (23.3e90.4)
50.8 (24.6e86.4)
72.9 (3.23e299.4) 3,156
47.57 (1.40e293.2) 2,083
338 14 23
90.13 3.73 6.13
251 18 18
87.46 6.27 6.27
6 23 206 101
1.60 6.13 54.93 26.93
7 31 156 30
2.44 10.80 54.36 10.45
77 (40e102) 117 258
31.20 68.80
77 (24e112) 68 219
23.69 76.31
60 (30e87) 141 234
37.60 62.40
60 (34.5e80) 126 161
43.90 56.10
67 (6e358) 21
5.60
63 (9-1,023) 14
4.88
Co 5 cobalt-60 source.
60
45.80 36.01 29.24 23.20 19.28
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Table 2 Baseline characteristics of the second primary malignancies of the evaluated Stage IIB and IIIB cervical cancer survivors according to types of radiotherapy, either high-dose-rate (HDR) 252Cf neutron brachytherapy (BT) or HDR 60Co photon BT (both in conjunction with 60Co teletherapy) HDR
HDR
60
Co BT
14
N
Age at diagnosis, years Median (range) Followup, months Median (range) Histopathology Squamous cell carcinoma Adenocarcinoma Other Histopathologic grade G1: well differentiated G2: moderately differentiated G3: poorly or undifferentiated Unknown Cumulative point A dose, Gy Median (range) !75 $75 Cumulative point B dose, Gy Median (range) !60 $60 Length of radiotherapy course, days Median (range) Cf 5 californium-252 source;
Cf BT
21
Second primary malignancies
252
252
%
N
%
56.6 (29.0e75.4)
52.7 (30.5e67.6)
165.9 (62.3e234.6)
142.3 (61.5e289.6)
20 0 1
95.24 0.00 4.76
12 1 1
85.71 7.14 7.14
1 1 10 6
4.76 4.76 47.62 28.57
0 0 6 3
0.00 0.00 42.86 21.43
75 (64e80) 10 11
47.62 52.38
76 (65e89) 4 10
28.57 71.43
60 (43e65) 10 11
47.62 52.38
56.8 (50e63) 11 3
78.57 21.43
58 (11e83)
44.5 (21e79)
Co 5 cobalt-60 source.
60
Table 3 Frequency of second primary malignancies according to types of radiotherapy, either high-dose-rate (HDR) 252Cf neutron brachytherapy (BT) or HDR 60Co photon BT (both in conjunction with 60Co teletherapy) and the magnitude of irradiated sites Total
HDR
252
Cf BT
HDR
60
Co BT
SPMs
ICD-10 (12)
Mean dose Gy (11)
N
N
%
N
%
All sites Heavily irradiated sites Small intestine Colon Rectum, rectosigmoid junction Vulva Corpus uteri Ovary Urinary tract Moderately irradiated sites Stomach Pancreas Liver Lightly irradiated sites Lung Skin Breast Brain and other parts of CNS Thyroid Other sites Hodgkins lymphoma Non-Hodgkins lymphoma Myeloid leukemia
C16-92
0.1e165
C17 C18 C19-20 C51 C54-55 C56 C66-67
10e20 24 30e60 66 165 32 30e60
35 16 1 2 3 2 3 3 2 2 1 0 1 14 8 2 2 1 1 3 1 1 1
21 8 1 2 1 1 0 1 2 2 1 0 1 8 3 2 1 1 1 3 1 1 1
5.60 2.13 0.27 0.53 0.27 0.27 0.00 0.27 0.53 0.53 0.27 0.00 0.27 2.13 0.80 0.53 0.27 0.27 0.27 0.80 0.27 0.27 0.27
14 8 0 0 2 1 3 2 0 0 0 0 0 6 5 0 1 0 0 0 0 0 0
4.88 2.79 0.00 0.00 0.70 0.35 1.05 0.70 0.00 0.00 0.00 0.00 0.00 2.09 1.74 0.00 0.35 0.00 0.00 0.00 0.00 0.00 0.00
C16 C25 C22
2 2 2
C34 C44 C50 C70 C73
0.3 0.1 0.1 0.1 0.1
C84 C85 C92
7 7 7
Cf 5 californium-252 source; 60Co 5 cobalt-60 source; CNS 5 central nervous system. Note. All cases of SPMs were coded according to the 10th revision of the International Classification of Diseases (ICD-10) (12).
252
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Methods and materials The study cohort comprised 662 women diagnosed with a primary cancer of the cervix uteri with Stage IIB or IIIB disease based on the International Federation of Gynecology and Obstetrics classification, who reported to hospital-based registry of the Lithuanian National Cancer Institute from 1989 to 1999. From the hospital registry, the following information was collected on SPMs: location, stage, histopathologic grade, histology type, length of radiotherapy, history of doses (e.g., cumulative point A and B dose), and other characteristics. All patients with multiple cervical cancers and all cases of cancer in situ were excluded. The retrospective cohort of women (median age 53.5 and 50.8 years in HDR 252Cf and cobalt-60 source [60Co] groups, respectively) in the present study was nonsmokers. On record review, all cases of SPMs were coded according to the 10th revision of the International Classification of Diseases (12). The institutional authority approved review of the records. Table 1 lists baseline characteristics of the cervical cancer survivors. This study used the ‘‘Cahan criteria’’ to determine whether observed secondary tumors qualify as SPMs (13): The tumor has arisen in a previously irradiated field, the latent period is no less than 4 years, primary and secondary tumors having different histologies, and the tissue being normal before radiation therapy. These criteria would strengthen the case for associating the SPM to radiation therapy as opposed to confounding factors such as lifestyle and smoking as stated in the Introduction.
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In our study, the primary tumor of cervix uteri was classified by histologic type according to the International Classification of Diseases for Oncology (ICD-O) code (14), as squamous cell carcinoma (ICD-O code 80703). SPMs of uterus were classified under histologies of adenocarcinoma (ICD-O codes 84603, 83803, and 81403). This confirms that these tumors are in fact new cancers in the uterus and not just a recurrence of an advanced cervical primary. Radiation-induced SPMs may occur in organs within the high-dose treatment field or distant organs well outside irradiation with moderate or low dose. These cancers are thought to be caused by the dose of scatter radiation reaching organs of the patients (15). Consequently, SPMs were grouped as found at heavily irradiated (organ doses O3 Gy) sites (small intestine, colon, rectum and rectosigmoid junction, urinary tract sites as bladder and ureter, corpus uteri, ovary, and vulva); at moderately irradiated (organ dose from 1 to 3 Gy) sites (liver, stomach, and pancreas); lightly irradiated (organ doses !1 Gy) sites (lung, breast, thyroid, skin, brain, and central nervous system); and other sites (myeloid leukemia, Hodgkin’s lymphoma, and non-Hodgkin lymphoma) according to Kleinerman et al. (11). All doses were estimated based on estimates from the clinical treatment planning system. For SPMs to be included, they had to occur at least 4 years after the start of radiotherapy of the cervical cancer. Followup continued until the diagnosis of a second primary cancer, date of death, or date of last followup, whichever occurred first. Data from both types of treatment totaled
Table 4 Second primary malignancies (SPMs) according to the sites of different irradiation of the body and length of latency period (mean and standard deviation) SPMs
ICD-10
Mean dose, Gy
N
Total time (months) mean SD
All sites Heavily irradiated sites Small intestine Colon Rectum, rectosigmoid junction Vulva Corpus uteri Ovary Urinary tract Moderately irradiated sites Stomach Liver Lightly irradiated sites Lung Skin Breast Brain and other CNS Thyroid Other sites Hodgkin’s lymphoma Non-Hodgkin’s lymphoma Myeloid leukemia
C16-92
0.1e165.0
C17 C18 C19-20 C51 C54-55 C56 C66-67
10e20 24 30e60 66 165 32 30e60
35 16 1 2 3 2 3 3 2 2 1 1 14 8 2 2 1 1 3 1 1 1
127.76 134.61 152.93 124.33 170.53 133.52 112.88 115.38 114.42 115.48 100.83 130.13 110.54 96.09 83.47 139.78 193.93 138.43 179.79 225.97 190.17 123.23
C16 C22
2 2
C34 C44 C50 C70 C73
0.3 0.1 0.1 0.1 0.1
C84 C85 C92
7 7 7
53.48 54.18
87.78 55.02 40.33 34.36 42.95 124.33 20.72
51.15 40.81 0.52 98.88
52.15
N 21 8 1 2 1 1 0 1 2 4 1 1 8 3 2 1 1 1 3 1 1 1
ICD-10 5 10th revision of the International Classification of Diseases; SD 5 standard deviation; source; CNS 5 central nervous system.
252 Cf time (months) mean SD
137.44 55.82 148.79 64.81 152.93 124.33 87.78 213.63 162.03 124.20 144.42 75.48 100.83 130.13 115.69 118.79 83.47 69.87 193.93 138.43 179.79 225.97 190.17 123.23
124.33 48.36 47.63 50.18 0.52
52.15
N 14 8 0 0 2 1 3 2 0 0 0 0 6 5 0 1 0 0 0 0 0 0
60 Co time (months) mean SD
113.26 48.05 120.44 40.39 148.98 57.16 105.00 112.88 34.36 110.97 59.77
103.68 59.39 82.47 32.20 209.70
Cf 5 californium-252 source;
252
60
Co 5 cobalt-60
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5224 patient-years of observational followup. The numbers of observed SPMs followed a Poisson distribution. Categorical variables were compared using the c2 test. The survival time and cumulative incidence were estimated by the KaplaneMeier method and compared with the log-rank test. The result was considered significant at 5% level of significance. Statistical analysis was performed using version 21.0 of the SPSS Statistics software (IBM Corporation, Armonk, NY).
Results The present study showed that among cervical cancer patients treated with combined radiotherapy, 35 SPMs (5.3%) were diagnosed over a period of 25 years. Table 2 lists cases of SPMs according to the various clinical characteristics of primary cervical cancer and the types of radiotherapy. Table 3 lists the frequency of SPMs, according to the irradiation levels and the mean dose at the initial treatment of cervical cancer. Most of the observed SPMs were carcinomas in the lung (N 5 8) or digestive tract (N 5 8). In patients (N 5 375) where HDR 252Cf BT was applied, 21 (5.6%) developed SPMs. SPMs were diagnosed at locations in 8 patients (2.1%) with heavily irradiated sites, 2 patients (0.5%) in moderately irradiated sites, 8 patients (2.1%) in lightly irradiated sites, and 3 patients (0.8%) in other body sites. In patients (N 5 287) where HDR 60Co BT was applied, 14 (4.9%) developed SPMs. SPMs were diagnosed at locations in 8 patients (2.8%) with heavily irradiated sites, 0 patient (0.0%) in a moderately irradiated site, 6 patients (2.1%) in lightly irradiated sites, and 0 patient (0%) in other body sites. The mean of SPMs latency period was about 128 months. SPMs from patients receiving HDR 252Cf BT developed 24 months later compared with the HDR 60Co BT group (Table 4). This trend was observed in all localizations of SPMs with the exception of breast cancer, which had a
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140-month difference. The curves of cumulative incidence of SPMs in both groups of patients are presented in Fig. 1 and did not show any statistically significant differences ( p 5 0.68) between SPM occurrences after 5, 10, 15, 20, and 25 year of the followup period. Analyzing the frequency of SPMs by patient age at the time of the diagnosis revealed that 10 SPMs (3.4%) have been found for younger (!50 years) patients and 25 (6.9) SPMs for older (over 50 years). Sixteen SPMs (7.6%) were diagnosed for older women in group of 252Cf and 9 SPMs (5.9%) in group of 60Co. Five SPMs (3.1%) were diagnosed for younger women in group of 252Cf and 5 SPMs (3.7%) in group of 60Co. Age was found (Table 5) in the present study to be a statistically significant factor in the occurrence of total SPMs among older cervical cancer survivors ( p 5 0.046). However, a less significant result ( p 5 0.061) was observed for cervical cancer survivors treated with HDR 252Cf BT. In Table 6, the frequency of SPMs observed in the present study (in total and for both BT treatment types) is compared with other published data.
Discussion According to the National Council on Radiation Protection and Measurements Report 116, colon, lung, and stomach are the most common sites for developing a fatal SPM after radiation exposure (24). Our results were similar, with colon 2(0), lung 3(5), and stomach 3(0) SPMs among cervical cancer survivors treated with HDR BT using either 252 Cf (or 60Co). Most epidemiologic studies have confirmed the importance of age in predicting SPM risk at the time radiation exposure. However, results of this study do not coincide with the large Boice et al. study (3), which showed higher risks of development of SPMs in younger women. Such differences may have been caused due to differences between monitored patient cohorts. In Lithuania, the patients were nonsmokers, generally ate natural foods, and most had a single sexual partner. Aside from that, there were also Table 5 Second primary malignancies (SPMs) according to patient age at diagnosis
Fig. 1. The cumulative incidence of second primary malignancies for Stage IIB and IIIB cervical cancer survivors according to types of radiotherapy, either high-dose-rate (HDR) 252Cf neutron brachytherapy (BT) or HDR 60Co photon BT (both in conjunction with 60Co teletherapy). 252 Cf 5 californium-252 source; 60Co 5 cobalt-60 source.
Age at diagnosis, years
N
SPMs
%
Total patients !50.00 $50.00 HDR 252Cf BT !50.00 $50.00 HDR 60Co BT !50.00 $50.00
662 297 365 375 163 212 287 134 153
35 10 25 21 5 16 14 5 9
5.29 3.37 6.85 5.60 3.07 7.55 4.88 3.73 5.88
p-Value 0.046
0.061
0.399
HDR 5 high dose rate; 252Cf 5 californium-252 source; BT 5 brachytherapy; 60Co 5 cobalt-60 source. Note. To discern the influence of age cutoffs, a p-Value of !0.05 was considered statistically significant.
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Table 6 Number and rate of SPMs between cervical cancer patients who underwent different types of treatment First author
Treatment technique
Present study Present study Present study Ota et al. (16) Arnold et al. (17) Chaturvedi et al. (18) Ohno et al. (19) Kleinerman et al. (10) Chen et al. (20) Kalliala et al. (21) Brener et al. (22) Dong et al. (23)
EBRT þ HDR BT ( Cf or EBRT þ HDR (252Cf) EBRT þ HDR (60Co) EBRT þ ICBT RT RT RT RT RT þ chemo RT þ chemo Sx þ RT þ Chemo Sx þ RT þ chemo 252
60
Co)
FIGO stages
Patients
Followup
SPMs
%
IIB and IIIB IIB and IIIB IIB and IIIB I, II, III, and IV I, II, III, and IV Invasive cancer I, II, III, and IV I, II, III, and IV Invasive cancer Invasive cancer I, II, III, and IV I, II, III, and IV
662 375 287 1600 13,557 52,613 2167 49,828 52,972 7564 2922 633,964
1989e2014 1989e2014 1989e2014 1971 1989e2008 1980e2008 1961e1986 1935e1990 1979e2008 1974e2003 1968e1987 1958e1996
35 21 14 13 676 6796 210 4820 3061 448 98 27,502
5.29 5.60 4.88 0.81 4.99 12.92 9.69 9.67 5.78 5.92 3.35 4.34
SPM 5 second primary malignancy; EBRT 5 external beam therapy; HDR BT 5 high-dose-rate brachytherapy; 252Cf 5 californium-252 source; Co 5 cobalt-60 source; ICBT 5 intracavitary brachytherapy; RT 5 radiotherapy; chemo 5 chemotherapy; Sx 5 surgery. Note. All disease stages are based on the International Federation of Gynecology and Obstetrics (FIGO) classification.
60
differences in patient age when SPMs arose. It may be that younger women who did not lead a healthy lifestyle had a higher likelihood for developing SPMs. These findings confirm the results of other authors, especially in Arnold et al. (17), Chen et al. (20), Kalliala et al. (21), Brener et al. (22), and Dong et al. (23). All the studies determined the minimum frequency of SPMs to occur in moderately irradiated anatomic sites, with the highest frequency of SPMs to occur in heavily and lightly irradiated anatomic sites (Table 7). Comparing the patients receiving 60 Co teletherapy and HDR BT with either 252Cf or 60Co showed similar trends in SPM frequencies in both groups ( p 5 0.68). These results suggest that the carcinogenic effects of 60Co teletherapy with HDR 252Cf BT and 60Co teletherapy with HDR 60Co BT were similar. However, this topic needs further investigation with larger samples of patients to increase the statistical power. Another study limitation was that human papilloma virus (HPV) status was unknown for the patient cohort examined in this study. As this was a retrospective study, it was
Table 7 Rate (%) of SPMs, depending on the degree of irradiation with heavily defined as O3 Gy, moderately between 1 Gy and 3 Gy, and lightly being !1 Gy Estimated dose to target organs (Gy) First author
Heavily
Present study (HDR 252Cf BT) Present study (HDR 60Co BT) Arnold et al. (17) Chaturvedi et al. (18) Kleinerman et al. (11) Chen et al. (20) Kalliala et al. (21)
38.10
Moderately
Lightly
Other sites
9.52
38.10
14.28
57.14
0.00
42.86
0.00
21.68 38.15 38.01 31.95 28.57
13.20 12.28 22.87
32.40 30.87 32.73 42.19
4.58 4.96 5.98
SPM 5 second primary malignancy; HDR 5 high dose rate; BT 5 brachytherapy; 252Cf 5 californium-252 source; 60Co 5 cobalt-60 source.
not a standard practice 25 years ago to test for human papilloma virus and no such tests were performed.
Conclusions As cure rates improve for patients treated with BT for cervical cancer, the number of long-term survivors is also increasing. Consequently, there is concern to determine the rate and distribution of SPMs. This study shows no significant difference in rates or distribution of SPMs in women treated with neutron BT compared with photon BT ( p 5 0.68). After reviewing related literature and our research results, it is evident that a detailed investigation of SPMs frequency, localization, and dose to adjacent organs is a suitable topic for further research. Although the length of followup in this study was sufficient to observed SPMs, no statistically significant differences in rates or distributions of SPMs were observed in the women treated with neutron BT compared with photon BT. The observed rates were similar between the two radiation qualities, and therefore, the patient sample sizes were too low to confidently determine statistically significant differences in SPM incidence between HDR BT using either 252Cf or 60 Co. Over a 25-year period, 35 SPMs were observed in total. These were primarily in heavily and lightly irradiated organs, which amounted to 5.3% of all evaluated (N 5 662) cervical cancer patients. The observed frequency of SPMs was similar to those documented in other investigations of SPMs. In summary, although modern therapies prolong the lives of cancer patients, this success carries a risk of late, adverse health effects such as SPMs.
Acknowledgments The authors wish to express their thanks to Ms. T. Rakovskaja for assistance with statistical methods and
V. Samerdokiene et al. / Brachytherapy
findings. This research was funded by a grant (no. MIP036/2013) from the Research Council of Lithuania.
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