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Low-Dose-Rate Californium-252 Neutron Intracavitary Afterloading Radiotherapy Combined With Conformal Radiotherapy for Treatment of Cervical Cancer
International Journal of
Radiation Oncology biology
physics
www.redjournal.org
Clinical Investigation: Gynecologic Cancer
Low-Dose-Rate Californium-252 Neutron Intracavitary Afterloading Radiotherapy Combined With Conformal Radiotherapy for Treatment of Cervical Cancer Min Zhang, M.D.,* Hong-De Xu, M.D.,y Song-Dan Pan, M.D.,* Shan Lin, M.D.,* Jian-Hua Yue, M.D.,* and Jian-Ren Liu, M.D.z *Department of Oncology, Armed Police Hospital of Hangzhou, Hangzhou, Zhejiang Province, PR China; yCancer Center, Armed Police Hospital of Hangzhou, Hangzhou, Zhejiang Province, PR China; and zSecond Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, PR China Received Apr 11, 2011, and in revised form Aug 4, 2011. Accepted for publication Aug 24, 2011
Summary This retrospective study reviewed clinical outcomes for cervical cancer patients treated with low-dose-rate 252 Cf neutron intracavitary afterloading radiotherapy combined with external beam radiation. LDR 252Cf neutron intracavitary afterloading appeared effective for the treatment of cervical cancer and provided results similar or superior to those with conventional g-emitters. This method resulted in rapid tumor regression and was associated with a low rate of complications.
Purpose: To study the efficacy of low-dose-rate californium-252 (252Cf) neutron intracavitary afterloading radiotherapy (RT) combined with external pelvic RT for treatment of cervical cancer. Methods and Materials: The records of 96 patients treated for cervical cancer from 2006 to 2010 were retrospectively reviewed. For patients with tumors 4 cm in diameter, external beam radiation was performed (1.8 Gy/day, five times/week) until the dose reached 20 Gy, and then 252 Cf neutron intracavitary afterloading RT (once/week) was begun, and the frequency of external beam radiation was changed to four times/week. For patients with tumors >4 cm, 252 Cf RT was performed one to two times before whole-pelvis external beam radiation. The tumor-eliminating dose was determined by using the depth limit of 5 mm below the mucosa as the reference point. In all patients, the total dose of the external beam radiation ranged from 46.8 to 50 Gy. For 252Cf RT, the dose delivered to point A was 6 Gy/fraction, once per week, for a total of seven times, and the total dose was 42 Gy. Results: The mean SD patient age was 54.7 13.7 years. Six patients had disease assessed at stage IB, 13 patients had stage IIA, 49 patients had stage IIB, 3 patients had stage IIIA, 24 patients had stage IIIB, and 1 patient had stage IVA. All patients obtained complete tumor regression (CR). The mean SD time to CR was 23.5 3.4 days. Vaginal bleeding was fully controlled in 80 patients within 1 to 8 days. The mean SD follow-up period was 27.6 12.7 months (range, 6e48 months). Five patients died due to recurrence or metastasis. The 3-year survival and disease-free recurrence rates were 89.6% and 87.5 %, respectively. Nine patients experienced mild radiation proctitis, and 4 patients developed radiocystitis. Conclusions: Low-dose-rate 252Cf neutron RT combined with external pelvic RT is effective for treating cervical cancer, with a low incidence of complications. Ó 2012 Elsevier Inc. Keywords: Brachytherapy, Californium, Cervical cancer, Low-dose rate, Neutron
Reprint requests to: Jian-Ren Liu, M.D., 88 Jiefang Road, Hangzhou, Zhejiang Province, PR China 310009. Tel: 86 571 87784812; Fax: 86 571 87784712; E-mail: [email protected] This work was supported by the National Natural Science Foundation of China (no. 30600193 and 81070914 to J.R.L.), a Qianjiang talent project Int J Radiation Oncol Biol Phys, Vol. 83, No. 3, pp. 966e971, 2012 0360-3016/$ - see front matter Ó 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.ijrobp.2011.08.031
grant from the Bureau of Science and Technology of Zhejiang province, China (no. 2009R10022 to J.R.L.), and by the Health Bureau of Zhejiang Province, China (no. 2007A100 to J.R.L.). Conflict of interest: none.
Volume 83 Number 3 2012
Introduction The primary treatment methods for cervical cancer are radiation therapy (RT) and surgery, and RT for cervical cancer includes intracavitary therapy and external beam radiation (1, 2). The combination of intracavitary and external beam radiation has resulted in 5-year survival rates ranging from 55% to 87%, depending on disease stage (3, 4). In addition, advances in radiation delivery have reduced doses to surrounding tissues, thus reducing the incidence of early and late complications (2). However, there is still debate regarding the effectiveness and safety of high-dose-rate (HDR) brachytherapy compared to lowdose-rate (LDR) brachytherapy for the treatment of cervical carcinoma (3e5). The isotopes most commonly used for intracavitary treatment of cervical cancer are g-emitting and include cobalt-60, cesium137, and iridium-192 (6). Since its discovery in the 1950s, californium-252 (252Cf) has been found useful for intracavitary and interstitial RT (6e10). 252Cf is primarily neutron-emitting, compared to the g-ray-emitting sources typically used, and offers many advantages over g emitters (6, 8). As interest has grown in the use of 252Cf for brachytherapy, studies, although few, have begun to examine its usefulness for the treatment of pelvic cancers. Zhao et al. (10) treated 128 patients with stage IIA to IIIB cervical cancer by using 252Cf brachytherapy combined with external radiation and reported 3- and 5-year local control rates of 93.5% and 87.9%, respectively. Lei et al. (9) treated 40 patients with stage IIB to IVA endometrial cancer with 252Cf intracavitary therapy combined with external radiation, and, with an average follow-up of 42 months, the authors reported 3-year local control and survival rates of 88% and 75%, respectively. Another study reported a 3-year local control rate of 94% and a 3-year overall survival rate of 82% with HDR 252Cf, which were slightly higher values than those with current traditional intracavitary afterloading RT (11).Other studies have reported results with 252Cf that were superior to those with g emitters for the treatment of cervical cancer and other pelvic tumors; however, all prior reports used HDR 252Cf (6, 8, 12). The aim of this retrospective study was to evaluate clinical outcomes and complications of cervical cancer patients treated with LDR 252Cf intracavitary afterloading RT combined with external beam radiation.
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external conformal RT. Pelvic conformal RT was selected in order to reduce skin radiation injury and to improve therapeutic effects. For patients with tumors 4 cm in diameter, external beam radiation was administered (1.8 Gy/day, five times per week) until the dose reached 20 Gy, and then 252Cf neutron intracavitary afterloading RT (once per week) was begun, and the frequency of external beam radiation was changed to four times per week. For patients with tumors >4 cm, 252Cf RT was administered one to two times before whole-pelvis external beam radiation was begun. This study was approved by the Institutional Review Board of our hospitals, and the requirement for informed patient consent was waived due to the retrospective nature of the study.
External beam radiation therapy A 10-MV linear accelerator was used to perform pelvic external conformal RT. The upper boundary was the fifth lumbar vertebra (in order to cover the common iliac lymph nodes); the lower boundary was the lower edge of the obturator foramen (covering the upper half of the vagina); the left and right boundaries were 1.5 to 2 cm beyond the outside of the true pelvis; and the anteroposterior field was usually 16 mm 16 mm. The anterior edge of the lateral fields reached the pubis symphysis (including the external iliac lymph nodes), and the posterior edge was located at the junction of the second and third sacral vertebrae (including the presacral lymph nodes). If the primary cervical lesion was large and the uterosacral ligament was involved, the posterior edge was adjusted so that it would reach the level of the third and fourth sacral vertebrae, and the lateral fields were usually 10 to 12 cm 16 cm. The small intestine was protected during lateral field irradiation. At the beginning of therapy, the dosage was 1.8 Gy/ day, five times per week. After the dose reached 20 Gy, 252Cf neutron intracavitary afterloading radiotherapy (once per week) was begun, and the frequency of external beam radiation was changed to four times per week because external beam radiation was not administered on the day when the intracavitary afterloading radiotherapy was given. When the dose reached 30 Gy, a 3-cm lead screen was placed at the center, and anteroposterior four-field radiation was performed until the total dose (DT) was 46.8 to 50.4 Gy.
Intracavitary afterloading RT
Methods and Materials The records of 96 patients with newly diagnosed primary cervical cancer (a diagnosis which was confirmed by biopsy results), who were treated with RT using 252Cf at the Armed Police Hospital of Hangzhou, Hangzhou, Zhejiang Province, PR China, from September 2006 to June 2010, were retrospectively reviewed. In all cases, the diagnosis of cervical cancer was confirmed by histopathological examination of cervical biopsy specimens. Cervical cancer was staged according to the clinical staging system developed by the International Federation of Gynecology and Obstetrics (FIGO, 1994) (13). Tumor size, lesion range, and lymph node enlargement or metastasis were determined using abdominal and/or transvaginal B-mode ultrasonography, computed tomography (CT), or magnetic resonance imaging (MRI) before treatment. The conventional scheme of RT consisted of LDR 252Cf intracavitary afterloading RT combined with four-field pelvic
A neutron brachytherapy machine (model ZH-1000; Burlington Technology Development Co., Ltd., Shenzhen, China) was used. The radioactive source was 252Cf with a half-life of 2.65 years, and the average energy was 2.35 MeV. The radioactive source was first used in 2001, and it decayed to 120 mg in September 2006, and then to 61.5 mg in September 2009. The dose rate at point A was 1.8 to 2.2 Gy/h during the treatment for cervical cancer in this study. Relative biological effect (RBE) values ranged from 4 to 6.38, which were in the LDR range. The duration of each treatment was approximately 3 h. The dosage delivered to point A was 6 Gy/fraction, once per week, for a total of seven treatments (the first three were three-canal cervical treatments, and the next four were single-canal cervical treatments). The cumulative dose was 42 Gy. The dosing proportion of the cervix to the vagina was 1.0 to 0.5 to 0.6 (14). For patients in whom the exogenous cervical tumor was >4 cm in diameter or a large ulcerative lesion with significant bleeding
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was present, one or two vaginal vault dual-canal tumor elimination treatments with 252Cf neutron afterloading RT were administered before external beam RT. The reference point was 5 mm submucosa, 10 Gy/fraction, once per week. The tumor-eliminating dose was not included in the dose delivered to point A. Pelvic external conformal radiotherapy was begun on the second day after intracavitary treatment was begun, which was followed by the conventional RT scheme. If biopsy analysis confirmed tumor infiltration in the middle and/or lower segment of the vagina before treatment, vaginal treatment was given using a vaginal plug after the conventional treatment. The reference point for the tumor elimination dose was 5 mm submucosa, and the reference dosage was 7 Gy/fraction, once per week, repeated three times. In all patients, if the hemoglobin level was <80 g/l at admission, measures were taken to increase the level to a minimum of 100 g/l in order to increase the tumor’s sensitivity to radiation. Uterine tandem applicators (Burlington Technology Co., Shenzhen, China) and a pair of ovoids were used during intracavity brachytherapy application. The applicator was inserted after routine sterilization and was positioned under the radiotherapy simulator. Appropriate anterior and posterior vaginal packing was used to fix the applicators’ positions and to displace the bladder and rectum away from the vaginal applicators. Then, the therapeutic plan was designed based on acquired imagery data, and radiation therapy was started. The applicator was removed after the treatment. The applicator allows the radioactive source to reach the lesion along the designated tract, guaranteeing maximal and homogenous radiation dose exposure to tumor tissues. The applicator is
International Journal of Radiation Oncology Biology Physics designed in accordance with the contour of the specific lesion. Representative images of isodose distribution of 252Cf application and applicator are shown in Figure 1.
Concurrent chemotherapy Sixty patients received concurrent chemotherapy given on Days 1 to 4 and Days 21 to 24 after pelvic external beam radiation. Exclusion criteria for concurrent chemotherapy were stage I to IIA cancer and tumor size of <4 cm, age >70 years, poor physical status (e.g., evidence of malnutrition; albumin level <30 g/l, blood leukocyte count <4.0 109 cells /l; platelet count <80 109 cells/l; hemoglobin level <80 g/l), severe cardiovascular disease, liver and/or kidney dysfunction, and declined chemotherapy. Chemotherapy consisted of intravenous cisplatin, 20 mg/d (infusion velocity, 20 mg/h), and intravenous 5-fluorouracil, 1 g/day (infusion velocity, 0.042 g/h). During treatment, patients received weekly gynecological examinations and pelvic B-mode ultrasonography to evaluate the status of the lesion. Complete disappearance of the tumor mass indicated complete regression (CR).
Follow-up Patients were followed once per month during the first 3 months after treatment, then every 3 months for the first 3 years after treatment, and then once per year. Cytological or histological examination was carried out based on the appearance of the cervix.
Fig. 1. (A) Representative isodose distribution of 252Cf application is shown. (B) A gynecologic applicator is shown. The long tandem is implanted in the uterus, and the two short ovoids are implanted in the bilateral fornix. (C) Connection of the afterloading unit and the applicator (fixed to the table) is shown.
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Table Summary of patient characteristics and treatment outcomes Patient characteristic (n Z 96) Mean age SD (years) Pretreatment tumor size (cm2) 4 cm >4 cm FIGO 1994 stage IB IIA IIB IIIA IIIB IVA Histological type Squamous cell carcinoma Adenocarcinoma Adenosquamous carcinoma Concurrent chemotherapy Treatment efficacy Mean SD time to CR (days) Obtained CR in 21 days Obtained CR in 28 days* Mean SD irregular vaginal bleeding (days) Complications immediately after treatment Mild radiation proctitis Tenesmus Down-bearing distention of the anus Diarrhea Radiocystitisy Complications within 10 months after treatment Radiation proctitis Mean SD follow-up period (months)
Outcome no. (% of total) 54.7 13.7 58 (60.4%) 38 (39.6%) 6 13 49 3 24 1
(6.3%) (13.5%) (51.0%) (3.1%) (25.0%) (1.0%)
87 7 2 60
(90.6%) (7.3%) (2.1%) (62.5%)
23.5 3.4 27 (28.1%) 88 (91.7%) 4.1 2.1
9 9 9 9 4
(9.4%) (9.4%) (9.4%) (9.4%) (4.2%)
4 (4.2%) 27.6 12.7
* Includes 27 patients who achieved complete regression with no visible tumor (CR) in 21 days. y Inflammation in the urinary bladder caused by irradiation.
Statistical analysis Continuous variables were summarized by means standard deviation (SD), and categorical variables were given as percentage values. Survival analyses of mortality and recurrence were performed by using Kaplan-Meier survival curves. Times to CR between those patients with a pretreatment tumor size of 4 cm and those with tumors >4-cm were compared by independent two-sample t-tests. The time effect on tumor sizes was evaluated by a linear mixed model. Statistical analyses were set with a significance level of 0.05. Statistical results were performed using SPSS version 15.0 software (SPSS Inc, Chicago, IL).
Results Patient characteristics Patient demographic and clinical data are presented in Table. The mean SD age of the patients was 54.7 13.7 years (range,
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23e83 years). Six patients had stage IB, 13 patients had stage IIA, 49 patients had stage IIB, 3 patients had stage IIIA, 24 patients had stage IIIB, and 1 patient had stage IVA disease. Histological classification was squamous cell carcinoma in 87 cases, adenocarcinoma in 7 cases, and adenosquamous carcinoma in 2 cases. In approximately 40% of patients, the pretreatment tumor size was >4 cm.
Treatment efficacy All 96 patients obtained CR during the follow-up period. Within 21 days of treatment, 27 patients (28.1%) obtained CR, and the number increased to 88 patients (91.7%) at 28 days posttreatment (Table). The mean SD time to CR was 23.5 3.4 days. In patients whose tumor diameter was 4 cm, the tumor mass began to shrink within 1 week after 252Cf RT, and the tumor was basically invisible to the naked eye after approximately 2 weeks. In patients whose tumor diameter was >4 cm, the tumor began to shrink within 2 weeks after 252Cf RT, and the tumor was basically invisible to the naked eye after approximately 4 weeks. Patients with pretreatment tumors >4 cm took significantly longer to reach CR than those with pretreatment tumor size of 4 cm (26.7 1.9 days vs. 21.4 2.4 days, respectively, p < 0.001). After 252Cf RT, vaginal bleeding was fully controlled in 80 patients within 1 to 8 days, and their irregular vaginal bleeding was controlled within an average of 4.1 2.1 days. Five patients were lost to follow-up. The mean SD follow-up period for the remaining patients was 27.6 12.7 months and ranged from 6 to 48 months (36 patients were followed for 36e48 months). Five patients died due to recurrence or metastasis; 1 patient died within 12 months of treatment; and 2 patients died within 24 months, 1 patient within 30 months and 1 patient within 36 months of treatment. Three-year survival and 3-year diseasefree recurrence rates were 89.6% and 87.5%, respectively (Fig. 2). A significant time effect was observed in tumor size after treatment (p < 0.001). The mean pretreatment tumor size was 17.63 13.31 cm2 and had decreased to 6.85 cm2 7 days after treatment. At 14, 21, and 28 days after treatment, mean tumor sizes were 2.09, 0.43, and 0.02 cm2, respectively (Fig. 3).
Complications Complications are summarized in Table. Immediately after treatment, 9 patients (9.4%) experienced mild radiation proctitis with symptoms of tenesmus, down-bearing distention of the anus, and diarrhea but without difficulty in defecation or bloody stool. They were treated with retention enemas consisting of 100 ml of saline, 0.8 g of cimetidine, 5 mg of dexamethasone, 6 g of montmorillonite powder, 10 mg of anisodamine, 1 mg of vitamin B12, and 80,000 units of gentamicin daily for 2 weeks. Another 4 patients (4.2%) experienced radiocystitis, which manifested as urinary frequency and urgency and pain while urinating; no patient experienced hematuria. These symptoms might have been related to the long duration of urethral catheter placement during each treatment (because the neutron source was in the second half-life, the duration of each treatment was 3 h). Patients were encouraged to increase their intake of water (hyperhydration, diuresis), and antibiotics were administered for 7 to 10 days. All symptoms resolved within 1 month after treatment. In the follow-up period, 4 patients (4.2%) experienced radiation proctitis for 10 months after treatment, which manifested as diarrhea,
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Fig. 2.
Kaplan-Meier survival curves for mortality (A) and recurrence (B) are shown.
tenesmus, down-bearing distention of the anus, difficult defecation, and bloody stool. They were treated with retention enemas as described above, intravenous hemostatic agents, antibiotics, and cimetidine and dexamethasone for 2 weeks. The symptoms were relieved after a week’s treatment, and disappeared after 2 weeks.
Discussion In this study we evaluated clinical outcomes and complications of LDR 252Cf intracavitary RT combined with external beam radiation for the treatment of 96 patients with stage IB to IVA cervical cancer and found all patients achieved CR, there were minimal side-effects, and 3-year survival and 3-year disease-free recurrence rates were 89.6% and 87.5%, respectively. Because two half-lives had passed, the 252Cf RT could be considered LDR. Brachytherapy combined with external beam radiation therapy is an effective means of treating cervical cancer, and g-rayemitting isotopes have included cobalt-60, cesium-137, and iridium-192. However, g-rays are associated with low linear energy transfer, and thus, their effects are affected by the oxygen content of the cells and the cell cycle phase (10). Since the late 1960s, 252Cf has been used as a radioactive source for intracavitary treatment in clinical practice (7, 9, 10, 15e17). The halflife of 252Cf is 2.65 years, and the average energy is 2.13 MeV (18); it releases g-rays and neutrons during decay; the Kerma rate of the neutrons is 15 times that of g-rays, and in the 1-cm standard water model, 80% of the total absorption comes from neutrons and 20% of absorption comes from g-rays; therefore, 252Cf is considered a neutron source (18). The RBE of a neutron source is higher than that of g emitters because g emitters have the disadvantage of low linear energy transfer, and, thus, their effects are affected by the oxygen content of the cells and cell cycle phase. Therefore, compared to g emitters, a neutron source is superior with respect to tumor damage (6, 10, 17). The reported 5-year survival rate in patients with cervical cancer undergoing HDR g-ray (cesium-137 and iridium-192) intracavitary afterloading RT combined with external beam radiation is between 60% and 80% (3e5). A study of 128 patients
with cervical cancer treated with HDR 252Cf neutron intracavitary afterloading RT combined with external beam RT by Zaho et al. (10) reported a 5-year survival rate of 70% to 80%. In a study in China of 115 patients with cervical cancer, Lei et al. (17) reported 5-year survival and local control rates of 79.2% and 82.6%, respectively, after 252Cf neutron intracavitary afterloading RT combined with whole-pelvis external beam RT. Tacev et al. (12) randomized 227 patients with stages IIB and IIIB cervical cancer to receive external beam radiation and either 252Cf or conventional g-ray intracavitary brachytherapy. Significantly better 5-year survival rates were seen in patients with both stages of cancer in the 252Cf-treated group than in the group that received conventional treatment. Debate remains as to the safety and efficacy of HDR versus LDR intracavitary therapy for the treatment of cervical cancer, although a recent meta-analysis by Viani et al. (4) indicated no differences between HDR and LDR with respect to overall survival, local recurrence, and late complications for stages I, II,
Fig. 3.
Tumor size is shown after treatment.
Volume 83 Number 3 2012 and III disease. In the current study, we used LDR 252Cf neutron intracavitary afterloading RT combined with pelvic external conformal radiotherapy, and the short-term CR rate was 100%, the average time to CR was 23.5 days, the 3-year local tumor control rate was 93.3%, and the 3-year survival rate was 88.8%. These results are similar to those in other reports of 252Cf therapy (7, 11, 13) and are comparable or better than results obtained using conventional g-ray emitters (1, 3, 5). In addition, the incidence of late radiation proctitis (5%) was lower than that in patients treated with HDR 252Cf intracavitary RT (6.69%) (17) and that in patients treated with iridium-192 afterloading (12%) (5). These results indicate that LDR 252Cf with a source intensity of 120 to 61 mg is capable of destroying tumors, has a high RBE (4e6), and causes little damage to normal tissues. Limitations of this study must be considered. First, this is a retrospective study. Second, the study did not include a control group in which a different radioactive source was used for treatment; thus results can only be compared to other reports in the literature.
Conclusions In summary, LDR 252Cf intracavitary afterloading RT is effective for the treatment of cervical cancer and provides results similar or superior to those using traditional g emitters. This method results in rapid tumor regression and is associated with minimal complications. Further clinical study of the use of 252Cf intracavitary afterloading radiotherapy is warranted.
References 1. Narayan K, van Dyk S, Bernshaw D, et al. Comparative study of LDR (Manchester system) and HDR image-guided conformal brachytherapy of cervical cancer: Patterns of failure, late complications, and survival. Int J Radiat Oncol Biol Phys 2009;74(5):1529e1535. 2. Ikushima H. Radiation therapy: State of the art and the future. J Med Invest 2010;57(1e2):1e11. 3. Hareyama M, Sakata K, Oouchi A, et al. High-dose-rate versus lowdose-rate intracavitary therapy for carcinoma of the uterine cervix: A randomized trial. Cancer 2002;94(1):117e124. 4. Viani GA, Manta GB, Stefano EJ, et al. Brachytherapy for cervix cancer: Low-dose rate or high-dose rate brachytherapydA metaanalysis of clinical trials. J Exp Clin Cancer Res 2009;28:47.
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5. Toita T, Kakinohana Y, Ogawa K, et al. Combination external beam radiotherapy and high-dose-rate intracavitary brachytherapy for uterine cancer. Analysis of dose and fractionation schedule. Int J Radiat Oncol Biol Phys 2003;56(5):1344e1353. 6. Maruyama Y, van Nagell JR, Yoneda J, et al. A review of californium252 neutron brachytherapy for cervical cancer. Cancer 1991;68(6): 1189e1197. 7. Maruyama Y, Bowen MG, Van Nagell JR, et al. A feasibility study of 252Cf neutron brachytherapy, cisplatin þ 5-FU chemo-adjuvant and accelerated hyperfractionated radiotherapy for advanced cervical cancer. Int J Radiat Oncol Biol Phys 1994;29(3):529e534. 8. Maruyama Y. Rapid clearance of advanced pelvic carcinomas by low dose rate 252Cf neutron therapy. Radiology 1979;133(2):473e475. 9. Lei X, Shan JL, Tang C, et al. [Follow-up study of clinical effects of californium-252 neutron intracavitary radiotherapy and external beam radiotherapy in endometrial cancer] [In Chinese]. Zhonghua Fu Chan Ke Za Zhi 2007;42(11):733e736. 10. Zhao H, Wang K, Sun J, et al. Clinical report on external irradiation combined with californium-252 neutron intraluminal brachytherapy for cervical carcinoma treatment. Tumori 2007;93(6):636e640. 11. Shan J, Lei X, Wang D, et al. Californium-252 intracavitary afterloading radiotherapy plus pelvic external beam radiotherapy for the treatment of cervical cancer. Chinese J Obstet Gynecol 2005;40(4): 223e226. 12. Tacev T, Pta´ckova´ B, Strnad V. Californium-252 (252Cf) versus conventional gamma radiation in the brachytherapy of advanced cervical carcinoma long-term treatment results of a randomized study. Strahlenther Onkol 2003;179(6):377e384. 13. Odicino F, Pecorelli S, Zigliani L, et al. History of the FIGO cancer staging system. Int J Gynaecol Obstet 2008;101(2):205e210. 14. Sun J. Brachytherapy for gynecological malignancies. Peking: Peking Union Medical College Press; 2005. 197. 15. Maruyama Y, Feola JM, Tai D, et al. Californinum Cf-252 for pelvic radiotherapy. Oncology 1978;35:172e178. 16. Yamashita T, Kaneta K, Tsuya A. Update on intracavitary therapy with Cf-252 for uterine cervical carcinoma at Japan Cancer Institute Hospital. Nucl Sci Appl 1991;4:193e196. 17. Lei X, Wang D, Shan J, et al. Application of californium-252 neutron in the radiation therapy of cervical cancer as a radioactive source. Chinese J Gynecol Obstet 2006;21(8):125e126. 18. Martin RC, Knauer JB, Balo PA. Production, distribution, and applications of Calfornium-252 neutron sources. Chemical Technology Division, Oak Ridge National Laboratory, Oak Ridge, TN. 1999. Available at: http://www.osti.gov/bridge/purl.cover.jsp;jsessionidZ D27DD516D0E158AA7E37A185BDCB90C3?purlZ/15053-AE6cnN /native/. Accessed 2011.
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Clinical Investigation: Gynecologic Cancer
Low-Dose-Rate Californium-252 Neutron Intracavitary Afterloading Radiotherapy Combined With Conformal Radiotherapy for Treatment of Cervical Cancer Min Zhang, M.D.,* Hong-De Xu, M.D.,y Song-Dan Pan, M.D.,* Shan Lin, M.D.,* Jian-Hua Yue, M.D.,* and Jian-Ren Liu, M.D.z *Department of Oncology, Armed Police Hospital of Hangzhou, Hangzhou, Zhejiang Province, PR China; yCancer Center, Armed Police Hospital of Hangzhou, Hangzhou, Zhejiang Province, PR China; and zSecond Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, PR China Received Apr 11, 2011, and in revised form Aug 4, 2011. Accepted for publication Aug 24, 2011
Summary This retrospective study reviewed clinical outcomes for cervical cancer patients treated with low-dose-rate 252 Cf neutron intracavitary afterloading radiotherapy combined with external beam radiation. LDR 252Cf neutron intracavitary afterloading appeared effective for the treatment of cervical cancer and provided results similar or superior to those with conventional g-emitters. This method resulted in rapid tumor regression and was associated with a low rate of complications.
Purpose: To study the efficacy of low-dose-rate californium-252 (252Cf) neutron intracavitary afterloading radiotherapy (RT) combined with external pelvic RT for treatment of cervical cancer. Methods and Materials: The records of 96 patients treated for cervical cancer from 2006 to 2010 were retrospectively reviewed. For patients with tumors 4 cm in diameter, external beam radiation was performed (1.8 Gy/day, five times/week) until the dose reached 20 Gy, and then 252 Cf neutron intracavitary afterloading RT (once/week) was begun, and the frequency of external beam radiation was changed to four times/week. For patients with tumors >4 cm, 252 Cf RT was performed one to two times before whole-pelvis external beam radiation. The tumor-eliminating dose was determined by using the depth limit of 5 mm below the mucosa as the reference point. In all patients, the total dose of the external beam radiation ranged from 46.8 to 50 Gy. For 252Cf RT, the dose delivered to point A was 6 Gy/fraction, once per week, for a total of seven times, and the total dose was 42 Gy. Results: The mean SD patient age was 54.7 13.7 years. Six patients had disease assessed at stage IB, 13 patients had stage IIA, 49 patients had stage IIB, 3 patients had stage IIIA, 24 patients had stage IIIB, and 1 patient had stage IVA. All patients obtained complete tumor regression (CR). The mean SD time to CR was 23.5 3.4 days. Vaginal bleeding was fully controlled in 80 patients within 1 to 8 days. The mean SD follow-up period was 27.6 12.7 months (range, 6e48 months). Five patients died due to recurrence or metastasis. The 3-year survival and disease-free recurrence rates were 89.6% and 87.5 %, respectively. Nine patients experienced mild radiation proctitis, and 4 patients developed radiocystitis. Conclusions: Low-dose-rate 252Cf neutron RT combined with external pelvic RT is effective for treating cervical cancer, with a low incidence of complications. Ó 2012 Elsevier Inc. Keywords: Brachytherapy, Californium, Cervical cancer, Low-dose rate, Neutron
Reprint requests to: Jian-Ren Liu, M.D., 88 Jiefang Road, Hangzhou, Zhejiang Province, PR China 310009. Tel: 86 571 87784812; Fax: 86 571 87784712; E-mail: [email protected] This work was supported by the National Natural Science Foundation of China (no. 30600193 and 81070914 to J.R.L.), a Qianjiang talent project Int J Radiation Oncol Biol Phys, Vol. 83, No. 3, pp. 966e971, 2012 0360-3016/$ - see front matter Ó 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.ijrobp.2011.08.031
grant from the Bureau of Science and Technology of Zhejiang province, China (no. 2009R10022 to J.R.L.), and by the Health Bureau of Zhejiang Province, China (no. 2007A100 to J.R.L.). Conflict of interest: none.
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Introduction The primary treatment methods for cervical cancer are radiation therapy (RT) and surgery, and RT for cervical cancer includes intracavitary therapy and external beam radiation (1, 2). The combination of intracavitary and external beam radiation has resulted in 5-year survival rates ranging from 55% to 87%, depending on disease stage (3, 4). In addition, advances in radiation delivery have reduced doses to surrounding tissues, thus reducing the incidence of early and late complications (2). However, there is still debate regarding the effectiveness and safety of high-dose-rate (HDR) brachytherapy compared to lowdose-rate (LDR) brachytherapy for the treatment of cervical carcinoma (3e5). The isotopes most commonly used for intracavitary treatment of cervical cancer are g-emitting and include cobalt-60, cesium137, and iridium-192 (6). Since its discovery in the 1950s, californium-252 (252Cf) has been found useful for intracavitary and interstitial RT (6e10). 252Cf is primarily neutron-emitting, compared to the g-ray-emitting sources typically used, and offers many advantages over g emitters (6, 8). As interest has grown in the use of 252Cf for brachytherapy, studies, although few, have begun to examine its usefulness for the treatment of pelvic cancers. Zhao et al. (10) treated 128 patients with stage IIA to IIIB cervical cancer by using 252Cf brachytherapy combined with external radiation and reported 3- and 5-year local control rates of 93.5% and 87.9%, respectively. Lei et al. (9) treated 40 patients with stage IIB to IVA endometrial cancer with 252Cf intracavitary therapy combined with external radiation, and, with an average follow-up of 42 months, the authors reported 3-year local control and survival rates of 88% and 75%, respectively. Another study reported a 3-year local control rate of 94% and a 3-year overall survival rate of 82% with HDR 252Cf, which were slightly higher values than those with current traditional intracavitary afterloading RT (11).Other studies have reported results with 252Cf that were superior to those with g emitters for the treatment of cervical cancer and other pelvic tumors; however, all prior reports used HDR 252Cf (6, 8, 12). The aim of this retrospective study was to evaluate clinical outcomes and complications of cervical cancer patients treated with LDR 252Cf intracavitary afterloading RT combined with external beam radiation.
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external conformal RT. Pelvic conformal RT was selected in order to reduce skin radiation injury and to improve therapeutic effects. For patients with tumors 4 cm in diameter, external beam radiation was administered (1.8 Gy/day, five times per week) until the dose reached 20 Gy, and then 252Cf neutron intracavitary afterloading RT (once per week) was begun, and the frequency of external beam radiation was changed to four times per week. For patients with tumors >4 cm, 252Cf RT was administered one to two times before whole-pelvis external beam radiation was begun. This study was approved by the Institutional Review Board of our hospitals, and the requirement for informed patient consent was waived due to the retrospective nature of the study.
External beam radiation therapy A 10-MV linear accelerator was used to perform pelvic external conformal RT. The upper boundary was the fifth lumbar vertebra (in order to cover the common iliac lymph nodes); the lower boundary was the lower edge of the obturator foramen (covering the upper half of the vagina); the left and right boundaries were 1.5 to 2 cm beyond the outside of the true pelvis; and the anteroposterior field was usually 16 mm 16 mm. The anterior edge of the lateral fields reached the pubis symphysis (including the external iliac lymph nodes), and the posterior edge was located at the junction of the second and third sacral vertebrae (including the presacral lymph nodes). If the primary cervical lesion was large and the uterosacral ligament was involved, the posterior edge was adjusted so that it would reach the level of the third and fourth sacral vertebrae, and the lateral fields were usually 10 to 12 cm 16 cm. The small intestine was protected during lateral field irradiation. At the beginning of therapy, the dosage was 1.8 Gy/ day, five times per week. After the dose reached 20 Gy, 252Cf neutron intracavitary afterloading radiotherapy (once per week) was begun, and the frequency of external beam radiation was changed to four times per week because external beam radiation was not administered on the day when the intracavitary afterloading radiotherapy was given. When the dose reached 30 Gy, a 3-cm lead screen was placed at the center, and anteroposterior four-field radiation was performed until the total dose (DT) was 46.8 to 50.4 Gy.
Intracavitary afterloading RT
Methods and Materials The records of 96 patients with newly diagnosed primary cervical cancer (a diagnosis which was confirmed by biopsy results), who were treated with RT using 252Cf at the Armed Police Hospital of Hangzhou, Hangzhou, Zhejiang Province, PR China, from September 2006 to June 2010, were retrospectively reviewed. In all cases, the diagnosis of cervical cancer was confirmed by histopathological examination of cervical biopsy specimens. Cervical cancer was staged according to the clinical staging system developed by the International Federation of Gynecology and Obstetrics (FIGO, 1994) (13). Tumor size, lesion range, and lymph node enlargement or metastasis were determined using abdominal and/or transvaginal B-mode ultrasonography, computed tomography (CT), or magnetic resonance imaging (MRI) before treatment. The conventional scheme of RT consisted of LDR 252Cf intracavitary afterloading RT combined with four-field pelvic
A neutron brachytherapy machine (model ZH-1000; Burlington Technology Development Co., Ltd., Shenzhen, China) was used. The radioactive source was 252Cf with a half-life of 2.65 years, and the average energy was 2.35 MeV. The radioactive source was first used in 2001, and it decayed to 120 mg in September 2006, and then to 61.5 mg in September 2009. The dose rate at point A was 1.8 to 2.2 Gy/h during the treatment for cervical cancer in this study. Relative biological effect (RBE) values ranged from 4 to 6.38, which were in the LDR range. The duration of each treatment was approximately 3 h. The dosage delivered to point A was 6 Gy/fraction, once per week, for a total of seven treatments (the first three were three-canal cervical treatments, and the next four were single-canal cervical treatments). The cumulative dose was 42 Gy. The dosing proportion of the cervix to the vagina was 1.0 to 0.5 to 0.6 (14). For patients in whom the exogenous cervical tumor was >4 cm in diameter or a large ulcerative lesion with significant bleeding
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was present, one or two vaginal vault dual-canal tumor elimination treatments with 252Cf neutron afterloading RT were administered before external beam RT. The reference point was 5 mm submucosa, 10 Gy/fraction, once per week. The tumor-eliminating dose was not included in the dose delivered to point A. Pelvic external conformal radiotherapy was begun on the second day after intracavitary treatment was begun, which was followed by the conventional RT scheme. If biopsy analysis confirmed tumor infiltration in the middle and/or lower segment of the vagina before treatment, vaginal treatment was given using a vaginal plug after the conventional treatment. The reference point for the tumor elimination dose was 5 mm submucosa, and the reference dosage was 7 Gy/fraction, once per week, repeated three times. In all patients, if the hemoglobin level was <80 g/l at admission, measures were taken to increase the level to a minimum of 100 g/l in order to increase the tumor’s sensitivity to radiation. Uterine tandem applicators (Burlington Technology Co., Shenzhen, China) and a pair of ovoids were used during intracavity brachytherapy application. The applicator was inserted after routine sterilization and was positioned under the radiotherapy simulator. Appropriate anterior and posterior vaginal packing was used to fix the applicators’ positions and to displace the bladder and rectum away from the vaginal applicators. Then, the therapeutic plan was designed based on acquired imagery data, and radiation therapy was started. The applicator was removed after the treatment. The applicator allows the radioactive source to reach the lesion along the designated tract, guaranteeing maximal and homogenous radiation dose exposure to tumor tissues. The applicator is
International Journal of Radiation Oncology Biology Physics designed in accordance with the contour of the specific lesion. Representative images of isodose distribution of 252Cf application and applicator are shown in Figure 1.
Concurrent chemotherapy Sixty patients received concurrent chemotherapy given on Days 1 to 4 and Days 21 to 24 after pelvic external beam radiation. Exclusion criteria for concurrent chemotherapy were stage I to IIA cancer and tumor size of <4 cm, age >70 years, poor physical status (e.g., evidence of malnutrition; albumin level <30 g/l, blood leukocyte count <4.0 109 cells /l; platelet count <80 109 cells/l; hemoglobin level <80 g/l), severe cardiovascular disease, liver and/or kidney dysfunction, and declined chemotherapy. Chemotherapy consisted of intravenous cisplatin, 20 mg/d (infusion velocity, 20 mg/h), and intravenous 5-fluorouracil, 1 g/day (infusion velocity, 0.042 g/h). During treatment, patients received weekly gynecological examinations and pelvic B-mode ultrasonography to evaluate the status of the lesion. Complete disappearance of the tumor mass indicated complete regression (CR).
Follow-up Patients were followed once per month during the first 3 months after treatment, then every 3 months for the first 3 years after treatment, and then once per year. Cytological or histological examination was carried out based on the appearance of the cervix.
Fig. 1. (A) Representative isodose distribution of 252Cf application is shown. (B) A gynecologic applicator is shown. The long tandem is implanted in the uterus, and the two short ovoids are implanted in the bilateral fornix. (C) Connection of the afterloading unit and the applicator (fixed to the table) is shown.
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Table Summary of patient characteristics and treatment outcomes Patient characteristic (n Z 96) Mean age SD (years) Pretreatment tumor size (cm2) 4 cm >4 cm FIGO 1994 stage IB IIA IIB IIIA IIIB IVA Histological type Squamous cell carcinoma Adenocarcinoma Adenosquamous carcinoma Concurrent chemotherapy Treatment efficacy Mean SD time to CR (days) Obtained CR in 21 days Obtained CR in 28 days* Mean SD irregular vaginal bleeding (days) Complications immediately after treatment Mild radiation proctitis Tenesmus Down-bearing distention of the anus Diarrhea Radiocystitisy Complications within 10 months after treatment Radiation proctitis Mean SD follow-up period (months)
Outcome no. (% of total) 54.7 13.7 58 (60.4%) 38 (39.6%) 6 13 49 3 24 1
(6.3%) (13.5%) (51.0%) (3.1%) (25.0%) (1.0%)
87 7 2 60
(90.6%) (7.3%) (2.1%) (62.5%)
23.5 3.4 27 (28.1%) 88 (91.7%) 4.1 2.1
9 9 9 9 4
(9.4%) (9.4%) (9.4%) (9.4%) (4.2%)
4 (4.2%) 27.6 12.7
* Includes 27 patients who achieved complete regression with no visible tumor (CR) in 21 days. y Inflammation in the urinary bladder caused by irradiation.
Statistical analysis Continuous variables were summarized by means standard deviation (SD), and categorical variables were given as percentage values. Survival analyses of mortality and recurrence were performed by using Kaplan-Meier survival curves. Times to CR between those patients with a pretreatment tumor size of 4 cm and those with tumors >4-cm were compared by independent two-sample t-tests. The time effect on tumor sizes was evaluated by a linear mixed model. Statistical analyses were set with a significance level of 0.05. Statistical results were performed using SPSS version 15.0 software (SPSS Inc, Chicago, IL).
Results Patient characteristics Patient demographic and clinical data are presented in Table. The mean SD age of the patients was 54.7 13.7 years (range,
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23e83 years). Six patients had stage IB, 13 patients had stage IIA, 49 patients had stage IIB, 3 patients had stage IIIA, 24 patients had stage IIIB, and 1 patient had stage IVA disease. Histological classification was squamous cell carcinoma in 87 cases, adenocarcinoma in 7 cases, and adenosquamous carcinoma in 2 cases. In approximately 40% of patients, the pretreatment tumor size was >4 cm.
Treatment efficacy All 96 patients obtained CR during the follow-up period. Within 21 days of treatment, 27 patients (28.1%) obtained CR, and the number increased to 88 patients (91.7%) at 28 days posttreatment (Table). The mean SD time to CR was 23.5 3.4 days. In patients whose tumor diameter was 4 cm, the tumor mass began to shrink within 1 week after 252Cf RT, and the tumor was basically invisible to the naked eye after approximately 2 weeks. In patients whose tumor diameter was >4 cm, the tumor began to shrink within 2 weeks after 252Cf RT, and the tumor was basically invisible to the naked eye after approximately 4 weeks. Patients with pretreatment tumors >4 cm took significantly longer to reach CR than those with pretreatment tumor size of 4 cm (26.7 1.9 days vs. 21.4 2.4 days, respectively, p < 0.001). After 252Cf RT, vaginal bleeding was fully controlled in 80 patients within 1 to 8 days, and their irregular vaginal bleeding was controlled within an average of 4.1 2.1 days. Five patients were lost to follow-up. The mean SD follow-up period for the remaining patients was 27.6 12.7 months and ranged from 6 to 48 months (36 patients were followed for 36e48 months). Five patients died due to recurrence or metastasis; 1 patient died within 12 months of treatment; and 2 patients died within 24 months, 1 patient within 30 months and 1 patient within 36 months of treatment. Three-year survival and 3-year diseasefree recurrence rates were 89.6% and 87.5%, respectively (Fig. 2). A significant time effect was observed in tumor size after treatment (p < 0.001). The mean pretreatment tumor size was 17.63 13.31 cm2 and had decreased to 6.85 cm2 7 days after treatment. At 14, 21, and 28 days after treatment, mean tumor sizes were 2.09, 0.43, and 0.02 cm2, respectively (Fig. 3).
Complications Complications are summarized in Table. Immediately after treatment, 9 patients (9.4%) experienced mild radiation proctitis with symptoms of tenesmus, down-bearing distention of the anus, and diarrhea but without difficulty in defecation or bloody stool. They were treated with retention enemas consisting of 100 ml of saline, 0.8 g of cimetidine, 5 mg of dexamethasone, 6 g of montmorillonite powder, 10 mg of anisodamine, 1 mg of vitamin B12, and 80,000 units of gentamicin daily for 2 weeks. Another 4 patients (4.2%) experienced radiocystitis, which manifested as urinary frequency and urgency and pain while urinating; no patient experienced hematuria. These symptoms might have been related to the long duration of urethral catheter placement during each treatment (because the neutron source was in the second half-life, the duration of each treatment was 3 h). Patients were encouraged to increase their intake of water (hyperhydration, diuresis), and antibiotics were administered for 7 to 10 days. All symptoms resolved within 1 month after treatment. In the follow-up period, 4 patients (4.2%) experienced radiation proctitis for 10 months after treatment, which manifested as diarrhea,
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Fig. 2.
Kaplan-Meier survival curves for mortality (A) and recurrence (B) are shown.
tenesmus, down-bearing distention of the anus, difficult defecation, and bloody stool. They were treated with retention enemas as described above, intravenous hemostatic agents, antibiotics, and cimetidine and dexamethasone for 2 weeks. The symptoms were relieved after a week’s treatment, and disappeared after 2 weeks.
Discussion In this study we evaluated clinical outcomes and complications of LDR 252Cf intracavitary RT combined with external beam radiation for the treatment of 96 patients with stage IB to IVA cervical cancer and found all patients achieved CR, there were minimal side-effects, and 3-year survival and 3-year disease-free recurrence rates were 89.6% and 87.5%, respectively. Because two half-lives had passed, the 252Cf RT could be considered LDR. Brachytherapy combined with external beam radiation therapy is an effective means of treating cervical cancer, and g-rayemitting isotopes have included cobalt-60, cesium-137, and iridium-192. However, g-rays are associated with low linear energy transfer, and thus, their effects are affected by the oxygen content of the cells and the cell cycle phase (10). Since the late 1960s, 252Cf has been used as a radioactive source for intracavitary treatment in clinical practice (7, 9, 10, 15e17). The halflife of 252Cf is 2.65 years, and the average energy is 2.13 MeV (18); it releases g-rays and neutrons during decay; the Kerma rate of the neutrons is 15 times that of g-rays, and in the 1-cm standard water model, 80% of the total absorption comes from neutrons and 20% of absorption comes from g-rays; therefore, 252Cf is considered a neutron source (18). The RBE of a neutron source is higher than that of g emitters because g emitters have the disadvantage of low linear energy transfer, and, thus, their effects are affected by the oxygen content of the cells and cell cycle phase. Therefore, compared to g emitters, a neutron source is superior with respect to tumor damage (6, 10, 17). The reported 5-year survival rate in patients with cervical cancer undergoing HDR g-ray (cesium-137 and iridium-192) intracavitary afterloading RT combined with external beam radiation is between 60% and 80% (3e5). A study of 128 patients
with cervical cancer treated with HDR 252Cf neutron intracavitary afterloading RT combined with external beam RT by Zaho et al. (10) reported a 5-year survival rate of 70% to 80%. In a study in China of 115 patients with cervical cancer, Lei et al. (17) reported 5-year survival and local control rates of 79.2% and 82.6%, respectively, after 252Cf neutron intracavitary afterloading RT combined with whole-pelvis external beam RT. Tacev et al. (12) randomized 227 patients with stages IIB and IIIB cervical cancer to receive external beam radiation and either 252Cf or conventional g-ray intracavitary brachytherapy. Significantly better 5-year survival rates were seen in patients with both stages of cancer in the 252Cf-treated group than in the group that received conventional treatment. Debate remains as to the safety and efficacy of HDR versus LDR intracavitary therapy for the treatment of cervical cancer, although a recent meta-analysis by Viani et al. (4) indicated no differences between HDR and LDR with respect to overall survival, local recurrence, and late complications for stages I, II,
Fig. 3.
Tumor size is shown after treatment.
Volume 83 Number 3 2012 and III disease. In the current study, we used LDR 252Cf neutron intracavitary afterloading RT combined with pelvic external conformal radiotherapy, and the short-term CR rate was 100%, the average time to CR was 23.5 days, the 3-year local tumor control rate was 93.3%, and the 3-year survival rate was 88.8%. These results are similar to those in other reports of 252Cf therapy (7, 11, 13) and are comparable or better than results obtained using conventional g-ray emitters (1, 3, 5). In addition, the incidence of late radiation proctitis (5%) was lower than that in patients treated with HDR 252Cf intracavitary RT (6.69%) (17) and that in patients treated with iridium-192 afterloading (12%) (5). These results indicate that LDR 252Cf with a source intensity of 120 to 61 mg is capable of destroying tumors, has a high RBE (4e6), and causes little damage to normal tissues. Limitations of this study must be considered. First, this is a retrospective study. Second, the study did not include a control group in which a different radioactive source was used for treatment; thus results can only be compared to other reports in the literature.
Conclusions In summary, LDR 252Cf intracavitary afterloading RT is effective for the treatment of cervical cancer and provides results similar or superior to those using traditional g emitters. This method results in rapid tumor regression and is associated with minimal complications. Further clinical study of the use of 252Cf intracavitary afterloading radiotherapy is warranted.
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