Patient population
Between January 2010 and December 2010, more than 400 patients with primary cervical cancer were treated with concurrent chemotherapy combined with 252Cf NBT and EBRT at the Armed Police Hospital of Guangdong Affiliated with Guangzhou Medical University, Guangzhou, China. The patients with newly diagnosed cervical cancer and without previous treatment were selected. Patients with any of the following conditions were excluded: (1) bone marrow suppression (peripheral blood leukocyte count <3 × 109/L and platelet count <7 × 109/L); (2) uncontrolled acute or sub-acute pelvic inflammatory disease; (3) extensive tumor, qualitative cachexia, or uraemia; (4) acute hepatitis or uncontrolled severe cardiovascular disease; and (5) pregnancy, a history of malignancies, or previous treatment with chemotherapy, surgery, or radiotherapy.
Cervical cancer was staged according to 1997 International Federation of Gynecology and Obstetrics recommendations. Prior to treatment, all patients underwent physical examination, gynecologic examination, chest computed tomography (CT), electrocardiography, and abdominal and urinary system B ultrasound. Also prior to treatment, tumor size and lymph node status were determined with magnetic resonance imaging (MRI) or CT. Lymph node metastasis was defined as the status that lymph node exhibited loss of oval shape and were greater than 1.0 cm in diameter. The Academic Committee of the Armed Police Hospital of Guangdong Affiliated with Guangzhou Medical University approved this study.
252Cf NBT
In the Department of Oncology at the Armed Police Hospital of Guangdong Affiliated with Guangzhou Medical University, 252Cf intracavitary after-loading NBT was performed using an LZH-1000 NBT instrument (Model ZH-1000; Linden Science and Technology, Shenzhen, Guangdong, China). The 252Cf neutron source of this unit was 712.787–503.881 µg with a half-life of 2.65 years, involving a decay process that launches neutron and gamma rays and has a neutron emission rate of 2.3 million neutrons per second, an average energy of 2.14 MeV (gamma rays), an average energy of 0.8 MeV (neutron rays), and a neutron relative biological effect (RBE) of 2–3 [18]. The radioactive source used for the patients included in the present study was changed in 2010.
Prior to the administration of 252Cf NBT, the patients received a rectal barium enema to visualize the rectum, and 7 mL of contrast media was injected into a Foley catheter through a urine catheter inserted into the bladder. A vaginal and rectal bimanual triple diagnosis was obtained by observation of the dilated cervix and vagina. Then, three passive cavity applicators were inserted into the uterine cavity and bilateral fornix, subsequently, the vagina was tight packing with gauze. According to the tumor size, the applicator was inserted after routine sterilization and was positioned and fixed to the vagina and uterine cavity. After the applicator was fixed, orthogonal radiographs of the pelvic cavity were acquired to display the position of the applicator and the extent and size of the tumor (Fig. 1). Dosimetry was prescribed to “point A,” defined by the Manchester system as 2.0 cm superior (along the tandem) to the flange abutting the external cervical os and 2.0 cm lateral from the axis of the tandem.
Correspondingly, the doses were calculated at standardized point B, which is located at 5.0 cm from the uterine central axis and represents part of the obturator lymph nodes as well as the bladder and rectal points.
The dose of 252Cf was calculated in Gy-equivalents (Gy-eq) according to the following formula:
$${\text{D }}\left( {{\text{Gy}} - {\text{eq}}} \right) = {\text{Dn}} \times {\text{RBEn}} + {\text{D}} \gamma \times {\text{RBE}}\gamma$$
where Dn is the dose of the neutron component of 252Cf, Dγ is the dose of the gamma-ray component of 252Cf, RBEn is the relative biological effectiveness of the neutrons, and RBEɣ is the relative biological effectiveness of the gamma rays.
The RBE of the neutron component of 252Cf for the tumor tissue was estimated to be 6 [18–20]. The doses at point A were calculated assuming a high-dose-rate delivery of 6 Gy-eq for each patient per fraction, administered once per week, to deliver a total dose of 30 Gy. Optimized treatment plans were based on tumor size; the exposure of the bladder and rectum was no more than 60% of the dose at point A.
External pelvic irradiation
The use of CT-based treatment planning and conformal blocking was considered the standard methods for EBRT. CT scans of the pelvic cavity were taken to determine the extent and size of the tumor. The external-beam radiation administered to the patients was produced by standard X-ray beams generated from a medical linear accelerator with an energy level of 8 MeV (Elekta, Stockholm, Sweden).
The applied dose was delivered at two opposite fields as divided doses to full and split fields of the pelvis, extending to the para-aortic lymph nodes. The anterior edge of the lateral fields included the external iliac lymph nodes, and the posterior edge included the presacral lymph nodes. In general, the upper boundary was the fifth lumbar vertebra; however, for patients with documented common iliac and/or para-aortic nodal involvement, the upper boundary reached the level of the renal vessels. The lower boundary was located on the lower edge of the obturator or ischial tuberosity, and the left and right boundaries were 1.5–2.0 cm beyond the outside of the pelvis. The typical size ranged from 15.0 to 17.0 cm. For patients with negative lymph nodes (i.e., the lymph nodes without metastasis as determined by CT and/or MRI scans), the irradiation volumes included the gross primary cervical tumor; the uterus; the paracervical, parametrial, and uterosacral regions; and the entire external iliac, internal iliac, and obturator nodal basins. For patients with bulk tumors (diameter >4.0 cm) or suspected nodes confined to the low pelvis, the irradiation volume was extended to cover the common iliacs. For patients with documented common iliac and/or para-aortic nodal involvement, the irradiation field was extended to the level of the renal vessels. The prescribed radiation dose for the clinical target was a daily fraction of 2.0 Gy, administered 5 days per week; a variation of up to 5% was considered acceptable. The total dose administered to the whole pelvis was 45–50 Gy. For patients with bulk tumors, the parametrial disease area was further irradiated with an additional boost of 8–10 Gy in 4–5 fractions, and the dose to the gross pelvic nodes reached 60–65 Gy.
Above all, the total target doses administered to all patients during the treatment were 85 Gy-eq at point A and approximately 60 Gy-eq at point B. In other words, EBRT was initiated (1.8–2.0 Gy/day) for the total dose at point A. Then, NBT at a total dose of 30 Gy-eq was delivered. The period during the treatment with 8-MV X-ray EBRT and 252Cf NBT was 6 weeks.
Amifostine application
To prevent irradiation-related enteritis, all patients received 2 mg (20 mL) amifostine, dissolving in saline to a concentration of 50 mg/mL, in the rectum for 30–45 min once per week [21]. To avoid infection and vaginal perineum contracture, the patients underwent perineal douche every day during the radiotherapy for the pelvis but not on the day of 252Cf NBT.
Concurrent chemotherapy
During pelvic EBRT, all 150 patients received 40 mg/m2 cisplatin on days 1, 8, 15, 22, 29 and 36. Prior to chemotherapy, anti-emetic drugs, preventive measures, and hydration treatments were administered to alleviate chemotherapy-related symptoms. Blood tests, blood biochemistry assessments, and gynecologic examinations were performed weekly to determine whether the lesions had regressed and to evaluate the clinical situation.
Evaluation and follow-up
After completion of therapy, all patients were followed up 1 month after treatment, then every 3 months up to 1 year, and thereafter every 6 months up to 3 years through outpatient department visits. The patients lost to follow-up were classified as censored. The follow-up included routine physical examination, blood cell counts, pelvic examination, MRI of the abdomen and pelvis, chest X-ray radiography, abdominal B ultrasound, cervical/vaginal cytology, and row biopsy for residual or recurrent local cervical tumors.
According to World Health Organization standards related to therapeutic effects in solid tumors, short-term local curative effects observed within 1 month after treatment were categorized as complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). For the patients with CR and PR, the treatment was considered effective. During the first month after treatment, the tumor masses in the abdomen and pelvis were evaluated through MRI. Progression-free survival (PFS) was calculated from the date when radiotherapy was administered to the date of local recurrence, distant metastasis, death, or the last follow-up. Overall survival (OS) was calculated from the date when the treatment of the patients was administered to the date of death or the last follow-up. The irradiation-related adverse effects were graded according to the 1995 Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer (RTOG/EORTC) guidelines. RTOG acute radiation morbidity criteria were used for the evaluations conducted during irradiation or within the first 90 days after treatment. RTOG late radiation morbidity criteria were used to evaluate adverse effects observed after completion of irradiation. Toxicity classified as grade 3 or higher was considered severe. The irradiation-related adverse effects included bone marrow suppression, gastrointestinal reactions, irradiation-related enteritis, intestinal obstruction, intestinal fistula, irradiation-related cystitis, and urinary fistula [7, 9, 13, 15].
Statistical analysis
All data were analyzed using SPSS 17.0 software (SPSS, Inc., Chicago, IL, USA). Kaplan–Meier plots were used for survival analysis and Cox regression was used for the multivariate analysis. Unless otherwise stated, all reported P values were two-tailed. P values less than 0.05 were considered statistically significant.