Therapeutic dosimetry for Cf-252 neutron brachytherapy of pelvic cancer

252Cf (Cf) was used to treat tumors of the cervix and uterus with neutron brachytherapy (NT) in an ongoing clinical trial. Tandem and ovoids insertions were used and combinations of single and multiple applications along with high dose whole pelvic irradiation. Dosimetric analysis of treated cases for patterns of tissue dose were carried out. Tissue dose for Cf-NT was, in general, high for neutron components in the central pelvis only, and fell off rapidly with distance from the applicators. The majority and balance of therapeutic dose was contributed by low linear energy transfer (LET) high energy photon beam radiation to the whole pelvis. Comparison with fast neutron beam therapy (NBT) isodose curves showed that much more homogeneous neutron dose was delivered to the pelvic tumor and organs by NBT. Complication frequency has been reported to be higher for neutron beam therapy than for Cf-NT. It appears that the higher integral neutron biological dose to normal tissues for NBT compared to intracavitary Cf-NT probably contributed to the frequency of side effects.     

RBE of CF-252 neutrons by mouse testes weight loss

Mouse testes weight decreased with increasing radiation dose following exposure to Cf-252 and its mixed neutron plus gamma radiation. The dose response for low dose rate (LDR) Cf-252 followed two components on an exponential plot of log percent weight loss vs. dose. Similar dose-response relationships were observed for acute 60Co or LDR Cs-137 radiations, but these required much larger doses to produce the same effect. The RBE was calculated against acute 60Co and Cs-137. There were no differences between acute 60Co and LDR Cs-137 effects. Cf-252 neutron RBE (n + gamma) was 3.7 for testes weight loss. RBEn for the neutrons-only was 5.1 RBE for the radiosensitive portion was 4.0.     

Study of acute 60Co, low dose rate CF-252 and CS-137 radiation on LSA ascites lymphoma in vivo

Dose response curves were determined for the LSA lymphoma for acute 60Co, low dose rate Cs-137 and Cf-252 radiations using in vivo survival time bioassay. Mean survival times increased with dose with a prominent oxygen effect noted for acute 60Co and Cs-137. OER was lowest for Cf-252 where it was approximately 1.4. The RBEn for oxic LSA cells to Cf-252 neutrons was 3.1 for acute 60Co and 4.2 for Cs-137. It was larger for hypoxic tumor and RBE was 5.3 for 60Co and 5.8 for Cs-137. Survival curves based on survival data used a multitarget dose-response model for photon radiation and exponential dose-response for Cf-252 radiation. When LSA was irradiated in advanced tumor stages in vivo, Cf-252 was much more effective than acute 60Co or LDR Cs-137 for increasing survival time. Tumor response in vivo matched the in vitro irradiated tumor data. No schedule dependence was observed for mixing of 60Co and Cf-252 radiations.     

三维适形放疗结合252锎中子腔内后装照射治疗中晚期食管癌的临床研究

目的:探讨三维适形放疗结合锎(252Cf)中子腔内后装照射治疗中晚期食管癌的疗效、不良反应及晚期并发症。方法:92例中晚期食管癌患者全部采用三维适形放疗结合锎(252Cf)中子腔内后装照射治疗。三维适形放疗总剂量为45Gy-54Gy,分25-30次,5-6周完成;腔内照射3-4Gy/次,1次/周,共2-4次,总吸收剂量10Gy-16Gy。结果:治疗结束3个月进食梗阻缓解率为95%。近期疗效:完全缓解(CR)27%,部分缓解(PR)69.6%。1、2、3年局部控制率分别为82%、51%、32%;1、2、3年生存率分别为:78%、35%、18%;急性放射性食管炎发生率为54%;晚期食管狭窄发生率9%;食管穿孔发生率2%。结论:中晚期食管癌采用三维适形放疗结合锎(252Cf)中子腔内后装照射能够迅速而持久地缓解进食梗阻症状,提高局部控制率及生活质量,近期疗效显著,放疗不良反应未见明显增加。     

Specimen histology after one or two preoperative CF-252 implants for bulky stage IB cervical cancer

Using hysterectomy specimens obtained 1 month after Cf-252 neutron brachytherapy plus fractionated radiotherapy, we determined the fraction of positive and negative specimens with neutron dose for bulky Stage IB cervical cancers. The specimens obtained and studied after an initial Cf-252 insertion when the sources were newer and less decayed were more frequently negative for histological evidence of cancer than after the sources had decayed and 2 insertions were needed. After two insertions to deliver a therapeutic dose preoperatively the specimens were more frequently positive. When a larger initial dose was delivered to the tumor a larger proportion of negative specimens was noted. The size of neutron dose fraction was important to local tumor clearance and to rendering the specimens negative as well as schedule in use.     

三维适形放疗结合252锎中子腔内后装照射治疗中晚期食管癌的临床研究

目的：探讨三维适形放疗结合锎（252Cf）中子腔内后装照射治疗中晚期食管癌的疗效、不良反应及晚期并发症。方法：92例中晚期食管癌患者全部采用三维适形放疗结合锎（252Cf）中子腔内后装照射治疗。三维适形放疗总剂量为45Gy-54Gy,分25-30次,5-6周完成;腔内照射3-4Gy/次,1次/周,共2-4次,总吸收剂量10Gy-16Gy。结果：治疗结束3个月进食梗阻缓解率为95%。近期疗效：完全缓解（CR）27%,部分缓解（PR）69.6%。1、2、3年局部控制率分别为82%、51%、32%;1、2、3年生存率分别为：78%、35%、18%;急性放射性食管炎发生率为54%;晚期食管狭窄发生率9%;食管穿孔发生率2%。结论：中晚期食管癌采用三维适形放疗结合锎（252Cf）中子腔内后装照射能够迅速而持久地缓解进食梗阻症状,提高局部控制率及生活质量,近期疗效显著,放疗不良反应未见明显增加。     

Perioperative neutron brachytherapy with californium-252.

Between 1973 and 1988, 495 patients were treated with Cf-252 neutron brachytherapy. Cf-252 neutron therapy sources developed in the USSR has been used in the trial. A numerical reconstruction method for localization of Cf-252 cell coordinates by projections on orthogonal radiographs has been designed and used for treatment planning. Eight (1.6%) patients with recurrent and persistent head and neck tumors and ages from 32 to 48 years (mean age 43 years) were treated with Cf-252 perioperative neutron brachytherapy. There were three patients with oral cavity, one with oropharynx, three with parotid gland cancers, and one with a skin tumor. The dose rate ranged fro 3.2 cGy/h to 11.1 cG/h, the minimal peripheral dose ranged from 3 Gy to 8 Gy. Initial local control was achieved in all patients. Local recurrence developed in two cases. Three patients died in first year after therapy. Three patients died during the second year. Two patients are long term cures, one patient more than nine years and one eight years, that is 25% of the treated patients.     

Clinical report on external irradiation combined with californium-252 neutron intraluminal brachytherapy for cervical carcinoma treatment

AIMS AND BACKGROUND: Neutron rays produce high linear energy transfer radiation, which has particular radiobiological characteristics. The aim of the study was to observe the curative effects and complications of external irradiation combined with californium-252 (252Cf) neutron intraluminal brachytherapy for treatment of cervical carcinoma. METHODS AND STUDY DESIGN: From December 2000 to December 2004, 128 cases of cervical carcinoma staged IIA to IIIB were treated with 252Cf neutron intraluminal brachytherapy using 8-10 Gy-eq per fraction, once a week. The total dose at reference point A was 36-40 Gy-eq in 4 to 5 fractions. From the second day after 252Cf neutron intraluminal brachytherapy, the whole pelvic cavity was treated with 6 MV X-ray external irradiation, applying 2 Gy per fraction 4 times per week. After 20-24 Gy of external irradiation, the center of the whole pelvic field was blocked with a 4-cm-wide lead shield; the total dose of external irradiation was 44-50 Gy. RESULTS: The short-term curative effects were 95.3% complete remissions and 4.7% partial remissions. The 3-year and 5-year local control rates were 93.5% and 87.9%, respectively. The 3-year and 5-year survival rates were 87.5% and 70%, respectively. The rates of radiation complications were 4.7% for radiation cystitis, 7.8% for radiation proctitis, 6.3% for vaginal contracture and adhesion, and 5.5% for protracted radiation proctitis. The results of univariate and multivariate analysis indicated that differentiation of tumor cells and lymphatic metastasis are the main factors related to the clinical prognosis of cervical carcinoma. CONCLUSIONS: A combination of external irradiation with 252Cf neutron intraluminal brachytherapy for treatment of cervical carcinoma can be well tolerated by patients. The rate of local tumor control is high and radiation complications are few.     

A clinical trial for advanced cervico-vaginal pelvic carcinomas using Californium Cf-252 fast neutron therapy: report of early responses

This report summarizes clinical experiences with Californium (Cf) 252 for the radiotherapy of advanced cervicovaginal carcinomas at the University of Kentucky Medical Center from November 1976 to April 1979. Fifty-nine patients were treated with Cf-252 during this period. After pilot studies, a treatment schedule was developed which appeared to offer improved local control and clearance of these tumors in ～90% of treated patients. However, a longer follow-up period is essential to determine whether local tumor control is sustained or whether local tumor recurrence remains as great a problem as for patients who receive conventional radio-nuclide therapy. Ultimate long term survival and outcome will depend upon the frequency of control of local-regional disease and the frequency of appearance of more disseminated and metastatic disease. Cf-252 neutron brachytherapy was combined with 4500–5500 rad of Cobalt 60 or linear accelerator external beam fractionated radiotherapy for 4–6 weeks. Neutron treated patients whose disease was in appropriate clinical stages were also treated with combined radiotherapy-surgery without problems. Stage dependent regression was noted; low stage tumors responded distinctly better and more rapidly than higher stage tumors. All histological patterns responded, and no unusual severe or unanticipated early side effects or toxic tissue reactions were observed.     

252锎中子腔内照射治疗宫颈癌62例

目的：观察252锎（252cf）中子腔内配合体外照射治疗宫颈癌的疗效及并发症。方法：总结62例未接受过治疗的Ⅱa-Ⅲb宫颈癌患者临床资料。首先用252cf中子腔内照射,宫旁A点剂量8—10Gy／次,1次／周,共治疗4—5次,A点总剂量36—40Gy;中子治疗后第二天用6MV—X射线盆腔外照射,全盆腔野前后对穿照射,2Gy／次,4次／周;外照射剂量20—25Gy后盆腔野中央挡铅4cm,继续四野照射至总剂量45—50Gy。结果：近期疗效：CR93．5％,PR4．2％。5年肿瘤局部控制率80．6％。5年生存率67．7％。单因素及多因素分析结果显示,肿瘤分化程度和淋巴结转移与宫颈癌的临床预后有关。放射性膀胱炎发生率4．8％,放射性直肠炎发生率8．2％,迁延型放射性直肠炎发生率6．5％,阴道挛缩、黏连发生率8．1％。结论：252锎中子腔内配合体外照射治疗宫颈癌,患者能够耐受,局部控制率较高,放疗并发症较低,具有-定的临床应用前景。     

Absence of a demonstrable gain factor for neutron beam therapy of epidermoid carcinoma of the head and neck

A comparison of normal tissue and tumor responses in patients treated with the high energy Fermilab neutron beam and conventional photons (Cobalt and 4 MeV X rays), yielded the following parameters. For neutrons the median dose for significant radiation injury in the irradiated tissues was 31 (±2) Gy and the median dose for local control of the tumor was 26 (±2) Gy. The corresponding doses for photons were 90 (±4) Gy for normal tissue injury and 74 (±3) Gy for local control of the tumor. These figures show that the therapeutic ratio is roughly 1.2 for both neutrons and photons. Similarly, the RBE of neutrons relative to photons is about the same for normal tissue tolerance and for tumor control. Under these conditions, there is no demonstrable therapeutic gain factor for neutrons relative to photons. The overall local control rate was the same for both modalities (44%).     

Evaluation of time-dose and fractionation for 252Cf neutrons in preoperative bulky/barrel-cervix carcinoma radiotherapy

Time-dose fractionation factors (TDF) were calculated for 252Cf (Cf) neutron therapy versus 137Cs for intracavitary use in the preoperative treatment of bulky/barrel-shaped Stage IB cervix cancers. The endpoint assessed was gross and microscopic tumor eradication from the hysterectomy specimen. We reviewed the data obtained in clinical trials between 1976-1987 at the University of Kentucky Medical Center. Preoperative photon therapy was approximately 45 Gy of whole pelvis irradiation in 5 weeks for both 137Cs and Cf treated patients. 137Cs implant was done after pelvic irradiation x1 to a mean dose of 2104 +/- 36 cGy at point A at a dose rate of 50.5 cGy/h. There were 37.5% positive specimens. Using Cf intracavitary implants, dose varied from 109 to 459 neutron cGy in 1-2 sessions. Specimens were more frequently cleared of tumor (up to 100% at appropriate dose) and showed a dose-response relationship, both by nominal dose and by TDF adjusted analysis of dose, dose-rate, number of sessions, and overall time. Limited understanding of relative biological effectiveness, schedule, effect of implants, and dose rate all made it difficult to use TDF to study neutron effects. Relative biological effectiveness (RBE) was estimated and showed that for Cf, RBE was a complex function of treatment variables. In the pilot clinical studies, a value of 6.0 had been assumed. The present findings of RBE for tumor destruction are larger than those assumed. Cf was effective for cervix tumor therapy and produced control without significant side effects due to the brachytherapy method used. The TDF model was of limited value in the present analysis and more information is still needed for RBE, dose-rate, and fractionation effects for Cf neutrons to develop a more sophisticated and relevant model.     

Five-year cure of cervical cancer treated using californium-252 neutron brachytherapy

Female pelvic carcinoma is one of the common malignancies seen at the University of Kentucky Medical Center and often presents in an advanced stage. In 1976, we began to test californium-252 neutron brachytherapy (NT) for its efficacy for control of primary and recurrent advanced uterine, cervix, and vaginal cancers. The first protocol used was 5000-5500 rad of whole pelvis irradiation followed by 1-2 Cf-252 insertions using a single tandem placed in the utero-cervico-vaginal region. Of 27 patients with primary carcinomas treated, 10 are alive and well 5 years later (37%). Two of two recurrent tumors were locally controlled but failed later. These patients had advanced cervical, vaginal, or endometrial carcinomas. In 1977, a transitional year, treatment of only unfavorable stages and presentations with NT was initiated. Similar results were obtained with NT as compared to conventional photon therapy (PT). Further improvement in treatment results can be anticipated as NT brachytherapy is used for advanced cancer therapy by more effective treatment schedules and radiation doses. Cf-252 can be used as a radium substitute and achieved similar rates of tumor control and 5-year survivals.     

Cf-252 neutron brachytherapy of short duration for bulky neck tumors

Cf-252 (Cf) neutron brachytherapy (NT) was tested for treatment of bulky neck tumor masses in 13 patients. Complete regression (CR) or partial regression (PR) was obtained in 100% and local control in 85%. Tumors cleared rapidly and completely after an implant therapy of 4-7 hrs. Short duration Cf-NT can produce rapid and complete clearance of bulky tumors. Efficacy was independent of the implant time duration and without unusual adverse side effects or complications. The median survival time (MST) of patients dying of their disease was 6.8 months and 48% of treated patients survived greater than 18 months despite their advanced diseased status.     

Neutron Radiobiology Revisited

The present paper reviews the experimental results of normal tissue and tumour studies in animals. The dose per fraction dependence of the RBE in normal tissues has been long recognised, together with the steeper increase of RBE at low doses for late responding tissues compared with acute reactions. The dose dependence for tumours is more complex, because of hypoxia and reoxygenation, as well as differences in repair capability after high LET damage. A comparison of tumour and normal tissue RBE values shows that there is little experimental evidence for a therapeutic advantage at clinically relevant doses. In particular, the RBE for slow growing tumours is even lower than that for the faster growing mouse tumours. The reasons for the loss of expected neutron benefits in clinically relevant experiments are discussed. The disappointing prospects for neutrons are contrasted with the current multifactorial approaches to overcoming resistance to more conventional low LET radiations, including acceleration, hyperfractionation and several types of hypoxic cell radiosensitizers.     

Intracerebral neutron brachytherapy for hemispheric glioblastoma multiforme

The University of Kentucky Brain Tumor Study and Research Group has developed a new treatment protocol of interstitial brain brachytherapy using Californium-252 neutron source implantation in 1980. Only patients with malignant gliomas were eligible for this pilot study. Nine patients entered the Phase I trial of the protocol study between November 1980 and October 1981. According to the design of the protocol, all patients who had a verified histologic diagnosis of glioblastoma multiforme underwent postoperative intracerebral Cf-252 neutron source implantation, followed by 6 000 cGy of external photon beam irradiation. The purpose of this pilot study was to test the feasibility of interstitial Cf-252 neutron source implantation and only one implant afterloading applicator was used for brachytherapy. The implant applicator was placed in the center of tumor and the procedure was performed under CT guidance. In the assessment of the procedure, Karnofsky functional performance status, intellectual status, neurological examination, CT scans, and complications were used. All patients tolerated the procedure well and no serious complications were encountered. Despite the quality of these early treatments, there was some evidence of short-term benefit in duration of survival of the patients. We believe that further technical improvement to achieve an adequate isodose distribution to cover the tumor volume might result in longer duration improvement in survival.     

252锎中子腔内照射加外照射治疗宫颈癌110例临床分析

目的 探讨252锎中子腔内照射加外照射治疗宫颈癌的疗效和并发症.方法 2002年11月至2007年11月间,252锎中子腔内照射加外照射治疗宫颈癌110例.全盆照射总剂量为20～30Gy后,中间挡铅4 cm,加量至45～54 Gy,每周4～5次,每次1.8 Gy.252锎中子腔内后装治疗采用SL(n)中子腔内治疗程序,每周1次腔内治疗,共6～10次,每次总剂量为6～8 Gy,A点总剂量为30～51 Gy,中位总剂量为42 Gy.结果 全组110例患者中位随访30个月,全组患者的3年总生存率为79.2%,其中Ⅰ期、Ⅱ期、Ⅲ期和Ⅳ期患者的3年生存率分别为50.0%、84.3%、53.7%和33.3%,Ⅱ 期和Ⅲ期患者间的差异有统计学意义(P＜0.05).全组患者的3年无病生存率为76.2%,其中Ⅱ期和Ⅲ期患者的3年无病生存率分别为80.4%和53.7%.全组患者的3年局部控制率为90.0%.治疗前血红蛋白水平正常者的3年生存率为78.2%,贫血者为42.4%,两组间差异有统计学意义(P＜0.05).病理类型为鳞癌和腺癌患者的3年生存率分别为78.5%和76.9%,肿瘤直径＜4 cm和≥4 cm患者的3年生存率分别为71.2%和68.1%,行介入治疗和未行介入治疗者的3年生存率分别为53.3%和74.5%,差异均无统计学意义(均P＞0.05).全组晚期放射性肠炎的发生率为11.8%,放射性膀胱炎的发生率为2.7%.结论 252锎是一种较好的腔内治疗的放射源,对于宫颈腺癌、直径≥4 cm的宫颈肿瘤以及受中子影响较大区域病变的治疗具有优势.     

252Cf brachytherapy

Value of Californium 252 brachytherapy was discussed from our experience of 117 cases treated with either mold, interstitial or intracavitary application. Differentiated adenocarcinomas, malignant melanomas or recurrent cancers occurred in anoxic scar tissues were considered to be treated more effectively by Californium 252 fast neutron than photon radiation. Optimum absorbed neutron dose was 12-18 Gy. It should be modified depending on condition of surrounding normal tissue, because normal tissue tolerance limits to fast neutron may not be the same as photon radiation.     

Clinical Report on Californium-252 Neutron Intraluminal Brachylherapy Combined with External Irradiation for Cervical Carcinoma Treatment

OBJECTIVE To observe the curative effects and complications of californium-252 （^252Cf） neutron intraluminal brachytherapy （IBT） combined with external irradiation （El） for treatment of cervical carcinoma. METHODS From December 2000 to December 2004, 128 cases of cer vical carcinoma staged into IIA-IIIB according to the International Federation of Gynecology and Obstetrics （FIGO） standards were treated with ^252Cf neutron IBT using 8-10 Gy per fraction, once a week. The total dose at reference A point was 36-40 Gy in 4-5 fractions. From the second day after ^252Cf neutron IBT treatment, the whole pelvic cavity was treated with ^60Co y-ray El, applying 2 Gy per fraction, 4 times per week. After 20-25Gy of El, the center of the whole pelvic field was blocked with 4 cm of lead in width. The total dose of El was 45-50 Gy. RESULTS The short-term therapeutic effects were CR 95.3% and PR 4.7%. The 3 and 5-year local control rates were 93.5% and 87.9%. The overall 3-year survival rate was 87.5% and for Stages Ⅱ and Ⅲ , 90.9% and 81.5% respectively; the overall 5-year survival rate was 70% and for Stages II and III, 76.2% and 61% respectively. The rate of radiation complications was 4.7% for radiation cystitis, 7.8% for radiation proctitis, 6.3% for vagina contracture and adhesion and 5.5% for protracted radiation proctitis. CONCLUSION An combination of ^252Cf neutron IBT with El for treatment of cervical carcinoma can be well-tolerated by cervical carcinoma patients. The rate of local tumor control is high and radiation complications are few.     

Head and neck brachytherapy

Experience accumulated over several decades in the treatment of head and neck tumors by irradiation has demonstrated the need for a high tumor dose to achieve local control. With external beam irradiation alone, it is difficult to spare adjacent normal tissues, resulting in undesirable late effects on the salivary glands, mandible, and muscles of mastication. Interstitial implantation is ideally suited to deliver a high dose limited to the volume of the primary tumor, thus maximizing tumor control while minimizing complications. A large experience has been accumulated with low dose rate (LDR) brachytherapy in treatment of carcinoma of oral cavity, oropharynx, and nasopharynx. Recent analysis of large clinical series provided data indicating that modalities of LDR brachytherapy should be optimized in treating these tumors for increasing therapeutic ratio. LDR brachytherapy is now challenged by high dose rate (HDR) brachytherapy and pulsed dose rate (PDR) brachytherapy. Preliminary results obtained with these 2 last modalities will be discussed.