External beam radiotherapy with or without californium-252 neutron brachytherapy for treatment of recurrence after definitive chemoradiotherapy.

We aimed to evaluate the application of external beam radiotherapy (EBRT) combined with californium-252 (252Cf) neutron intraluminal brachytherapy (NBT) in patients with local recurrent esophageal cancer after definitive chemoradiotherapy (CRT). Sixty-two patients with local recurrent esophageal squamous cell carcinoma after definitive CRT were retrospectively analyzed; 31 patients underwent NBT+EBRT, and 31 received EBRT alone. The response rate; 1-, 2-, and 3-year overall survival rates; and adverse event occurrence rates were compared between these two patient groups. The response rate was 83.87% (26/31) in the NBT+EBRT group and 67.74% (21/31) in the EBRT group (p < 0.001). The 1-, 2-, and 3-year overall survival rates were 80.6%, 32.3%, and 6.5%, respectively, in the EBRT group, with a median survival time of 18 months. The 1-, 2-, and 3-year overall survival rates were 83.8%, 41.9%, and 6.9%, respectively, in the NBT+EBRT group, with a median survival time of 19 months. The differences between the groups were not significant (p = 0.352). Regarding acute toxicity, no incidences of fistula or massive bleeding were observed during the treatment period. The incidences of severe and late complications were not significantly different between the two groups (p = 0.080). However, the causes of death for all patients differed between the groups. Our data indicate that 252Cf-NBT+EBRT produces favorable local control for patients with local recurrent esophageal cancer after CRT, with tolerable side effects.

Effect of tissue inhomogeneities on dose distributions from Cf-252 brachytherapy source.

The Monte Carlo method was used to determine the effect of tissue inhomogeneities on dose distribution from a Cf-252 brachytherapy source. Neutron and gamma-ray fluences, energy spectra and dose rate distributions were determined in both homogenous and inhomogeneous phantoms. Simulations were performed using the MCNP5 code. Obtained results were compared with experimentally measured values published in literature. Results showed a significant change in neutron dose rate distributions in presence of heterogeneities. However, their effect on gamma rays dose distribution is minimal.

Low-dose-rate californium-252 neutron intracavitary afterloading radiotherapy combined with conformal radiotherapy for treatment of cervical cancer.

PURPOSE: To study the efficacy of low-dose-rate californium-252 ((252)Cf) 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 (252)Cf 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, 6-48 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 (252)Cf neutron RT combined with external pelvic RT is effective for treating cervical cancer, with a low incidence of complications.

Clinical brachytherapy with neutron emitting 252Cf sources and adherence to AAPM TG-43 dosimetry protocol.

Using Monte Carlo methods, neutron dosimetry for 252Cf Applicator Tube (AT) type medical sources available from Oak Ridge National Laboratory (ORNL) has for the first time been determined in terms of TG-43 formalism. This approach, as compared to previous "along-away" formalisms, demonstrates the relative angular independence of dose rate data, when the geometry factor has been removed. As the ORNL-made 252Cf AT type sources are considerably physically larger than most clinical sources used today, the radial dose function increases for radii less than 3.0 mm due to breakdown of the line source model. A comparison of the 252Cf neutron radial dose function with those for other medical sources revealed similarities with that from 137Cs. Differences with respect to previous 252Cf AT source neutron dosimetry data generally increased at increasing distances. This was attributed to differences in the various 252Cf AT source models and phantom compositions. The current status of 252Cf medical source fabrication and calibration procedures at ORNL is presented.

Neutron brachytherapy in the treatment of melanoma.

PURPOSE: The use of Cf-252 for treatment of cutaneous malignant melanoma is presented. METHODS AND MATERIALS: From 1975 to 1992, plaque Cf-252 applicator neutron brachytherapy was performed in nine patients with skin malignant melanoma of head and neck or chest wall. Neutron brachytherapy alone was applied in six patients; two patients received neutron brachytherapy before and one after photon teletherapy. Tumor neutron brachytherapy doses ranged from 3.9-11.5 Gy. Four patients underwent surgical resection of the primary tumor and in six cases, regional lymph node dissection was done. RESULTS: The patients survival times ranged from 3 months to 12 years; 2-year survival was 50% and 30% of the patients lived 3 years. The mean survival time was 39 months. All but 1 patients died because of distant metastases. Local tumor control was achieved in all cases. CONCLUSION: The clinical study shows the relative sensitivity of melanoma to the neutron irradiation and offer new possibilities in Cf-252 brachytherapy.

Clinical evaluation of 252Cf neutron intracavitary therapy for primary endometrial adenocarcinoma.

BACKGROUND: A pilot feasibility study of the neutron-emitting radioisotope 252Cf was done on patients with uterine adenocarcinoma and medically inoperable disease or unfavorable G3 histologic findings. METHODS: 252Cf intracavitary therapy was combined with 40-45 Gy of fractionated whole-pelvis photon therapy. In select patients, hysterectomy was performed. RESULTS: Thirty-one patients with Stage I-III adenocarcinoma of the corpus uteri were treated with 252Cf neutron brachytherapy. The patients treated often were in poor general medical condition and had multiple chronic medical illnesses for which conventional radiation and surgery usually would not be recommended. 252Cf allowed short implant treatment time (hours), was usable in a small number of insertions (the average number of insertions was two), and was useful for treating large volume tumors. Stage and grade of the tumor were important determinants of patient survival. The 5-year actuarial survival was 83% for patients with Stage I disease but only 37% for those with Stage II disease (primarily adenosquamous cell carcinomas). The 5-year survival was 100% for patients with Grade 1 tumors, 88% for those with Grade 2 tumors, and 21% for those with Grade 3 tumors. CONCLUSION: 252Cf neutron brachytherapy was found to be an effective and well-tolerated therapy for endometrial carcinoma. The excellent therapeutic efficacy and good patient tolerance make it suitable for additional evaluation in future Phase II-III trials.

Schedule in Cf-252 neutron brachytherapy: complications after delayed implant therapy for cervical cancer in a phase II trial.

The objective of this study was to review severe complication frequency in a protocol study using a defined prescribed dose combined with fractionated whole pelvis radiotherapy to 40-45 Gy. The method used a dose of Cf neutrons to 35 Gy equivalents (relative biological effectiveness or RBE adjusted) to a total tumor dose of 80 Gy-eq in one to four implant sessions. Compliance was excellent, and most patients received two implants to 35 (0.4) (SE) Gy-eq in two sessions plus external radiation to a total point A or paracervical region dose of 80 (0.3) Gy-eqs. In patients who received delayed implants, the severe complication rate (pelvic necrosis, fistulas) was significantly greater (40% versus 3%). We postulate that neutron brachytherapy caused tumors to regress rapidly and completely, which allowed the neutron dose to adjacent radiosensitive organs (bladder, rectum, sigmoid colon, and bowel) to become excessive. The delayed Cf implant apparently contributed to the greater risk for normal tissue complications.

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.

[Influence of the dose rate and postradiation hyperthermia on the cytogenetic effect of irradiation of cells in the G0 stage by 252Cf and 60Co sources]. / Vliianie moshchnosti dozy i postradiatsionnoi gipertermii na tsitogeneticheskii éffekt pri obluchenii kletok v stadii G0 istochnikami 252Cf i 60Co.

The paper is concerned with the results of a comparative study of radiation injury of chromosomes of human lymphocytes at the G0 stage resulting from the influence of 60Co gamma quanta and high activity 252Cf radiation sources and depending on a dose and dose rate; with the potentialities of modifying a cytogenetic effect of irradiation by postradiation hyperthermia of cells. It has been shown that at the G0 stage of a cell cycle the frequency of chromosome aberrations does not depend on the dose rate of 252Cf radiation within the range of 0.0035-0.35 Gy/min. by the neutron component. Linear correlation between the frequency of induced chromosome aberrations and a dose was observed within a dose range of 0.27-3.1 Gy. Thus, a conclusion is that postradiation hyperthermia at the G0 stage does not almost influence the frequency of chromosome aberrations during 252Cf radiation, and increases it insignificantly during 60Co gamma-radiation.

[Principles of dosimetric planning in contact therapy with highly active Cf-252 sources]. / Prinzipien der dosimetrischen Planung bei der Kontakttherapie mit hochaktiven Cf-252-Quellen.

In clinical practice, some dosimetric problems of contact therapy with CF-252 are not yet sufficiently clarified. One possibility to solve these problems is to apply the conception of total photon-equivalent energy doses. This conception serves to calculate clinical guidance values of the RBE of the Cf-252 neutron constituent for radiogenic late effects in dependence on the total dose rate of the mixed radiation. The correlations indicated are valid for dose rates of 0.05 to 4 Gy/h and 4 to 1.25.10(4) Gy/h. On the basis of these functional correlations and taking into consideration the critical normal tissues of rectum and urinary bladder, the minimum RBE values of the tumors are indicated which allow a therapeutic effect of more than 1 in case of application of Cf-252. The formulas for the RBE dependence of the Cf-252 neutron constituent on the total dose rate permit to take into account any modifications of this value caused by varying source distances in contact therapy. It is concluded from these investigations that in oncologic patients, better results are to be expected from a treatment with high-energy Cf-252 sources, if the other treatment conditions are identical.

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.

Implantation of brain tumors with Cf-252. Use of computed tomography and magnetic resonance imaging to guide insertion and evaluate response.

Magnetic resonance imaging (MR) was evaluated as a guide to planning and follow-up of Cf-252 neutron brachytherapy in 8 patients with malignant glioma of the cerebral hemispheres. A combination of sagittal, transverse, and coronal views allowed three-dimensional assessment of the dimensions and extent of tumor; by comparison, CT scans delineated the tumor less sharply, multiple views were not routinely obtained, and the reconstructed sagittal images were inadequate. Both techniques were complementary in enabling accurate tumor localization as well as separating enhanced zones from central avascular regions and tumor from edema. However, MR images provided more detail than serial CT scans, making MR the preferred method of follow-up.

Intracerebral neutron brachytherapy for hemispheric glioblastoma multiforme. A pilot study.

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.

CT and MR for brain tumor implant therapy using CF-252 neutrons.

Magnetic resonance (MR) imaging of the brain allows very effective localization of tumor in brain, visualization of brain reaction to tumor, peritumoral edema, as well as destruction of normal anatomy and spread of tumor. MR readily imaged the brain in multiple views allowing three dimensional (3D) evaluation and more precise localization of tumor in the depths of the brain. It also assessed the extent of tumor infiltration away from the primary site. In an ongoing study of Cf-252 neutron brachytherapy of hemispheric malignant gliomas of the brain, we have found that the extent of tumor and the planning of the placement of multiple applicators in the brain for implant therapy was facilitated by both CT and MR scanning, but MR allowed better 3D localization, assessment of response and follow-up of tumor response. MR gave additional and different types of information about the tumor than CT scanning based upon proton distribution which greatly aided planning of tumor implant therapy and understanding of patterns of tumor response and recurrence after therapy.

[Blastomogenic effect in rats exposed to separate uptake of osteotropic radionuclides and in combination with 131I]. / Blastomogennyi éffekt u krys pri razdel'nom postuplenii osteotropnykh radionuklidov i v sochetanii s 131I.

A comparative study was made of tumor induction in rats by 45Ca and 90Sr administered separately and in a combination with 131I. The combination of the radionuclides was shown to reduce the occurrence of tumors as compared to 45Ca and 90Sr administered separately.

[Radiation ulcers after Cf-252 treatment of patients with cancer of the tongue]. / Luchevye iazvy posle terapii istochnikami 252Cf bol'nykh rakom iazyka.

A study was made of the frequency, clinical appearance and therapeutic methods of radiation injuries in 12 out of 57 patients who were treated for cancer of the tongue using interstitial therapy with 252Cf. The most frequent radiation injuries were observed in patients (6 out of 18, i.e. 34%) who were treated for recurrent and residual tumors after previous radiotherapeutic courses as compared to the treatment of primary malignant lesions in 6 out 39 (15%) patients. The clinical picture of radiation injuries of the tongue presented an ulcer of various sizes. A clinical classification of radiation injuries of the tongue was developed depending on the degree of the manifestations. Among causative factors the most important role is played by an absorbed tumor dose which when exceeding 9 Gy in patients with primary tumors and 8 Gy in patients with recurrent and residual tumors, resulted in radiation injuries. The development of radiation injuries is also influenced by poor hygiene and the oral cavity, and such harmful habits as smoking and alcohol consumption. Conservative therapeutic measures made it possible to achieve a complete epithelization of ulcers.

A tumor/normal tissue advantage for low dose rate neutron brachytherapy.

Reports on clinical study of Cf-252 pelvic brachytherapy are reviewed and show that complication frequency is low. Low dose rate (LDR) neutron brachytherapy has been shown to be effective against cervical and advanced pelvic cancers; and produces 5 year cures without a high frequency of normal tissue complications. This is attributed to a high relative biological effectiveness (RBE) for the bulky, hypoxic tumor which along with an oxygen enhancement ratio (OER) advantage and dose-rate independent effects, produces rapid tumor regression and good local tumor control. Adjacent normal tissues which are oxygenated have lower RBE values than that of hypoxic tumors. Cf-252 brachytherapy increases the dose differential, therapeutic gain and the probability of local tumor control, since the high RBE of Cf-252 for hypoxic tumor is much less in normal tissues. Cf-252 radiation concentrated in the tumor, and for this reason, has had much fewer attendant normal tissue complications compared to neutron beam therapy.

Neutron and gamma dose distribution for tandem, tandem and ovoid and plaque for intracavitary 252Cf therapy of cervix carcinoma.

252Cf was used to treat tumors of the cervix in an ongoing clinical trial. Tandem and ovoids were used as well as a combination of single and multiple applications. Dosimetric analysis of these treated cases revealed the patterns of neutron dose rate and neutron/gamma ray dose ratios which were achievable using a variety of loading arrangements. Although pelvic tumor reference points and tissue dose was in general similar whether a tandem or tandem plus ovoids were used, vaginal dose was increased over two-fold or more by the use of vaginal applicators and sources. This indicates that a variety of individualized arrangements for different clinical presentations can be used for brachytherapy of gynecological pelvic neoplasm.

[Dosage fields of the "ANET-B" apparatus with 252Cf]. / Doznye polia apparata "ANET-B" s 252Cf.

The paper is concerned with the results of the calculation of dose fields of neutron and gamma-radiation for an ANET-B unit. Experimental measurements were done in the tissue equivalent phantom by using photoluminescent and alumophosphate glasses, thermoluminescent and threshold detectors with neptunium foil. Divergences between calculated and all experimental data did not exceed 10-12%. It has been shown that the ratio of the contribution of neutron and gamma-components of 252Cf radiation for the ANET-B unit to the summary absorbed dose at an arbitrary point of a tissue equivalent phantom depends considerably on a distance between this point and the center of a source and changes from 2 (for a distance of 0.5 cm) to 1 (for a distance of 10 cm).

[Recovery processes in damage to rats by 252Cf]. / Vosstanovitel'nye protsessy pri porazhenii krys 252Cf.

The types of recovery processes were demonstrated in experiments on albino rats damaged with 252Cf. The frequency and the degree of manifestation of both pathological and recovery processes were function of radiation dose and time of its formation. The results obtained indicate that changes induced by the incorporation of 252Cf, within a wide range of doses, are compensated incompletely to be manifested later by sklerotic, hyperplastic and neoplastic processes.