Jacek Wierzbicki

Regeneration in cervic cancer after 252Cf neutron brachytherapy

Regeneration of clonogens in human cervical cancer was assessed by the pathological evaluation of the hysterectomy specimen after intracavitary 252Cf neutron brachytherapy implants separated by varying time intervals followed by extrafascial hysterectomy. In this study, patients with bulky/barrel shaped Stage IB cervical cancers received 252Cf implants plus approximately 45 Gy of whole pelvis linear accelerator radiotherapy in approximately 25 fractions in 5 weeks followed by hysterectomy 4-6 weeks after radiotherapy. The specimens were studied grossly and microscopically for residual tumor. It was found that the fraction of positive specimens increased with elapsed time interval between implants. These findings support the hypothesis that there is repopulation of surviving clonogens with increased time interval between the implants. The observation also supports current concerns that rapid depopulation of tumor can lead to rapid repopulation, that is, rapid shrinkage of tumor can alter the physiological environment such that clonogens can rapidly regenerate.

A feasibility study of 252Cf neutron brachytherapy, cisplatin + 5-FU chemo-adjuvant and accelerated hyperfractionated radiotherapy for advanced cervical cancer

PURPOSE To evaluate the feasibility and toxicity of 252Cf neutron brachytherapy combined with hyperaccelerated chemoradiotherapy for Stage III and IV cervical cancers. METHODS AND MATERIALS Eleven patients with advanced Stage IIIB-IVA cervical cancers were treated with 252Cf neutron brachytherapy in an up-front schedule followed by cisplatin (CDDP; 50 mg/m2) chemotherapy and hyperfractionated accelerated (1.2 Gy bid) radiotherapy given concurrently with intravenous infusion of 5-Fluorouracil (5-FU) (1000 mg/m2/day x 4 days) in weeks 1 and 4 with conventional radiation (weeks 2, 3, 5, and 6). Total dose at a paracervical point A isodose surface was 80-85 Gy-eq by external and intracavitary therapy and 60 Gy at the pelvic sidewalls. RESULTS Patients tolerated the protocol well. There was 91% compliance with the chemotherapy and full compliance with the 252Cf brachytherapy and the external beam radiotherapy. There were no problems with acute chemo or radiation toxicity. One patient developed a rectovaginal fistula (Grade 3-4 RTOG criteria) but no other patients developed significant late cystitis, proctitis or enteritis. There was complete response (CR) observed in all cases. With mean follow-up to 26 months, local control has been achieved with 90% actuarial 3-year survival with no evidence of disease (NED). CONCLUSION 252Cf neutrons can be combined with cisplatin and 5-FU infusion chemotherapy plus hyperaccelerated chemoradiotherapy without unusual side effects or toxicity and with a high local response and tumor control rate. Further study of 252Cf neutron-chemoradiotherapy for advanced and bulky cervical cancer are indicated. We found chemotherapy was more effective with the improved local tumor control.

Study of biological effects of varying mixtures of Cf-252 and gamma radiation on the acute radiation syndromes: Relevance to clinical radiotherapy of radioresistant cancer

PURPOSE Data for the 30 day bone marrow syndrome (BM-50) and the 6-10 day gastrointestinal (GI-50) syndrome for a one and two fraction schedule and acute and low dose rate irradiation using pure and mixed Cf-252 and photon radiation are presented. METHODS AND MATERIALS The radiations of Cf-252 is a mixture of neutrons and gamma rays. We total body irradiated Balb/c mice of both sexes with acute Co-60, low dose rate Cs-137 and Cf-252 using a 1 x and 2 x schedule. For low linear energy transfer radiations of Co-60 or Cs-137 there was expected to be an increase in the dose to produce the gastrointestinal and bone marrow syndromes with minimal change for Cf-252 neutrons. However, the radiations from Cf-252 are approximately 65% neutrons and approximately 35% photons and hence some repair may be expected. We further altered the proportion of photons in the Cf-252 radiation field by mixing Cs-137 with the Cf-252 sources and total body irradiated the mice to determine the effects on the syndromes. We determined the effects of mixing Cf-252 neutrons with different proportions of photons on the radiation syndromes. RESULTS There was increase in BM-50 and GI-50 doses with fractionated or low dose rate photon irradiations and the dose modifying factors were 1.3-1.4 for the GI syndrome and 1.2 for the bone marrow syndrome. For Cf-252 there was minimal fractionation effect for the GI-50 syndrome, which increased by a 1.1 for x 1 vs. x 2 fractions; for the BM-50 syndrome it rose by a 1.1 factor. For LDR Cs-137 the dose for the GI-50 syndrome rose by a 2.2 fold. For mixed neutron-photon radiation of 0%, 15%, 35%, and 65% eta/gamma mixtures, the dose to produce the BM-50 and GI-50 endpoints dropped sharply from 0 to 35% neutrons and remained flat thereafter. CONCLUSION For major tissues such as the bone marrow and G-I tract, Cf-252 behaved as high linear energy transfer for mixtures of neutrons and gamma rays of approximately 35% neutrons when the radiation were delivered simultaneously at the low dose rates studied. There was little or no additional contribution to the effectiveness of the mixed radiations if neutrons contributed 35% or more of the dose.

Tandem-vaginal cylinder applicator for radiation therapy of uterine adenocarcinoma

Preoperative radiotherapy for stage II adenocarcinoma of the endometrium was studied in 74 patients using the University of Kentucky tandem-vaginal cylinder applicator. The intrauterine tandem and vaginal cylinder were inserted and loaded at the same time or sequentially. Forty to 45 Gy of fractionated whole pelvis photon radiotherapy was combined with the single intracavitary insertion which gave 20 Gy to a parauterine isodose at 2 cm and to the vaginal surface. Treatment with this system gave a 5 year survival rate of 88% with a 4% complication rate for stage II corpus adenocarcinomas.

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.

Cf-252 Neutrons for the Treatment of Superficial Carcinomas

The use of broad beams of thennal/epithermal neutrons £rpm reactors or accelerators used in conjunction with chemical agents containing Boron-10 (10 B) or Gadolinium-157 has been postulated to allow selective therapy in tumor and the target volume. We have proposed that neutron emitting radioactive sources such as Cf-252 implanted in tumor can be used to deliver selective and localized neutron therapy to the tumor and that 10B or Gd-157 enhancement can be used to augment the high LET radiation dose(1,2,3). Neutron capture therapy using chemical agents can be used to enhance local and regional anti-tumor therapy. For Cf-252, the thermal neutrons result from the tumor/tissue interactions of the fast neutrons. The treatment of superficial carcinomas represents a situation where considerable radioresistance can be encountered with recurrent tumors, e.g. melanoma, breast, head and neck cancers and sarcomas, especially after prior surgery and radiation. Both Cf-252 neutron therapy and BNCT have potential for improving the local control and palliation of these turners(4). In this paper we describe plaque therapy methods using Cf-252 for the treatment of superficial carcinomas.

Californium-252 Brachytherapy of Intracerebral Melanoma with and without Administration of Boronophenylalanine Utilizing a Nude Rat Model

Californium-252 brachytherapy has been used clinically to treat bulky localized tumors such as cervical carcinomas and glioblastoma multiforme1,2. Results from the initial therapy trials have been promising, and have stimulated others to consider this therapeutic modality1,2.

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.

CF-252 Neutron Brachytherapy, Neutron Capture Therapy and Teletherapy for Melanoma and Malignant Gliomas

I review a few of our past and our projected clinical studies in this report. We began our work testing Cf-252 (Cf) neutron brachytherapy (NBT) for the treatment of bulky and advanced and localized cancers1. We used the brachytherapy method which is the direct placement of radiation sources into the tumor. When we began our studies other centers had tested but not discovered the great potential of Cf-252 neutrons for cancer therapy of radioresistant tumors. By our early studies we found that a very small radiation dose using Cf-252 produced a very marked effect compared to Cs-1371 photon brachytherapy1. This effect is termed relative biological effectiveness (RBE)1. Tumors also regressed rapidly after treatment compared to photon therapy2. This led to the testing of a novel “early” or “up-front”2 schedule for use of neutrons i.e., performed before photon beam therapy. In our trials we almost always combined Cf-252 implants with large doses of regional photon beam therapy1. These methods have led to highly successful trials based on local tumor control, patient survival and cure and absence of complications or significant late effects. This led to clinical trials testing feasibility, Phase I, Phase II, and Phase III trials, all conducted at a single institution. We have now entered into a phase aimed to test boron neutron capture therapy (BNCT) enhancement of brachytherapy3 and the design and development of a Cf-252 teletherapy machine for hospital-based BNCT4.