Jose M. Feola

Biological Effects of Cf-252 Neutrons at Low Dose Rates

The EMT6 tumour of the Balb/c mouse and the LSA ascites lymphoma of the C57BL/YM mouse have been used to study the effects of Cf-252 neutrons at low dose rates. EMT6 and LSA cells were irradiated in vitro in a hypoxic state; EMT6/KY cells were plated after exposure for colony-forming ability assays, while TD50 assays were used to test the tumour-forming ability of LSA cells. EMT6 cells showed r.b.e.n values of 5.3, 4.7, and 3.0 for Cf-252 dose rates of 26.8, 10.2, and 5.2 cGy/hour (= rad/hour), respectively, when compared to Cs-137 irradiations at dose rates of 79.7, 25.7 and 12.1 cGy/hour, respectively. The LSA ascites gave r.b.e.n values of 5.6 and 5.2 at dose rates of 27.0 and 6.94 cGy/hour of Cf-252, when compared to Cs-137 irradiations at 79.6 and 24.9 cGy/hour, respectively. However, changes in r.b.e. values for both systems were entirely dependent on comparison with Cs-137 survival curves.

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 brachytherapy is better than conventional radiotherapy in advanced cervical cancer

Californium-252 (252Cf), a fast-neutron emitting radioisotope, was used for neutron brachytherapy (NT) of 82 patients with advanced (stage III and IV) cervical cancer. The results were compared with caesium-137 brachytherapy; both isotopes were given in combination with high-dose fractionated pelvic radiotherapy. In patients with stage IIIB disease (ie, tumour to the pelvic side-wall), 252Cf intracavitary therapy resulted in 54% 5-year survival compared with 12% in the caesium group. To be effective, Cf-NT must be given before external beam (photon) therapy.

A clinical trial for advanced cervico-vaginal pelvic carcinomas using californium CF-252 fast neutron therapy: Report of early responses☆

Abstract 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.

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.

RBE of spleen CFU-S to low dose rate Cf-252 or photon radiation in vivo

The biological effects of low dose rate (LDR) Cf-252 radiation were compared to LDR Cs-137 photon radiation and acute 60Co radiation. The RBEn for endogenous CFU-S in vivo was 2.1 for neutron radiation at a dose rate of 9.9 cGy/hr of Cf-252 radiation. The value was consistent with previous in vitro experiments where a value of 2.1 was found. For the low doses and low dose rates studied, we tested an acute assay dose following the LDR irradiation to determine dose-effect and RBEn. Organ size shrinkage and regeneration patterns after LDR Cf-252 and Cs-137 were also studied and showed greater growth delay for Cf-252 irradiated lympho-hemopoietic tissues.

Californium Cf-252 for pelvic radiotherapy.

Clinical data about therapy concerning tumors of the female gynecological cancers of the cervix, vagina and uterus are reviewed. Dosimetric, laboratory and radiobiological research data form the basis for an approach to such tumors using Cf-252 as a form of boost brachytherapy. Extreme personnel hazards are a real and important consideration and indicate that maximal containment and isolation procedures should be exercised in its use. But it is anticipated that new possibilities for successful radiotherapy of an important cagegory of tumor will be realised by its clinical evaluation and application.

HeLa cell tumor response to 60Co, Cs‐137, Cf‐252 radiations and cisplatin chemotherapy in nude mice

HeLa cells were implanted into athymic nude mice from tissue culture and solid tumors established (HeLa cell tumor or HCT). Large cell numbers of 1 x 107 were required to obtain consistent and progressive growth, and tumor growth followed a Gompertzian mode. Irradiation studies were carried out using acute Cobalt‐60 (60Co), low‐dose‐rate (LDR) Cs‐137 and LDR Cf‐252. Cf‐252, a neutron‐emitting radioisotope, produced an immediate tumor shrinkage and regression response after a dose of 279 cGy. Acute 60Co or LDR Cs‐137 irradiation with 1000 cGy had little effect on the HCT. After a dose of 2000 cGy of 60Co radiation tumor shrinkage followed a latent period of approximately 5 days. Cisplatin had no effect on the HCT in nude mice in stationary or late exponential growth.

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.

RBE of spleen CFU-S to low dose rate Cf-252 neutron or photon radiation

SummaryThe RBE of Cf-252 neutron irradiation was determined for hemopoietic tissue using spleen CFU-S. Radiosensitivity was compared to acute Cobalt-60 radiation and low dose rate Cesium-137 under identical irradiation conditions. The RBE for the neutron component of the Cf-252 radiation was 2.1. No dose rate effect was observed for hemopoietic CFU-S to acute doses or low dose rate photon irradiation.