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Twenty-seven patients with operable Stage II cervical cancer with a mean diameter tumor of 8.0 cm were studied in a feasibility study using preoperative 252Cf implants plus whole-pelvis radiation to 45 Gy followed by extrafascial total abdominal hysterectomy and bilateral salpingo-oophorectomy 4 to 6 weeks later. Hysterectomy specimens were studied by a set protocol. With the protocol used, 13/27 (51%) specimens and abdominal stagings were negative for residual tumor. The survival rate for the patients with negative findings was 93% at 5 years. In 14/27 (49%) patients the specimens were positive for residual tumor. In contrast, the 5-year survival rate for this group was 46% (P less than 0.001). In these patients several interrelated factors were determined to be of importance, i.e., (1) tumor size greater than 8 cm in maximum diameter, (2) positive or negative residual tumor status, and (3) total dose of radiation given. Survival was lower for larger tumors and specimens were more likely to show residual tumor. A lower treatment dose led to more positive specimens, as well as to poorer survival. While the patients with Stage II disease fared very well when negative specimens were found, further prospective studies of the appropriate treatment for those with positive tumor specimens are needed.

Since 1976 a clinical trial has been conducted to test the feasibility, the potential, and to develop methods for using the neutron-emitting radioactive isotope, californium-252 (Cf-252), for the treatment of cervical cancer. A total of 218 patients were treated in the initial study period from 1976 until 1983. The trials initially treated advanced (Stages III and IV) cervical cancer patients using different doses and schedules; they were extended to include unfavorable presentations of Stages I and II because of favorable results in the initial trials. The authors began to treat patients with Stage IB bulky or barrel-shaped tumors and the majority were treated with both radiation and hysterectomy. Actuarial survival was determined for Stage IB disease and was 87% at 5 years and 82% at 10 years. For those tested with preoperative radiation it was 92% at 5 and 87% at 10 years. For Stage II, it was 62% 5 years and 61% at 10. Survival 5 years after combined radiation and surgical therapy for Stage II disease was 68%. For Stage III, it was 33% at 5 years and 25% at 10. However, 5-year survival using the early neutron implant was 46% versus approximately 19% for delayed Cf-252 or cesium 137. Different schedules and sequences of neutrons and photons greatly altered outcome. Neutron treatment before external photon therapy was better for all stages of disease. Only about 5% of all patients developed complications after neutron therapy. No hematologic or mesenchymal second tumors were observed. Neutron brachytherapy was found to be very effective for producing rapid response and greatly improved local control of bulky, barrel, or advanced cervical cancers. The clinical trial identified and evolved schedules, doses, doses per session, and developed methods different from standard photon therapy but highly effective for local control and cure of cervical cancers of all stages. Clinical and radiobiologic understanding for the use of neutron therapy was greatly advanced by this trial. Future trials will focus on patients with advanced disease and will require evaluation of adjuvant chemotherapy studies and neutron-enhancing chemicals.

252Cf neutron brachytherapy was tested in a feasibility trial for efficacy for cervix cancer therapy vs. high stage radioresistant and subsequently for all stages of disease. Actuarial survival curves were analyzed for 218 patients treated between 1976 and 1983 and followed five to 14 years to the present time. A variety of doses, schedules and methods for brachytherapy was tested during this period, and a dose-response relationship for tumor eradication studied. All treatments were combined with whole-pelvis photon radiotherapy to approximately 45 to 60 Gy. This combination was found effective, particularly if an early implant schedule was used for the Cf implant, followed by whole-pelvis photon radiotherapy. For bulky/barrel shaped low-stage disease in medically fit patients, 252Cf implants were combined with surgery, i.e., extrafascial hysterectomy and was readily usable for treatment without complications and with high cure rates (92% five-year survival). All survivals and outcomes to 13 years match the best results of conventional photon radiotherapy. For all stages better results were observed for bulky, barrel, and advanced-stage tumors, especially for local tumor control, if optimal schedules, doses and implant numbers were used. Knowledge about neutron dose, dose per implant, number of implants and combination with photon beam therapy evolved during the trials. 252Cf represents a new quick acting effective radioisotope for human cancer therapy especially for treatment of radioresistant, bulky and high stage cancers.

Twenty patients with Stage IVA and IVB cervic cancers were treated with Californium-252 (Cf) neutron brachytherapy (NT) in a feasibility trial between 1976 and 1986. Eleven patients had Stage IVA disease; nine patients had Stage IVB disease. Patient compliance with therapy was poor in four of nine patients with Stage IVB disease, and the 50% survival time was 6 months. In Stage IVA disease there were 18% 3-year survivals. For those that failed, the 50% survival time was 7.5 months. Because of the frequency of disseminated metastases, effective adjuvant therapy needs to be developed to use after the tumor debulking therapy, especially for Stage IVB disease. A single early Cf-NT implant followed by 6000 cGy of whole-pelvis fractionated radiation would accomplish this adequately for local tumor control and palliation.

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.

A fast-neutron-emitting radioisotope, 252Cf, is being tested in clinical trials of neutron brachytherapy for cervical cancer. The efficacy for histological eradication of bulky stage IB cervical tumors (mean diameter, approximately 6 cm) using combined radiation and surgery was studied in 65 patients treated with 137Cs or 252Cf before surgery during 1983-1986. Forty-four patients were treated with 137Cs and 21 were treated with 252Cf at equivalent doses of radiation. Fifteen of the 44 specimens (34%) were positive after 137Cs therapy. Only one of the 21 specimens was positive after 252Cf therapy (P = .025), and that patient was treated in a delayed schedule 21 days after the start of external-beam irradiation rather than early in the course. 252Cf therapy required a much lower radiation dose and shorter treatment time. The study compared tumor destruction of an identically staged human cervical tumor in situ by direct histological means, using 252Cf neutron therapy or conventional photon therapy at an identical and equivalent dose adjusted by a relative biological effectiveness of 6.0 for 252Cf.

From January 1977 to July 1984, 32 patients with Stage IIIB cervical cancer were treated at the University of Kentucky Medical Center by a combination of outpatient neutron brachytherapy and external pelvic radiation. These patients received 4500 to 5000 rad external photon therapy and two or three outpatient Californium-252 (252Cf) implants, plus sidewall boost irradiation. Treatment results were compared retrospectively to those obtained in a historical control group of patients with Stage IIIB cervical cancer treated with external radiation and conventional photon brachytherapy from 1972 to 1976. Local or regional tumor recurrence developed in 53% of patients treated with neutron therapy and an additional 9% experienced distant metastases. Thirty-eight percent of patients remain free of disease 12 to 96 months (mean, 51 months) after therapy. The 2-year and 5-year survival rates of patients treated with neutron therapy were 53% and 36%, which were not significantly different than those obtained with photon brachytherapy (2-year survival, 61%; 5-year survival, 34%). Complications of neutron therapy were minimal and included proctitis (19%) and vaginal stenosis (9%). There were no cases of enteric fistulae. Outpatient neutron brachytherapy was cost effective and was well tolerated by patients.

A trial of Cf-252 for the radiotherapy of primary or recurrent corpus adenocarcinoma was carried out at the University of Kentucky. The patients with primary tumors were of advanced age, poor general medical condition, and had multiple chronic medical illness, poorly differentiated tumors and/or metastatic Stage IVB disease. Fourteen patients with primary tumors were treated and all achieved complete local tumor control. The five year actuarial disease-free survival rate by the Kaplan-Meier method was 100% for Stage I-III disease, although 36% died of other, usually medical, causes. For eight patients treated with recurrent tumors, long term tumor control was 40% four year actuarial disease survival. Local control was 100% for vault recurrences of 3 cm diameter size, but only 6/8 (75%) cleared their pelvic tumors completely. Those that did not had tumors of massive size, distant metastatic disease and adenosquamous or poorly-differentiated (G3) pattern. One additional cut across, infected tumor was controlled for 26 months. Corpus carcinoma was highly sensitive to Cf-252 neutron radiation therapy.

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.

From June 1977 to June 1983, 32 patients with bulky (greater than 4 cm diameter), barrel-shaped Stage IB cervical cancer were treated at the University of Kentucky Medical Center by a combination of outpatient neutron brachytherapy using californium 252 (252Cf) and external pelvic radiation followed by extrafascial hysterectomy. Nineteen patients had cervical tumors 4 to 6 cm in diameter, and 13 patients had lesions in excess of 6 cm in diameter. A dose of 4500 rad external photon therapy was given from a linear accelerator, and one or two 6-hour 252Cf implants were given during or immediately after external radiation. Extrafascial hysterectomy with bilateral salpingo-oophorectomy was performed 6 weeks after completion of radiation therapy. Complications during and after radiation were minimal and included vaginal stenosis (three) and proctitis (two). Tumor clearance in the hysterectomy specimen was complete in 23 patients (72%) and residual cervical tumor was present in 9 patients (28%). Two patients developed tumor recurrence and died of disease 15 and 27 months after therapy, respectively. Thirty patients remain free of disease 26 to 96 months (median, 52 months) after treatment, and none have been lost to follow-up. The actuarial survival of these patients is 97% at 2 years and 94% at 5 years. Intracavitary neutron therapy is well tolerated and is effective when combined with external radiation and hysterectomy in the treatment of bulky, barrel-shaped Stage IB cervical cancer.

252Cf, a neutron emitting radioactive transplutonium isotope, was tested for its efficacy against advanced bulky Stage III-IV cancers of the cervix in a clinical trial at the University of Kentucky Medical Center. Eighty-two patients were treated during 1976-1979 and followed for 5-year survival and tumor control. Three different treatment methods went on sequentially and concurrently, that is, (a) conventional whole pelvis photon with delayed 137Cs implants, (b) conventional photon therapy with delayed 252Cf implants, and (c) 252Cf implants ("early") preceding photon therapy. There were 12% 5-year survival for Stage IIIB cancers by conventional therapy, and 15% by delayed 252Cf implant therapy. For early 252Cf implant therapy there were 54% 5-year survivals with 4% complications and 65% 5-year local control, but distant metastases became a prominent delayed failure pattern.

Intracavitary Californium-252 combined with whole-pelvis photon radiotherapy was tested as the sole form of treatment for 22 patients with Stage IB carcinoma of the cervix. Californium-252 (Cf) is a fast neutron-emitting radioisotope currently being tested in trials of neutron brachytherapy (NT). The outcomes of the treated group of patients were traced for local tumor control, survival, patterns of failure, and complications. The Cf intracavitary therapy combined with whole-pelvis photon radiotherapy resulted in 95% 2-year and 91% 5-year actuarial survival. There were 9% Grade II-III complications by the Stockholm scale and 4% local failures. These results were obtained in an early clinical trial with a group of largely poor-risk patients with tumors of mean diameter of 4.3 cm.