J. Yoneda

Therapeutic implications of patterns of recurrence in cancer of the uterine cervix

Five hundred twenty‐six patients with invasive cervical cancer, treated at the University of Kentucky from 1964 to 1976, were followed 2–12 years after therapy. One hundred and sixty patients (31%) developed tumor recurrence. Recurrent cancer was noted within 1 year after therapy in 58% of patients and within 2 years of treatment in 76% of patients. Only 6% of patients with recurrent cervical cancer survived 3 or more years. Stage of disease, cell type, lesion size, and the presence of lymph vascular space invasion by tumor cells were all shown to be prognostically significant. The addition of extrafascial hysterectomy to radiation therapy significantly decreased the incidence of recurrence in stage IB cervical tumors 5 cm or more in diameter. Analysis of this data suggests that radical hysterectomy and pelvic lymphadenectomy is as effective as irradiation only in the treatment of large cell squamous carcinomas 2 cm or less in diameter.

Combined radiation therapy and extrafascial hysterectomy in the treatment of stage IB barrel‐shaped cervical cancer

Seventy‐five patients with bulky barrel‐shaped Stage IB cervical cancers, treated at the University of Kentucky from 1965 to 1981, were the subjects of this investigation. Thirty‐two of these patients were treated with radiation therapy alone and 43 were treated with radiation followed by extrafascial hysterectomy. There were no significant differences in age, gravidity, or tumor cell type between the two treatment groups. Patients were seen at regular intervals from 2 to 11 years after treatment and none were lost to follow‐up. Recurrent cancer was noted in 47% of patients treated by radiation alone as compared to 16% of those treated with combined therapy (P < 0.01). The incidence of pelvic recurrence was reduced from 19% to 2% and extrapelvic recurrence from 16% to 7% in patients treated by combination therapy. No rectal or urinary tract fistulae were noted after extrafascial hysterectomy. The findings of this study suggest that the use of extrafascial hysterectomy following radiation therapy in patients with bulky Stage IB cervical cancer causes a significant reduction in tumor recurrence without producing an increase in treatment‐related complications.

Radiation‐induced tumor regression as a prognostic factor in patients with invasive cervical cancer

Radiation‐induced tumor regression was evaluated as a prognostic factor in 200 patients with invasive cervical cancer treated at the University of Kentucky Medical Center during the years 1973–1977. Radiation responses were classified as complete (Type A), intermediate (Type B), or incomplete (Type C) based upon pelvic examination findings one month following completion of therapy. Patients with Type A response to radiation had a recurrence rate of 5%, as compared with 27% in patients with a Type B response and 85% in patients with a Type C response. The direct relationship between radiation response and the incidence of tumor recurrence was observed in all stages of disease. Seventy‐five percent of patients with Stages IB and IIB disease and a Type C response to radiation developed recurrent cancer, and tumor recurrences were confined to the central pelvis in the majority of cases. Patients with keratinizing squamous cell cancers had the lowest incidence of complete response to radiation. These findings suggest that careful observation of cervical cancer throughout radiation therapy can provide prognostically significant information concerning radiation‐induced tumor regression. The therapeutic implications of this data is discussed.

A review of californium-252 neutron brachytherapy for cervical cancer

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.

Tumor regression and histologic clearance after neutron brachytherapy for bulky localized cervical carcinoma

The response of bulky, advanced Stage IB and early Stage II carcinoma of the cervix to neutron brachytherapy (NT and radiotherapy) was studied using combined NT radiation and extrafascial hysterectomy with histologic evaluation. Scheduling of neutron therapy relative to external beam photon therapy, tumor volume, tumor stage, tumor histology, and clinical tumor clearance were assessed in these studies. NT was easily combined with surgery in this study. Low stage tumors, small tumor volume and ‘early’ neutron implants (scheduled within ± one week of the start of fractionated radiation) showed more frequent histologic clearance of tumor. Long‐term tumor control has been achieved and failures developed distant metastases without pelvic or local recurrence. This experience indicates that NT was effective for tumor clearance and control and represents a promising new modality for localized, advanced tumor 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.

Phase II clinical trial using californium 252 fast neutron brachytherapy, external pelvic radiation, and extrafascial hysterectomy in the treatment of bulky, barrel-shaped stage IB cervical cancer

From June 1977 to June 1983, 32 patients with bulky (>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.

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.

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.

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.