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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.

From November 1987 to April 1989, 1000 women 40 years or older underwent screening vaginal sonography at the University of Kentucky Medical Center (Lexington, KY). Patients included in this investigation were all asymptomatic and had no known pelvic abnormalities. Each ovary was measured in three planes and ovarian volume was calculated using the prolate ellipsoid formula. The upper limit of normal for ovarian volume was 18 cm3 in premenopausal women and 8 cm3 in postmenopausal women. In patients with normal scans, mean ovarian volumes decreased from 6.8 cm3 to 3.0 cm3 with menopause. Thirty-one patients (3.1%) had abnormal vaginal sonograms and 24 underwent exploratory laparotomy. All patients undergoing surgery had ovarian or fallopian tube tumors with dimensions identical to those predicted by ultrasound. Histologic diagnoses of these tumors included the following: adenocarcinoma, one, serous cystadenoma, eight; endometrioma, six; and cystic teratomas, two. Vaginal sonography was performed easily and without complications, and was well accepted by patients. All patients with normal sonograms have been rescreened annually and none have subsequently developed ovarian cancer. Further clinical trials to determine the efficacy of vaginal sonography as a screening method for ovarian cancer are indicated.

Immunoperoxidase staining for carcinoembryonic antigen (CEA) was performed on the tumors of 241 patients with invasive carcinoma of the cervix. Positive tissue staining indicative of a CEA concentration of at least 3 microgram/gm was present in 154 tumors (63%) as opposed to 0 of 30 specimens of normal cervix (p less than .001). Plasma CEA values were obtained at the time of tissue staining on all patients. Plasma CEA concentration was related more directly to total tumor burden (tumor CEA content x extent of disease) than to tumor CEA concentration alone. Progressively rising plasma CEA levels predicted recurrent disease in over 80% of patients whose tumors stained positively for CEA. In contrast, serial plasma CEA values correlated positively with clinical disease status in only 28% of patients whose tumors were devoid of CEA. Immunoperoxidase staining of tissue specimens identifies those patients whose tumors contain high levels of CEA and who therefore should benefit most from subsequent plasma antigen determinations.

One hundred forty-four patients found to have cervical intraepithelial neoplasia (CIN) III on colposcopically directed biopsy who had completed childbearing were treated with a vaginal hysterectomy (112 patients) or abdominal hysterectomy (32 patients). The mean age of these patients was 28.6 years and the mean gravidity, 3.4. All patients had adequate colposcopy of the cervix and vagina. The transformation zone and lesion(s) were completely visualized. The uterus was submitted for histologic examination in all cases. The cervix was sectioned in a radial fashion (minimum 12 sections), and the proximal endocervix and lower uterine segment were sectioned transversely. CIN III was present in the cervix of 117 patients, CIN II in 9 patients, CIN I in 8 patients, and no evidence of residual neoplasia in 9 patients. Microinvasive cancer (1.3 mm stromal invasion without lymph-vascular space invasion) was present in one patient. After surgery, patients were seen every 3 months for 2 years and every 6 months thereafter. All 144 patients were followed up for at least 12 months, 124 patients for 24 months, 103 patients for 36 months, and 60 patients for 60 to 120 months. To date, all patients are alive and well and there have been no cases of recurrent vaginal neoplasia or cancer. These data suggest that: adequate colposcopy is an accurate method to rule out invasive cervical cancer and abdominal or vaginal hysterectomy is an effective therapeutic procedure in women with CIN III who have completed reproductive function.

Surgical specimens from 111 patients with Stage I endometrial cancer were reviewed for the presence of lymph-vascular space invasion by tumor cells. Lymph-vascular space invasion was noted in 16 cases, and occurred most frequently in poorly differentiated tumors with deep myometrial penetration. Tumor recurrence developed in 44% of patients whose tumors demonstrated lymph-vascular space invasion as opposed to only 2% of patients without this finding (p less than 0.001). Of seven patients with lymph-vascular space invasion who experienced tumor recurrence, five developed extra-pelvic metastases. Discriminant function analysis of these data revealed a statistically significant correlation between lymph-vascular space invasion and tumor recurrence, independent of histologic differentiation of myometrial penetration. These findings suggest that lymph-vascular space invasion by tumor cells is an important prognostic variable in Stage I endometrial cancer which should be considered in treatment planning.

From November 1973 to May 1986, 50 patients with Stage I epithelial ovarian cancer were treated at the University of Kentucky Medical Center (Lexington, KY) with oral Alkeran (melphalan) chemotherapy after primary surgery. Twenty-two patients had Grade 1 tumors, 23 patients had Grade 2 tumors, and five patients had Grade 3 tumors. Patients with ovarian tumors of borderline malignancy were excluded from this study. Twenty-eight patients received from six to 11 courses of chemotherapy and 22 patients completed 12 courses of chemotherapy. Chemotherapy was well tolerated and no patient died of chemotherapy-related complications. Thirty-eight patients underwent second-look laparotomy died of disease 41 months after diagnosis and one patient died with no evidence of disease 6 months after treatment. The actuarial survival of the total group of patients was 98% at 2 years and 94% at 5 years. Fewer than 12 months of chemotherapy may be necessary to obtain long-term survival in these patients.

From 1975 to 1987, 80 patients with bulky or barrel-shaped Stage IB cervical cancer were treated with preoperative irradiation and Cs-137 intracavitary implant therapy, before a planned extrafascial abdominal hysterectomy, using a consistent treatment policy. Of the hysterectomy specimens obtained, 37% were positive histologically at 89 +/- 2.3 days after the start of radiotherapy and at 4 to 6 weeks after the completion of radiation therapy. Sixty-three percent were negative after a total external and internal cervix irradiation dose of 9642 cGy at point T. The average point A dose contributed by intracavitary therapy was 2104 cGy. The survival rate at 5 years was 84%: At 10 years the survival rate was 78%. The failure pattern was analyzed for patients who had positive and negative specimens. The patients with positive specimens failed pelvically or pelvically and distantly. Patients with negative specimens failed in extrapelvic or distant metastatic sites. Preoperative radiotherapy led to excellent local and pelvic control of tumor, and the failures became predominantly distant metastases. The combined radiosurgical therapy was tolerated well and allowed surgical staging of disease. This permitted earlier and selective consideration of adjunctive therapy (i.e., paraaortic irradiation, chemotherapy, or chemoradiotherapy). The dose-response data give insight into the effects of photon radiotherapy on bulky or barrel Stage IB cervical cancers and correlate histologic status with failure pattern, outcome, and long-term survival.

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.

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.

From 1973 to 1987, 16 patients with International Federation of Gynecology and Obstetrics (FIGO) Stage I serous papillary endometrial carcinoma were evaluated and treated at the University of Kentucky Medical Center (Lexington, KY). All patients were 60 years of age or older, and all were postmenopausal. Patients were treated with total abdominal hysterectomy, bilateral salpingo-oophorectomy, and paraaortic lymph node sampling, and 38% were noted to have more extensive disease than appreciated clinically. Nine patients were given adjuvant postoperative radiation. Seven patients (44%) developed recurrent cancer with liver, lung, and upper abdomen being the most common sites of spread. Prognosis was most directly related to the presence of lymph vascular space invasion and the depth of myometrial penetration. No patient with serous papillary carcinoma confined to the endometrium developed recurrent cancer. In contrast, the recurrence rate of patients having myometrial invasion was 70% (P less than 0.03). Hormonal therapy was of limited value in the treatment of recurrent disease. This data suggests the need for adjuvant systemic therapy in the treatment of patients with Stage I serous papillary carcinoma of the endometrium who have myometrial invasion.

From 1962 to 1985, 2201 patients with invasive cervical cancer were staged, evaluated, and treated at the University of Kentucky Medical Center. After a thorough evaluation, 25 cases (1.1%) fulfilled the histologic criteria for small cell cancer defined by Reagan and coworkers. These patients were computer-matched for age, disease stage, and lesion size to 25 patients with large cell nonkeratinizing cancer and 25 patients with keratinizing squamous cell cancer. Morphometric analyses of nuclear size and maximum nuclear diameter were performed on all cases without knowledge of cell type. Small cell cancers were characterized by a nuclear area of 160 mu 2 or less and a maximum nuclear diameter of 16.2 mu, which was significantly lower than that for large cell tumors. Thirty-three percent of the small cell carcinomas stained positively for the neuroendocrine markers (neuron-specific enolase [NSE] and chromogranin [CGR]), whereas the remainder contained only epithelial markers such as cytokeratin (CYK) and epithelial membrane antigen (EMA). Small cell cancers were associated with a high frequency of lymph-vascular space invasion and a diminished lymphoplasmacytic response. Patients with small cell cancer had a significantly higher recurrence rate, particularly to extrapelvic sites, than the matched patients with large cell cancers, and their survival was lower. Clinical trials to determine the efficacy of adjuvant chemotherapy in the treatment of small cell cervical cancer are needed.

Seven patients with Stage I uterine sarcomas (greater than or equal to 10 mitoses/10 high-power fields) were treated with surgery plus adjuvant vincristine, dactinomycin, and cyclophosphamide (VAC) chemotherapy in a pilot study conducted at the University of Kentucky Medical Center from 1978 to 1983. Surgery consisted of total abdominal hysterectomy, bilateral salpingo-oophorectomy, and para-aortic lymph node sampling. Chemotherapy was begun within 1 week of surgery, and all patients received at least six monthly courses of VAC. This chemotherapeutic regimen was well-tolerated, and toxicity was minimal. Two patients had recurrent sarcoma, and one of them has died of disease. The remaining five patients are alive and well with no evidence of disease 48 to 73 months after therapy. The recurrence rate of patients with Stage I uterine sarcomas treated with adjuvant VAC chemotherapy was significantly (P less than 0.02) less than that for similar patients treated at this institution (1964-1977) by surgery alone or surgery plus pelvic radiation. These results suggest that primary adjuvant chemotherapy is beneficial in patients with Stage I uterine sarcomas.

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 extra-fascial 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 less than 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 extra-fascial hysterectomy. The findings of this study suggest that the use of extra-fascial 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.

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.