Anthony E. Howes

Combination of external beam irradiation and multiple-site perineal applicator (MUPIT) for treatment of locally advanced or recurrent prostatic, anorectal, and gynecologic malignancies

We have devised a single after-loading applicator, the Martinez Universal Perineal Interstitial Template (MUPIT), which has been used in combination with external beam irradiation to treat 104 patients with either locally advanced or recurrent malignancies of the cervix, vagina, female urethra, prostate, or anorectal region. Twenty-six patients treated for prostate cancer are excluded because of their short follow-up. Local failure developed in 13 of the 78 remaining patients (16.6%)--major complications developed in 4 patients (5.1%). Follow-up has been 1 year to 7 1/2 years; 60/78 patients have been followed for more than 2 years. All local recurrences and complications occurred before 18 months. The device consists of two acrylic cylinders, an acrylic template with an array of holes that serve as guides for trocars, and a cover plate. In use, the cylinders are placed in the vagina and/or rectum or both and then fastened to the template so that a fixed geometric relationship among the tumor volume, normal structures, and source placement is preserved throughout the course of the implantation. Appropriate computer programs have been developed to calculate the dose from these implants. The advantages of the system are (a) greater control of the placement of sources relative to the tumor volume and critical structures, as a result of the fixed geometry provided by the template and cylinders, and (b) improved dose-rate distributions obtained by means of computerized optimization of the source placement and strength during the planning phase. We conclude that the local control rate (83.4%) with low morbidity (5.1%) achieved with the combination of external beam irradiation and MUPIT applicator in these patients with locally advanced malignancies represents an improvement over previous published results with other applicators.

Postoperative radiation therapy for epithelial ovarian cancer: the curative role based on a 24-year experience.

We updated 152 cases of epithelial ovarian cancer, International Federation of Gynecology and Obstetrics (FIGO) stages I through III, treated at the Stanford Medical Center (Stanford, Calif) with irradiation as the only postoperative therapy. In 133 patients, radiation was directed only to those regions of known disease, while it was delivered to the whole abdomen and pelvis by the Martinez technique in 19 patients. Mean follow-up time was 6.8 years. The results were analyzed as freedom from relapse (FFR) at 15 years; overall, FFR constituted 44% of the patients. Statistically significant differences of FFR appeared between stages II (60%) and III (16%); among the histopathologic variants endometrioid (64%), serous papillary (45%), and undifferentiated (7%); between pathologic grades 2 (68%) and 3 (20%); between amounts of postoperative residual disease less than 2 cm (48%) and greater than 2 cm (16%); and between ages less than 40 (80%) and greater than or equal to 40 (38%). Considering all stages and grades together, FFR in the 54 cases with unfavorable residuum (greater than 2 cm) was 14%. Among the 98 with favorable residuum (none, or less than 2 cm) FFR was 62%; and 14 (39%) of the 36 relapses were in the untreated upper abdomen. Results in the favorable group support effectiveness of irradiation as postoperative therapy. These patterns of relapse suggest that whole-abdominopelvic irradiation would further increase FFR. We believe that, for favorable disease as defined such radiotherapy should be the standard for comparison.

Therapeutic approaches to uterine papillary serous carcinoma: A preliminary report

Uterine papillary serous carcinoma (UPSC) is a recently identified and characterized unique histopathologic subtype of endometrial cancer. Unlike the more common types of endometrial cancer, UPSC has a high likelihood of transperitoneal seeding and upper abdominal recurrence. Since our initial report of 26 patients with UPSC, an additional 10 patients with FIGO stage I disease have been diagnosed, operatively staged, and managed by an individualized approach. Operative staging revealed 5 of the 10 patients to have more advanced disease than had been determined clinically. Adjuvant postoperative abdominopelvic radiation was administered to 6 patients, 4 of whom remain free of disease within the treated area. Two patients received adjunctive hormonal and chemotherapy; neither has recurred. Two patients received no adjunctive therapy. One of these failed initially in the vagina with subsequent recurrence in the lungs and supraclavicular nodes. The value of operative staging and selection of appropriate adjunctive therapy awaits additional patient accrual and follow-up.

Toxicity of open-field whole abdominal irradiation as primary postoperative treatment in gynecologic malignancy

Between June 1979 and March 1985, 77 patients received whole abdominal radiation as the sole postoperative treatment for gynecologic malignancy. With an open-field technique of irradiation, a median of 3,000 cGy was delivered to the entire abdominal contents with partial liver and kidney shielding; the total dose to the pelvis after boosts was 5,100 cGy, and that to the sub-diaphragmatic and para-aortic nodal regions was 4,200 cGy. The primary sites of malignancy were the endometrium in 41 patients, ovary in 25, uterus in 5, fallopian tube in 4, and cervix in 2. Seven patients (9%), all older than 60 years, experienced acute gastrointestinal toxicity that interrupted treatment, only one of whom failed to complete the prescribed course as a result. Hematologic toxicity was sufficient to interrupt therapy in 21 patients (27%), 1 of whom failed to complete therapy as a result. Hematologic toxicity was not increased in elderly patients. All patients were followed up for a minimum of 30 months (median, 43 months) or until death. Six patients experienced a treatment-related bowel obstruction (two of whom had concomitant progressive intra-abdominal disease); the 3-year actuarial risk for a treatment-related bowel obstruction was 9%. This risk was significantly increased by high-dose boosting for residual disease. Only one instance of clinical radiation pneumonitis occurred, and no cases of clinical hepatitis were noted; however, subclinical evidence of pulmonary and hepatic radiation effect was frequent. Whole abdominal irradiation as described has modest toxicity for patients with gynecologic cancer who are at high risk for intra-abdominal failure.

The current status of drug development of hypoxic cell radiosensitizers and their potential role in gynecologic oncology

Both laboratory and clinical data suggest that hypoxia contributes to the failure of radiotherapy to achieve local control of bulky gynecologic tumors. As part of a Phase I trial of hypoxic cell radiosensitizers, 19 women at Stanford University with advanced (n = 6) or recurrent (n = 13) pelvic neoplasms were treated with radiotherapy plus desmethylmisonidazole. Complete or partial response occurred in 42% of patients with some patients achieving local control for over 1 year. It is unknown if the sensitizer added to the results of radiotherapy alone. A Phase I trial of a theoretically superior sensitizer, SR-2508, is soon to begin. It is anticipated that the dose-limiting neurotoxicity seen with misonidazole and desmethylmisonidazole will either be eliminated or will occur at a much higher total dose of drug. Many patients with gynecologic tumors could potentially benefit from participation in the new drug trials.

The use of para-aortic radiation therapy based on lymphangiogram interpretation in uterine cervical carcinoma☆

From January, 1965, to June, 1979, 79 nonrandomized patients with carcinoma of the uterine cervix had a bipedal lymphangiogram (LAG) prior to radiotherapy at the Stanford University Medical Center. In 32 patients the LAGs were interpreted as normal. Of the remaining 47 patients, 28 had LAGs interpreted as positive for metastatic involvement of pelvic nodes alone, 11 as positive for pelvic and para-aortic (PA) metastasis, and 8 as positive in PA nodes alone. Five-year survival and freedom from relapse (FFR) were found to be similar for patients with LAGs interpreted as normal or positive in pelvic nodes only (all stages combined). The addition of elective PA irradiation in those patients with positive pelvic nodes alone (median 5000 rad/5 weeks) did not enhance either survival or FFR in this group. The 19 patients with positive PA nodes had significantly worse survival and FFR when compared with the other groups. Survival was not enhanced by the addition of therapeutic PA irradiation (median 5000 rad/5 weeks) and the 7 patients in this group so treated appeared to have a reduced FFR when compared to the 12 untreated patients. Irrespective of the location of nodal abnormality on LAG and regardless of stage, the majority of relapses (16/23) occurred either centrally or at the pelvic sidewalls. It is concluded that the LAG is a good predictor of subsequent relapse and survival, but that the addition of either elective or therapeutic PA radiotherapy based on LAG interpretation does not affect survival of FFR and should, therefore, be considered for investigational or palliative use only.