Dolores A. Buchler

THE ADVERSE EFFECT OF TREATMENT PROLONGATION IN CERVICAL CARCINOMA

PURPOSE Proliferation of surviving tumor clonogens during a course of protracted radiation therapy may be a cause of local failure in cervical carcinoma. The effect of total treatment time was analyzed retrospectively in relation to pelvic control and overall survival for squamous cell carcinomas of the uterine cervix. METHODS AND MATERIALS Two hundred and nine patients (Stage IB-IIIB) treated with a combination of external beam and low dose rate intracavitary irradiation were evaluable for study. Multivariate analysis and Kaplan-Meier statistical methods were used to determine the effect of treatment time on pelvic control and survival at 5 years. RESULTS The median treatment duration was 55 days. For all stages combined, the 5-year survival and pelvic control rates were significantly different with treatment times < 55 days vs. > or = 55 days: 65 and 54% (p = 0.03), 87 and 72% (p = 0.006), respectively. By stage, a shorter treatment duration (i.e., < 55 days vs. > or = 55 days) was significant for 5-year overall survival and pelvic control for Stages IB/IIA and III, but not for Stage IIB: Stage IB/IIA (81 and 67%, 96 and 84%), Stage III disease (52 and 42%, 76 and 55%) and Stage IIB (43 and 50%, 74 and 80%, respectively). Survival decreased 0.6%/day and pelvic control decreased 0.7%/day for each additional day of treatment beyond 55 days for all stages of disease. Additionally, significant late complications were not influenced by treatment time. CONCLUSION These results suggest that prolongation of treatment time is associated with decreased local control and survival in patients with cervical carcinoma. This is consistent with emerging data from other institutions. Therapeutic implications include avoidance of unnecessary treatment breaks, the design of fractionation schemes that decrease treatment duration, and possibly the use of tumor cytostatic drugs during conventional radiation.

High dose rate intracavitary brachytherapy for carcinoma of the cervix: the Madison system: I. Clinical and radiobiological considerations.

The decision to use five high dose rate intracavitary (HDR-ICR) insertions at weekly intervals for invasive carcinoma of the cervix treated at the University of Wisconsin Comprehensive Cancer Center (UWCCC) was made clinically. It was based on practical considerations and on previous clinical experience worldwide which showed that between 2 and 16 insertions have been used with apparently acceptable results. Although radiobiological considerations favor a large number of small doses, such a large number of HDR-ICR insertions is not clinically practical. Our strategy was to keep the biological effects of external beam and intracavitary insertions in the same ratio as used on a large series of patients treated here with low dose rate (LDR) therapy. This means keeping the same external beam treatment scheme and finding high dose rate (HDR) doses that are biologically equivalent to the previous LDR therapy, as far as possible. External beam and HDR intracavitary dose schedules for the Madison System of treating cervical carcinoma are described in detail. Because there is more repairable damage in late-reacting normal tissues, there is a bigger loss of sparing in these tissues than in tumors when changing from LDR to HDR, so total doses should be reduced more for equal late complications than for equal tumor control. The clinical decision was made to aim at equal tumor control. The possible increase in late complications has to be avoided by reducing the doses to critical normal tissues using extremely careful anatomic positioning of the HDR sources. Critical normal tissues must be kept further away from the radiation sources so that their doses are about 20% lower than with LDR geometry. This requires an extra separation of some millimeters depending on the anatomy and geometry of the individual insertion. The strategy is that the unfavourable radiobiological effects of a few large fractions must be counteracted by better physical dose distributions with HDR-ICR than with the previous LDR insertions. These good distributions are obtainable with the short exposures at HDR.

The management of ovarian-cancer-caused bowel obstruction

Abstract The records of 518 patients with ovarian cancer between 1969 and 1977 were retrospectively analyzed. During the course of their disease, 127 patients developed intestinal obstruction. Obstructions occurred in 17 (13.9%) of stage I patients, 17 (16.8%) of stage II patients, 72 (30.0%) of stage III patients, 20 (36.4%) of stage IV patients, and in 1 of the 3 patients whose initial staging was unknown. At advanced stages, patients developed intestinal obstruction more quickly. Patients deemed terminal and thus inoperable survived an average of 2 months. Those treated surgically for these obstructions survived an average of 7 months. Colostomy patients lived for 6.6 months. The degree of obstruction, partial or complete, was not significantly related to survival. The median time of survival for all patients with obstruction was 112 days.

A comparison of the efficacy and complication rates of low dose-rate versus high dose-rate brachytherapy in the treatment of uterine cervical carcinoma

PURPOSE To compare the outcome and complication rates for treatment of uterine cervical carcinoma with low dose-rate (LDR) vs. high dose-rate (HDR) brachytherapy at the University of Wisconsin Comprehensive Cancer Center (UWCCC). METHODS AND MATERIALS One-hundred ninety-eight evaluable patients with cervical carcinoma, Stages IB to IIIB, treated with curative intent with a combination of megavoltage teletherapy and LDR brachytherapy from 1977 to 1988 were the subject of an initial review. In 1989, a HDR treatment program was initiated where all patients with cervical carcinoma were subsequently treated with a combination of HDR brachytherapy and teletherapy. Using the linear-quadratic model (LQ), the dose and schedule of HDR brachytherapy and teletherapy were designed to give similar tumor control and late effects as LDR therapy. Technically, the HDR schedule required meticulous attention to treatment geometry to limit severe late effects. Forty patients treated with the HDR program with 2-4 year follow-up were reviewed and compared to the previous LDR patient group. The LDR and HDR treatment groups were comparable with regards to age, weight, stage distribution, bulk of disease, and histology. RESULTS No significant difference in survival was found between the LDR and HDR groups with 3-year actuarial overall survival being 66% and 77%, respectively. Three-year actuarial pelvic control rates were similar at 80% and 77% for the LDR and HDR groups, respectively. No significant difference in late treatment complications requiring hospitalization or surgery was found between the two treatment groups with a complication rate of 10% (20/198) for the LDR patients and 2.5% (1/40) for the HDR patients. CONCLUSION As predicted by our LQ calculations, treatment results for LDR and HDR brachytherapy were similar with respect to survival, pelvic control and late complications in the treatment of cervical carcinoma. The HDR brachytherapy program at the UWCCC appears to be a safe and effective alternative to LDR therapy in the treatment of cervical carcinoma.

Inguinofemoral radiation of N0,N1 vulvar cancer may be equivalent to lymphadenectomy if proper radiation technique is used

PURPOSE To update a previous retrospective study that compared inguinofemoral irradiation (N = 23) to lymphadenectomy (N = 25) for N0,N1 vulvar carcinoma with more patients and longer follow-up. These results, unlike the recent randomized Gynecologic Oncology Group (GOG study), suggest that radiation is a viable alternative to groin dissection, and the differences may be explained on the basis of irradiation technique. METHODS AND MATERIALS Based on a growing body of data supporting control of subclinical nodal disease with irradiation in vulvar cancer, the decision was made to offer patients with squamous cell carcinoma of the vulva and clinically negative groins (N0,N1), either lymphadenectomy or inguinofemoral irradiation based on clinical factors. Because of the acute skin reaction and possible underdosing of deep femoral nodes with electrons as used in the GOG study, opposed photon fields to 50 Gy were used. From 1983 to 1991, 48 patients underwent a radical vulvectomy followed by either lymphadenectomy (Group I, n = 25) or inguinofemoral irradiation (Group II, n = 23). RESULTS The actuarial nodal control was 100% in Group I and 91% in Group II (p = 0.14). In addition, there was no difference in cause specific survival at 3 years (96% and 90%, respectively, p = 0.47). The morbidity of lymphadenectomy (Group I) included: 16% lymphedema, 16% seromas, 44% infection, and 68% wound separation. In the irradiated patients (Group II), 16% developed lymphedema and only 9% had a significant skin reaction. CONCLUSION Based on this analysis of local control and survival with longer follow-up and more patients, irradiation of the N0, N1 inguinofemoral nodes may be a viable alternative to lymphadenectomy for squamous cell carcinoma of the vulva if proper radiation technique and dose are used. In addition, the acute and delayed morbidity of lymphadenectomy exceeds that of irradiation.

POSTOPERATIVE VAGINAL CUFF IRRADIATION USING HIGH DOSE RATE REMOTE AFTERLOADING: A PHASE II CLINICAL PROTOCOL

PURPOSE In September 1989, a postoperative Phase II high dose rate (HDR) brachytherapy protocol was started for International Federation of Gynecology and Obstetrics (FIGO) Stage I endometrial adenocarcinoma. This review reports the overall survival, local control, and complication rates for the initial 63 patients treated in this Phase II study. METHODS AND MATERIALS High dose rate brachytherapy was delivered using an Iridium-192 HDR remote afterloader. Sixty-three patients were entered into the Phase II protocol, each receiving two vaginal cuff treatments 1 week apart (range 4-12 days) with vaginal ovoids (diameter 2.0-3.0 cm). No patient received adjuvant external beam radiation. A dose of 32.4 Gy in two fractions was prescribed to the ovoid surface in 63 patients. The first three patients treated at our institution received 15, 16.2, and 29 Gy, respectively, to determine acute effects. RESULTS At a median follow-up of 1.6 years (range 0.75-4.3 years) no patient has developed a vaginal cuff recurrence. One regional recurrence (1.6%) occurred at 1.2 years at the pelvic side wall. This patient is alive and without evidence of disease 7 months after completion of salvage irradiation, which resulted in the only vaginal stenosis (1.6%). Fourteen patients (22%) experienced vaginal apex fibrosis by physical exam, which was clinically symptomatic in four patients. Two patients reported stress incontinence; however, these symptoms were noted prior to their HDR therapy. One patient died 2.4 years after HDR therapy due to cardiovascular disease without evidence of cancer at autopsy. CONCLUSION Preliminary results of our phase II HDR vaginal cuff protocol for postoperative FIGO Stage IA, Grade 3 or Stage IB, Grade 1-2 patients demonstrate that 32.4 Gy in two fractions is well tolerated by the vaginal cuff mucosa. Local control appears comparable to our prior experience and others with low dose rate (LDR) brachytherapy. Additional patient accrual and further follow-up will better determine the late morbidity, local control, and overall survival of these patients.

Carcinoma of vagina 10 or more years following pelvic irradiation therapy

Gynecologic cancer records of 4,238 patients treated between 1956 and 1974 were reviewed. Sixteen patients developed noeplasia in the cervix or vagina 10 or more years following pelvic irradiation. Three patients had squamous carcinoma in situ; the other 13 patients had invasive squamous cancer involving the upper vagina. Only 1.26 per cent of invasive carcinoma of the cervix treated by radiation therapy from 1956 to 1966 presented with a late or recurrent or new primary tumor involving the vagina or cervix 10 or more years after primary treatment. The authors conclude that the risk of developing radiation-induced carcinoma in the upper vagina or cervix following pelvic irradiation is low. Follow-up Pap smears are indicated for all patients treated for cervical or vaginal malignancies by radiation therapy in order to detect vaginal neoplasia as well as recurrent carcinoma of the cervix.

Estrogen use — Risk of endometrial carcinoma

Abstract A retrospective analysis was carried out to determine the prior usage rate of exogenous estrogens in all patients treated for adenocarcinoma of the endometrium in our institution from 1960 to 1974, and in a series of matched controls. Hospital records were reviewed, and patients were matched with controls who had a different gynecologic malignancy. The crude usage rate for all patients with endometrial carcinoma was 18.4% compared with 9.2% of controls yielding a relative risk of 2.2. There was a statistically significant increase in estrogen exposure since 1970, but the risk did not change. Hypertension, diabetes mellitus, and obesity were significant risk factors by themselves, but estrogen exposure in these patients did not appear to put them at further increased risk. There was no significant difference between the exposed and nonexposed groups in respect to grade or stage. In spite of a low exposure rate in this area, the relative risk for estrogen exposure was significant, independent of other variables.

Resource utilization. High dose rate versus low dose rate brachytherapy for gynecologic cancer.

A comparative analysis of anesthesia use, perioperative morbidity and mortality, capital, and treatment cost of high dose rate versus low dose rate intracavitary brachytherapy for gynecologic malignancy is presented. To assess current anesthesia utilization, application location, and high dose rate afterloader availability for gynecologic brachytherapy in private and academic practices, a nine-question survey was sent to 150 radiotherapy centers in the United States, of which 95 (63%) responded. Of these 95 respondents, 95% used low dose rate brachytherapy, and 18% possessed high dose rate capability. General anesthesia was used in 95% of programs for tandem + ovoid and in 31% for ovoids-only placement. Differences among private and academic practice respondents were minimal. In our institution, a cost comparison for low dose rate therapy (two applications with 3 hospital days per application, operating and recovery room use, spinal anesthesia, radiotherapy) versus high dose rate treatment (five outpatient departmental applications, intravenous anesthesia without an anesthesiologist, radiotherapy) revealed a 244% higher overall charge for low dose rate treatment, primarily due to hospital and operating room expenses. In addition to its ability to save thousands of dollars per intracavitary patient, high dose rate therapy generated a “cost-shift,” increasing radiotherapy departmental billings by 438%. More importantly, perioperative morbidity and mortality in our experience of 500+ high dose rate applications compared favorably with recently reported data using low dose rate intracavitary treatment. Capital investment, maintenance requirements, and depreciation costs for high dose rate capability are reviewed. Application of the defined “revenue-cost ratio” formula demonstrates the importance of high application numbers and consistent reimbursement for parity in high dose rate operation. Logically, inadequate third-party reimbursement (e.g., Medicare) reduces high dose rate parity and threatens the future availability of high dose rate technology.

Radiation reactions in cervical cancer therapy

Abstract Between 1961 and 1969, there were 410 patients treated for invasive squamous cell carcinoma of the cervix with either intracavitary therapy alone or in combination with external radiation. This group of patients was reviewed for reactions occurring during treatment as well as one month after completion of treatment. The reactions were subdivided into mild, moderate, and severe. As the gastrointestinal reactions became more severe, the chance for a subsequent complication increased significantly. Though patients had no problems during the course of radiation therapy, it appears a certain per cent will still develop complications later. The same relationship was not observed for the genitourinary system. The majority of patients developing a genitourinary complication had no significant symptoms during the reaction period.