Efficacy of radiotherapy for ovarian ablation
also see this Danish trial here
                Results of a Breast Intergroup study. Cancer 2004;101:969

In 1994, the Eastern Cooperative Oncology Group (ECOG) initiated for the Breast Intergroup a randomized clinical trial (E3193) in premenopausal patients with early-stage breast carcinoma comparing tamoxifen as adjuvant systemic therapy with tamoxifen and ovarian ablation by one of three different methods. Ovarian ablation could be accomplished either via radiotherapy (RT) (20 Gray [Gy]/10 fractions to a modified pelvic volume), surgical oophorectomy, or goserelin/leuprolide injections as per patient/physician choice. In the current study, we report the efficacy of pelvic RT with this dose-fractionation scheme in the induction of ovarian ablation.
 

Although it is disappointing that the protocol study did not achieve its accrual goal, notable data were obtained concerning the rate of ovarian ablation using the protocol's RT scheme. Castration levels of estradiol or FSH were achieved in 75%of evaluable irradiated patients, using a well tolerated, reproducible radiation plan. Although surgical or medical ovarian ablation is likely to be the treatment of choice for ovarian ablation in the U.S. at the current time, RT is a reasonable alternative. One advantage of ablation by RT is the ability to deliver the treatment with minimal acute morbidity at the time breast conservation patients receive breast RT, or at the time of palliative RT for metastatic disease.

Reports in the literature regarding the use of RT for ovarian ablation are problematic. To our knowledge, most reports do not include detailed descriptions of RT parameters including total dose, fractionation, treatment volume, treatment duration, or beam energy. Fewer still include toxicity data or documentation of castration hormonal levels. However, some common themes have been observed. A total dose of 10-20 Gy usually was recommended. Large daily fractions of 3-4 Gy were more commonly used. A dose response curve has not been well established because of the varying fraction sizes used by different investigators. For example, Leung  reported that the rate of ovarian ablation was 72% using a dose of 12 Gy in 4 fractions and Meakin  reported that the rate of ovarian ablation was 97% using 20 Gy at a dose of 4 Gy per fraction. In both studies, the rate of ovarian ablation was found to be age-related, with a decreased rate of ovarian ablation reported in younger patients.

In the context of these reports, the results presented herein are not unexpected. The dose and fractionation regimen for the current study was selected by the ECOG Radiation Oncology Committee. It was believed to be less likely to produce acute or long-term side effects than previously published hypofractionated regimens, while delivering a total dose that was predicted to be highly efficacious. As expected, side effects occurring during the administration of the 2-week course of RT were minimal and castration levels of estradiol or FSH were achieved in 75% of patients. We believe that this regimen represents one acceptable treatment protocol for ovarian ablation by RT.

Before the advent of systemic chemotherapy, ovarian ablation by RT or oophorectomy was a commonly used systemic therapy for patients with primary and metastatic breast carcinoma. Between the 1940s and the 1970s, several randomized trials were performed comparing adjuvant ovarian ablation with no adjuvant systemic therapy, which demonstrated a survival advantage for ovarian ablation. Data from the 1995 Oxford overview analysis (Early Breast Cancer Trialists' Collaborative Group) demonstrate that ovarian ablation produces a 24% reduction in mortality in premenopausal patients in the absence of chemotherapy, with an absolute reduction in mortality at 15 years of 5.6% and 12.5%, respectively, in lymph node-negative and lymph-node positive patients. What is remarkable about this fact is that these patients were not selected for the presence of hormone receptor, implying a significant underestimation of the actual effect in receptor-positive patients. However, in the presence of adjuvant chemotherapy, the addition of ovarian ablation was found to have a nonsignificant effect on overall survival. Therefore, to our knowledge, the role of ovarian ablation as adjuvant therapy in this era of systemic polychemotherapy remains conjectural. It is interesting to note that recent analyses of young women treated with adjuvant cytotoxic chemotherapy have suggested both greater benefit in those women whose menses did not return, and benefit from the addition of goserelin to chemotherapy (unpublished data).

The success and reversibility of ovarian ablation varies substantially. RT ovarian ablation generally took months to achieve, and was reported to be successful in approximately 75% of patients in the current study and is irreversible. This varies from the success rates observed in chemical castration. For example, the Zoladex Early Breast Cancer Research Association Study evaluated amenorrhea rates, but not estradiol levels, in premenopausal patients with lymph node-positive breast carcinoma who were treated with either 2 years of goserelin or 6 months of cyclophosphamide, methotrexate, and fluorouracil (CMF). RT was found to compare unfavorably with the use of goserelin, in which amenorrhea was noted in 95% of patients at 6 months, and only somewhat more favorably than the amenorrhea rate of 58.6% noted at 6 months with the use of polychemotherapy. In that same study, amenorrhea persisted at 3 years in 22.6% and 76.9%, respectively, of patients treated with goserelin and CMF. These data imply that in cases in which the reliability and reversibility of ovarian ablation are important, luteinizing hormone-releasing analogs may be a more advantageous choice than RT. Generally, if immediate, irreversible ovarian ablation is desired, surgery may be preferable.

Despite these provocative data, ovarian ablation by external beam irradiation is a seldom-used treatment for breast carcinoma in the U.S. at this time. It should be considered an option in situations in which adjuvant or therapeutic ovarian ablation is desired, because it may be easily delivered when breast or palliative irradiation is given.