David A. Kantorowitz

Effect of conjoint administration of tamoxifen and high-dose radiation on the development of mammary carcinoma

PURPOSE Tamoxifen is currently advocated for post-menopausal breast cancer patients receiving definitive irradiation after limited surgery. The purpose of this study was to assess in an experimental model for breast cancer whether the efficacy of irradiation is altered by conjoint administration of tamoxifen. To this end, rats with small tumors induced by 1-methyl-1-nitrosourea (MNU) were treated with tamoxifen, radiation, or a combination of the two modalities. METHODS AND MATERIALS Female Sprague Dawley rats were injected i.p. with 50 mg MNU/kg body weight at 50 days of age. At 64 days post carcinogen, the majority of the rats had at least one palpable mammary tumor. At that time radiation with or without tamoxifen treatment was initiated and given 5 days per week for 5 weeks. Radiation dose was 4500 cGy delivered as 25, 180 cGy fractions. Tamoxifen, 500 mg/kg body weight, was administered subcutaneously each day during the irradiation interval. The study was terminated 28 weeks after carcinogen treatment. RESULTS High dose radiation alone induced a reduction in the size of existing tumors, but resulted in a significant increase in the number of tumors that were detected. Treatment with tamoxifen alone also caused a reduction in tumor volume, but had no effect on final incidence or number of mammary tumors. Combined modality treatment resulted in a significant reduction in the volume of existing tumors and suppressed the enhanced occurrence of additional tumors observed when only radiation alone was administered. CONCLUSION The findings of this study indicate that in the context of fractionated, high dose radiation treatment of established mammary cancers, tamoxifen may reduce the likelihood of subsequent tumor development and by so doing prove a helpful simultaneous conjoint adjuvant treatment to post-operative irradiation.

Preoperative vs. postoperative radiation prophylaxis of heterotopic ossification : A rural community hospital's experience

PURPOSE In vivo data employing a rat model, suggest equivalent suppression of ectopic bone formation by single-fraction irradiation given either pre (< or = 4 h)- or post (< or = 24 h)-surgery. Two subsequent randomized clinical trials, from tertiary academic centers with robust experience in heterotopic bone prophylaxis, have reached similar conclusions. To assess the transferability of the above data to the community setting we reviewed our rural community hospital experience with pre- and postoperative radiation prophylaxis. METHODS AND MATERIALS Between 11/90 and 6/96, 16 surgerized hips with high risk of heterotopic bone formation received 7.00-8.00 Gy in one fraction either preoperatively (< or = 4 h) (n = 9) or postoperatively (< or = 3 days for six hips; day 7 for one hip) (n = 7). Initial patients were routinely treated postoperatively. In late 1992, treatment preference was switched to preoperative irradiation in response to evolving data. The two groups were similar with respect to age, sex, nature of surgery, presurgical Brooker and Harris scores, and in U. of Rochester risk classification distribution. Irradiation was given via 4-20 MV photons through equally weighted AP:PA portals to the periacetabular tissues and proximal one third to one-half of the femoral component. Radiation dose, energy, portal, and blocking design were all similar for the two groups. Hip radiographs were obtained immediately postsurgery and at last follow-up: Delta grades (Brooker grade at follow-up--Brooker grade immediately postsurgery) were computed. Harris scale scores of hip function and movement were assigned via personal interviews and examinations performed prior to irradiation and at last follow-up. RESULTS All 16 hips are evaluable. Follow-up interval among the post-operative group (mean = 39.8 months; range 18.6-65.8) was significantly longer than among the preoperative group (mean = 20.4 months; range 8.6-41.3) (p < 0.02). The mean Delta grade among the postoperative and preoperative groups was identical (-0.02). Similarly, improvement in Harris scale scores, from preirradiation to last follow-up, were nonsignificantly different among postoperative (+43.3) and preoperative (+44.8) groups. There was one postoperative infection in either group; there was no acute or late toxicity attributable to irradiation. CONCLUSION As heterotopic bone formation is complete within 6 months, the data for both treatment groups may be considered mature. Our community generated results parallel those derived from tertiary care centers. Single-fraction radiation prophylaxis of heterotopic ossification may be given with similar efficacy either < or = 4 h pre- or < or = 24 h postsurgery. For reasons of minimizing patient discomfort, postsurgical movement and radiation staff resource utilization, we prefer and recommend preoperative radiation prophylaxis.

The impact of dose-specification policies upon nominal radiation dose received by breast tissue in the conservation treatment of breast cancer

PURPOSE In the context of breast conservation treatment, absorbed dose is influenced by (1) prescribed nominal dose, and (2) dose-specification characteristics employed. Breast doses are generally specified either at tangent isocenter, varying anatomical points within the breast, or at isodoses varying from 90% to 100%. Boost doses are generally specified at 80-100%. METHODS An idealized axial slice of breast tissue at central axis is presented. Assuming varying dose-specification characteristics, absorbed doses are normalized and compared to those received by nominal prescriptions of 46 Gy to the breast and 20 Gy to the boost volume, both specified at 100%. RESULTS Absorbed doses vary from the normalized total of 66 Gy (with specification of breast and boost at 100%) in gradations up to a maximum of 76.11 Gy (when breast dose is specified at the 90% isodose and boost dose at 80%), a 13.3% difference. CONCLUSION The impact of dose specification is largely ignored in the breast irradiation literature and unappreciated in clinical practice. Its impact, however, is illustrated as dwarfing modest nominal dose escalations commonly recommended and prescribed among margin compromised patients. Progress in delineation of a dose-response relationship for treatment of breast cancer requires consensus as to dose specification. Arguments are offered that ICRU Report 50 dose-specification standards, as verified for reproducibility by the EORTC (22881/10882) trial group, constitutes the best data source currently available from which dose-specification consensus may be reached (1, 2). Dose to PTV(1) (whole breast plus 1- to 2-cm margin) should be specified at the tangent beam intersection on the central plane or, where such point is irrelevant, at two-thirds distance from dorsal beam edge to skin along the perpendicular breast bisector. Where irradiated via electrons, dose to the boost PTV(2) (lumpectomy cavity plus 1- to 3-cm margins) should be specified at 90%. Electron energy sufficient to provide 85% isodose coverage to all aspects of PTV(2) is recommended.