Melvin A. Astrahan

Treatment of uterine sarcomas.

During a 21‐year period, 66 patients with uterine sarcomas were treated at California Medical Center. Histological diagnoses were mixed mesodermal sarcoma in 32 patients (48%), leiomyosarcoma in 24 (36%), and endometrial stromal sarcoma in 10 (15%) patients. The majority of patients (73%) had Stage I tumors. The treatment consisted of surgery alone in 27 (41%), surgery in combination with radiation therapy in 36 (55%), and radiation therapy alone in three (4%) patients. The overall 1‐, 2‐, and 5‐year actuarial survival was 74%, 57%, and 38%, respectively. The 1‐, 2‐, and 5‐year actuarial survival for the 27 surgery alone patients was 73%, 50%, and 25%, which compared with 75%, 61%, and 44% for the 36 surgery plus radiation therapy patients (P = 0.12). The disease‐free survival was better for the surgery plus radiation therapy patients, as compared with the surgery alone group (38% vs. 18% at 5 years, P = 0.081). The 5‐year survival by histology was 70% for the 10 endometrial stromal sarcoma patients, 40% for the 24 leiomyosarcoma patients, and 23% for the 32 mesodermal sarcoma patients (P = 0.064). As expected, survival depended on the stage of disease (P < 0.0001). Treatment failure was observed in 35 (53%) patients, which included 9 (14%) with failure in the pelvis. There was no difference in the incidence of failure among patients in the three treatment groups and also in the three histologic groups. There was, however, a significant difference in the incidence of pelvic failure between surgery alone and surgery plus radiation therapy patients. in the 27 surgery alone patients, nine (33%) relapsed in the pelvis, whereas none of the 36 surgery plus radiation therapy patients had locoregional failure, P < 0.0001. Adjuvant radiation therapy is an important treatment in the management of patients with sarcoma of the uterus.

Some implications of linear-quadratic-linear radiation dose-response with regard to hypofractionation

Recent technological advances enable radiation therapy to be delivered in a highly conformal manner to targets located almost anywhere in the body. This capability has renewed the clinical interest in hypofractionation wherein the tumor is delivered a few fractions of very large dose per fraction. Extrapolating clinical experience from conventional regimens to fractions of high dose is important to designing hypofractionated treatments. The concept of biologically effective dose (BED) based on the linear-quadratic (LQ) formulation e(-(alphaD+betaD2) is a useful tool for intercomparing conventional fractionations but may be hampered if the value of alpha/beta is dose range dependent and/or when extrapolating to fractions of high dose because the LQ curve bends continuously on the log-linear plot. This does not coincide with what is observed experimentally in many clonogenic cell survival studies at high dose wherein radiation dose-response relationships more closely approximate a straight line. Intercomparison of conventional fractionations with hypofractionated regimens may benefit from BED calculations which instead use a dose range independent linear-quadratic-linear (LQ-L) formulation which better fits the experimental data across a wider range of dose. The dosimetric implications of LQ-L are explored using a simple model which requires only the specification of a dose D(T) at which the LQ curve transitions to final linearity and the log(e) cell kill per Gy in the final linear portion of the survival curve at high dose. It is shown that the line tangent to the LQ curve at transition dose D(T) can often be used to approximate the final slope of the dose response curve. When D(T) = 2alpha/ beta Gy, the line tangent to the LQ curve at D(T) intersects the e(-alphaD) and e(-betaD2) curves at dose alpha/ beta Gy and also closely fits the linear response in the high dose region of some classic in vitro cell survival curves for which the value of alpha/beta is low. It is hypothesized that D(T) will increase as the magnitude of alpha/beta increases. Examples are presented illustrating how to recognize LQ-L behavior in multifraction isoeffect studies of late responses such as spinal cord and lung. When planning hypofractionated regimens involving reactions with low alpha/beta, recognizing LQ-L behavior could be important because the dose-response is likely to transition to final linearity within the contemplated range of hypofractional doses.

Transurethral Hyperthermia for Benign Prostatic Hyperplasia: Preliminary Clinical Results

A total of 21 patients with biopsy proved benign prostatic hyperplasia underwent treatment on a pilot protocol involving intracavitary transurethral radiating microwave (630 or 915 MHz.) antenna hyperthermia. Acute and subacute toxicity was mild and consisted primarily of bladder spasm (26% of the patients), hematuria (23%) and dysuria (9%), none of which significantly limited the achievement of desired temperatures during the treatment sessions. No chronic treatment-related morbidity or mortality was observed. Detailed thermal mapping, performed along the course of the prostatic urethra, recorded temperatures of 43C or more at greater than 75% of the loci. Highly significant increases in urine flow rate, decrease in post-void residual urine capacity and decrease in frequency of nocturia were observed. A marginally significant decrease in prostate volume was noted and, with a median followup of 12.5 months, only 3 patients have required subsequent prostatic resection. Transurethral hyperthermia represents a safe and promising outpatient approach to treatment of benign prostatic hyperplasia, particularly for patients who are not candidates for conventional surgical approaches because of medical or personal reasons. Further studies with the goal of optimizing the technique appear to be warranted, although long-term results would be best evaluated with prospective phase 3 trials.

Microwave applicator for transurethral hyperthermia of benign prostatic hyperplasia

An applicator for heating the prostate gland using a transurethral approach is described. This technique uses three microwave antennas and a thermometry sensor attached to the outer surface of a balloon (Foley) type urological catheter. Each microwave antenna also includes a built-in thermistor to control temperature and balance power. The balloon catheter assures rapid and reproducible localization of the antennas in the prostatic urethra. The two-dimensional SAR and steady-state temperature distributions surrounding the applicator in tissue equivalent phantom are reported. Longitudinal temperature distributions measured in situ at the applicator-urethral interface and the longitudinal and radial temperature distributions measured in normal canine prostate are presented and discussed. The technique appears to be capable of elevating temperature to greater than 42 degrees C in a cylindrically symmetrical volume up to 5 cm length and 0.5 cm radial penetration surrounding the applicator.

Optimization of mammosite therapy

PURPOSE Radiation source anisotropy causes about 10% of a spherically shaped planning target volume surrounding a MammoSite balloon to receive less than the prescribed dose. The principal dose-limiting factor for MammoSite therapy is the dose to the overlying skin. Additional limiting factors potentially include the dose to portions of the heart and lung. The goal of optimization is to deliver the prescribed dose to as much of the planning target volume as possible while avoiding toxicity to adjacent organs. METHODS AND MATERIALS An experimental CT-based high-dose-rate brachytherapy treatment planning system was used to investigate optimization strategies for MammoSite treatment. This system implements a linear optimization of high-dose-rate dwell times on the basis of constraints assigned to points of interest and a set of potential dwell positions. RESULTS The cylindrical symmetry of the MammoSite catheter limits the optimization process to creating spherical, ellipsoidal, or egg-shaped isodose distributions whose major axis is oriented along the catheter axis. If the dose to a limiting structure, such as skin, is not an issue, the use of multiple dwell positions can compensate for source anisotropy and create a more spherical isodose surface enclosing the planning target volume compared with a single dwell position. When skin becomes a dose-limiting factor, the catheter axis orientation, source anisotropy, dwell position, and dwell weighting can be exploited to limit the skin dose while simultaneously preserving the prescribed dose to as much of the target volume as possible. CONCLUSION Optimization of MammoSite therapy using multiple dwell positions within the balloon is both possible and practical.

Transurethral Microwave Hyperthermia for Benign Prostatic Hyperplasia: Preliminary Clinical and Pathological Results

Transurethral microwave hyperthermia is a new conservative treatment modality for benign prostatic hyperplasia. We treated 15 patients with 915 MHz. microwaves delivered transurethrally by a helical applicator. Of the patients 12 showed substantial objective and subjective improvement of obstructive outflow parameters. Significant improvement in objective study parameters included increased mean flow rate (p less than 0.00021), decreased mean residual volume (p less than 0.00001) and decreased mean prostatic volume (p less than 0.0077). Analysis of patterns of failure showed chronic bladder atony, prostate asymmetry and middle lobe configuration as important factors that could explain the failure of hyperthermia in 3 patients. Toxicity was mild, consisting of bladder spasms, perineal pain, dysuria and hematuria. Hyperthermia-induced pathological changes in prostatic tissues, causing periurethral shrinking and secondary dilatation of the prostatic urethra, are described. The reported clinical results of this phase I study are preliminary due to the short followup. A phase II study to optimize transurethral hyperthermia currently is underway. A phase III study is to be phased in comparing hyperthermia with transurethral resection of the prostate.

An interactive treatment planning system for ophthalmic plaque radiotherapy

Brachytherapy using removable episcleral plaques containing sealed radioisotope sources is being studied as an alternative to enucleation in the treatment of choroidal melanoma and other tumors of the eye. Encouraging early results have been reported, but late complications which lead to loss of vision continue to be a problem. A randomized national study, the Collaborative Ocular Melanoma Study (COMS) is currently in progress to evaluate the procedure. The COMS specified isotope is 125I. Precise dosimetric calculations near the plaque may correlate strongly with complications and could also be used to optimize isotope loading patterns in the plaques. A microcomputer based treatment planning system has been developed for ophthalmic plaque brachytherapy. The program incorporates an interactive, 3-dimensional, solid-surface, color-graphic interface. The program currently supports 125I and 192Ir seeds which are treated as anisotropic line sources. Collimation effects related to plaque structure are accounted for, permitting detailed study of shielding effectiveness near the lip of a plaque. A dose distribution matrix may be calculated in any subregion of a transverse, sagittal, or coronal planar cross section of the eye, in any plane transecting the plaque and crossing the eye diametrically, or on a spherical surface within or surrounding the eye. Spherical surfaces may be displayed as 3-dimensional perspective projections or as funduscopic diagrams. Isodose contours are interpolated from the dose matrix. A pointer is also available to explicitly calculate and display dose at any location on the dosimetry surface. An interactive editing capability allows new plaque designs to be rapidly added to the system.

Heating characteristics of a helical microwave applicator for transurethral hyperthermia of benign prostatic hyperplasia

A new applicator for intraurethral hyperthermic treatment of benign prostatic hyperplasia is described. The applicator uses an insulated helical antenna wound on the outer surface of a silicone urological (Foley) balloon catheter. The balloon catheter assures rapid and reproducible localization of the antenna in the prostatic urethra. Two small cannulae are fixed to the exterior surface of the applicator. One holds a temperature control sensor at a fixed location, the other is used to map temperature along the applicator. Two-dimensional SAR and steady-state temperature distributions measured in a plane tangent to the applicator in a tissue-equivalent phantom are presented, as well as longitudinal temperature distributions measured in situ at the applicator-urethral interface. Prostatic temperatures were also measured intraoperatively. The applicator appears to be capable of elevating temperature to greater than 42 degrees C in a cylindrically symmetric volume of about 4 cm length and about 0.5 cm radial penetration surrounding the antenna. The heating characteristics of this applicator are similar to an earlier design that employed an array of three dipoles. The helical applicator is narrower, more flexible and simpler to use than the earlier design.

REGIONAL HYPERTHERMIA FOR ADVANCED TUMORS: A CLINICAL STUDY OF 353 PATIENTS

A Phase I study using deep regional hyperthermia (HT) with an annular phased array was conducted in 14 U.S. medical centers from 1980 through 1986. There were 353 patients whose average age was 57 years. All patients had advanced recurrent or persistent tumors. Prior frequently complex, multimodality anti-cancer therapy was received by 71% of the patients. Gastrointestinal adenocarcinoma was present in 146 (41%) patients, genitourinary tumors in 86 (24%), soft tissue sarcomas in 46 (13%), malignant melanoma in 21 (6%) and 15% had other tumors. The sites treated included: pelvis 55%, abdomen 21%, liver 14%, thorax 6%, and other sites 3%. All patients received deep regional HT with an average frequency of 55 MHz. A total of 1412 HT treatments was administered to these 353 patients with an aim to increase the temperature in the volume of interest to greater than 42 degrees C for greater than or equal to 30 minutes. Thermal dose (TD in equivalent minutes at 42.5 degrees C) was less than 50 in 104 (29%), greater than or equal to 50 less than 100 in 30 (11%), greater than or equal to 100 in 26 (7%), and greater than 200 in 34 (10%). The remaining 150 (42%) patients had TD = 0. In addition to HT, 260 (74%) received radiotherapy (RT). RT was given at 180 or 200 cGy daily with an average total dose of 33.4 Gy. A total of 42 (12%) patients were given chemotherapy (CT) with HT, and 15 (4%) CT + HT + RT/HT alone was given to 47 (13%) patients. Complete response (CR) was obtained in 35 (10%) and partial response (PR) in 59 (17%) patients. CR was 12% in patients who received RT, vs 2% in those who did not receive it, p = 0.003. Radiation dose was an important factor influencing response, p less than 0.001. Thermal dose was not an important parameter influencing tumor response. A duration of CR ranged from 4 to 73 weeks with an average duration of 31 weeks and the median duration of 28 weeks. The overall 2-year survival was 13% with the median survival of 42 weeks. Patients with CR and PR had a 2 year survival of 41%, and a median survival of 71 weeks. This compared with 8% 2-year survival and 24 weeks median survival in patients who did not have CR or PR, p less than 0.001. Of the patients presenting with significant pain, 62% had complete or partial pain relief.(ABSTRACT TRUNCATED AT 400 WORDS)

The Relative Importance of Genetics and Environment on Mammographic Density

Background: Although several environmental factors predict mammographic density, estimates of its heritability have been quite high. We investigated whether part of the presumed heritability might be attributed to differential sharing of modifiable risk factors in monozygotic (MZ) and dizygotic (DZ) twins. Methods: We measured percent and absolute mammographic density using mammograms from 257 MZ and 296 DZ twin pairs. The correlation of intrapair mammographic density was compared according to zygosity across strata of modifiable risk factors. Portions of variance attributable to additive genetic factors, shared environment, and individual environment were calculated using a variance component methodology in the entire set, and within twin pairs stratified by environmental trait similarity. Results: Both percent density and absolute mammographic density were more highly correlated between MZ twins than DZ twins, but the correlations varied across strata. Body mass index (BMI) and parity strongly predicted differences in mammographic density within MZ twin pairs. After adjusting for covariates, 53% of the total variance in percent density and 59% of that in absolute density seemed attributable to genetic effects, but these estimates varied greatly by stratum. For twins dissimilar on BMI (difference >2.5 kg/m2), the additive genetic component of absolute density was estimated at only 20% (±19%), and the common and individual environment at 21% (±14%) and 49%, respectively (P value for heterogeneity across BMI = 0.0001). Conclusion: Our results confirm that the genome is an important determinant of mammographic density but suggest that an unknown portion of the mammographic density effect attributed to the genome may be due to shared modifiable environmental factors. (Cancer Epidemiol Biomarkers Prev 2009;18(1):102–12)