Paul Y. Song

Enhancement of replication of genetically engineered herpes simplex viruses by ionizing radiation : a new paradigm for destruction of therapeutically intractable tumors

Human U-87 malignant glioma xenografts in mice were exposed to ionizing radiation, inoculated with a herpes simplex virus 1 mutant R3616 lacking both copies of the γ134.5 gene, or received both virus and radiation. Dual treatment caused a significantly greater reduction in volume or total regression of tumors than either radiation or infection alone. The significantly enhanced oncolytic effects of the combined treatment correlate with two- to five-fold enhanced replication in irradiated tumor cells than in tumors receiving virus only. In addition, in situ hybridization with viral DNA probes showed that infected tumor cells were the dominant landscape of irradiated tumors and much less apparent in the nonirradiated tumors administered this virus.

A comparison of four patient immobilization devices in the treatment of prostate cancer patients with three dimensional conformal radiotherapy.

PURPOSE To determine the variability of patient positioning during three-dimensional conformal radiotherapy (3D-CRT) for prostate cancer treated with no immobilization or one of four immunobilization devices, and to determine the effects of patient body habitus and pelvic circumference on patient movement with each individual inmobilization technique. METHODS AND MATERIALS To see whether our immobilization techniques have improved day-to-day patient movement, a retrospective analysis was carried out. A total of 62 patients treated at one facility on a single machine with 3D-CRT via a four-field box technique (anterior-posterior and opposed laterals) in the supine position with either no immobilization or one of four immobilization devices. Five groups of patients were compared: (a) group 1-no immobilization; (b) group 2-alpha cradle from the waist to upper thigh; (c) group 3-alpha cradle from waist to below the knees; (d) group 4-styrofoam leg immobilizer (below knees); and (e) group 5-aquaplast cast encompassing the entire abdomen and pelvis to midthigh with alpha cradle immobilization to their lower legs and feet. Prior to starting radiotherapy, portal films of all four treatment fields were obtained 1 day before treatment. Subsequently, portal films were then obtained at least once a week. Portal films were compared with the simulation films and appropriate changes were made and verified on the next day prior to treatment. A deviation of greater than 0.5 cm or greater was considered to be clincally significant in our analysis. We studied the difference among the types of immobilization and no immobilization by looking at the frequency of movements (overall, and on each of the three axes) that a patient had during the course of his treatment. Using a logistic regression model, the probability of overall and individual directional movement for each group was obtained. In addition, the effects of patient body habitus and pelvic circumference on movement were analyzed. RESULTS The maximum deviation was 2 cm and the median deviation was 1.2 cm. For each patient, the probability of movement ranged from 0 to 76%, with a mean of 39%. There was no significant difference seen in overall movement with any of the immobilzation devices compared to no immobilization, but there was less vertical (9 vs. 18%; p = 0.03) and AP (6 vs. 15%; p = 0.14) movement with the aquaplast than any other group. However, when examining the lateral direction, the aquaplast had significantly more movement (32 vs. 9%; p < 0.001). When accounting for body habitus and pelvic circumference, no immobilization device was effective in reducing movement in obese patients or in patients with pelvic circumference greater than 105 cm. The aquaplast group had a significantly increased amount of lateral movement with obesity (42 vs. 23%; p < 0.05), and with pelvic circumference >105 cm (33 vs. 29%; p < 0.05). CONCLUSIONS There was no significant reduction in overall patient movement noted with any of the immobilization devices compared to no immobilization. The aquaplast group had reduced vertical and AP movement of greater than 0.5 cm. There was significantly more lateral movement with aquaplast appreciated in obese patients or patients with pelvic circumferences greater than 105 cm. The aquaplast immobilization appears to be useful in reducing movement in two very clinicaly important dimensions (AP and vertical). Despite our findings, other immobilization may still be useful especially in the treatment of nonobese patients. It is clear that the optimal immobilization technique and patient positioning are yet to be determined.

A method of analyzing rectal surface area irradiated and rectal complications in prostate conformal radiotherapy

PURPOSE To develop a method of analyzing rectal surface area irradiated and rectal complications in prostate conformal radiotherapy. METHODS AND MATERIALS Dose-surface histograms of the rectum, which state the rectal surface area irradiated to any given dose, were calculated for a group of 27 patients treated with a four-field box technique to a total (tumor minimum) dose ranging from 68 to 70 Gy. Occurrences of rectal toxicities as defined by the Radiation Therapy Oncology Group (RTOG) were recorded and examined in terms of dose and rectal surface area irradiated. For a specified end point of rectal complication, the complication probability was analyzed as a function of dose irradiated to a fixed rectal area, and as a function of area receiving a fixed dose. Lymans model of normal tissue complication probability (NTCP) was used to fit the data. RESULTS The observed occurrences of rectal complications appear to depend on the rectal surface area irradiated to a given dose level. The patient distribution of each toxicity grade exhibits a maximum as a function of percentage surface area irradiated, and the maximum moves to higher values of percentage surface area as the toxicity grade increases. The dependence of the NTCP for the specified end point on dose and percentage surface area irradiated was fitted to Lymans NTCP model with a set of parameters. The curvature of the NTCP as a function of the surface area suggests that the rectum is a parallel structured organ. CONCLUSIONS The described method of analyzing rectal surface area irradiated yields interesting insight into understanding rectal complications in prostate conformal radiotherapy. Application of the method to a larger patient data set has the potential to facilitate the construction of a full dose-surface-complication relationship, which would be most useful in guiding clinical practice.

Dose-surface histograms as treatment planning tool for prostate conformal therapy

Dose-surface histograms are studied and compared with dose-volume histograms, as an evaluation tool for prostate treatment planning. For thin walled hollow organs, such as the rectum and bladder, the surface area irradiated is a more appropriate measure of the biological effect than the full volume. It is also more accurate and efficient to define the surface for a hollow structure and compute the surface area histograms. Application of the dose-surface histograms provide new insights into prostate treatment planning. A simple idealized geometry model demonstrates that the percentage surface area intersected by the geometric beam edge differs from the percentage volume intersected. For a group of prostate patients, it is shown that the dose-surface histograms yield substantially different results from the dose-volume histograms in ranking four-, six-, and, eight-field treatment plans and in calculating the fraction of the rectum irradiated to high dose. The difference in terms of surface area between these plans in the high-dose region is usually less than that in terms of the volume, and a reverse of plan ranking order can consequently occur. The percentage of organ surface irradiated to high dose is typically greater than the percentage volume by 5% to 10%. The use of the dose-surface histograms in analysis of organ motion and/or patient setup uncertainty, and analysis of rectal complications, is also discussed.

Self-assessed health-related quality of life in men being treated for prostate cancer with radiotherapy: instrument validation and its relation to patient-assessed bother of symptoms

OBJECTIVES To develop a psychometrically valid and clinically useful questionnaire to assess health-related quality of life (HRQOL) in patients with prostate cancer (PCa) undergoing external beam radiotherapy. The most important factors in three dimensions (bowel function [BF], urinary function [UF], and sexual function [SF]) were identified by patient survey. METHODS Three HRQOL dimensions were assessed using Likert-type questions. Responses were analyzed by factor analysis to create HRQOL scales. Reliability and validity of the scales were assessed. Because patients can suffer symptoms yet not report their lives to be affected, the scales were compared with patient-reported bother. RESULTS Two scales were identified within each dimension: BF, urgency and daily living; UF, urgency and weakness of stream; and SF, interest/satisfaction and impotence. Cronbachs alpha for the scales ranged from 0.63 to 0.94, and item-scale correlations and item-scale divergence correlations supported scale validity. Rising median scores correlated with rising levels of perceived bother. CONCLUSIONS The questionnaire is a suitable tool for assessing HRQOL in three distinct dimensions for patients undergoing radiotherapy for PCa. Six dimensions of HRQOL were found to be related to bother, suggesting important relationships to be monitored for patients. Urgency of bowel movements, urgency of urination, and level of interest/satisfaction in sex correlated most strongly with bother.

137 Enhanced tumor control of human glioblastoma multiforme xenografts with the concomitant use of radiotherapy and an attentuated herpes simplex-1 virus (ASTRO Research Fellowship)

Purpose: Glioblastoma Multifonne remains one of the most incurable of human tumors. The current treatment outcomes are dismal. There are several recent reports which suggest that some human glioblastoma xenografts implanted in the brains of athymic mice may be potentially cured with the use of an attenuated herpes simplex-l virus alone. We have chosen a replication competent, non-neurovimlent HSV-1 mutant, designated R3616 to determine whether there is an interactive cell killing and enhanced tumor control with radiotherapy in the treatment of a human glioblastoma xenograft.

Inhibition of Poly(ADP-Ribosyl)ation and Sister Chromatid Exchange Induction

Sister chromatid exchanges (SCEs) represent reciprocal exchanges between homologous daughter chromosomes. Although their mechanism of formation and their significance are unknown, they are thought of as cytological markers of some process important in carcinogenesis, possibly recombination (1). Exposure of cells to inhibitors of poly(ADP-ribose) polymerase, such as 3-aminobenzamide (3AB), will result in an increase in the baseline frequency of SCEs (2–4). At concentrations that dramatically increase SCE frequency, 3AB is nontoxic, nonmutagenic and noncarcinogenic (5, 6). Furthermore, while 3AB will interact with certain DNA damaging agents to affect cytotoxicity, mutagenicity and carcinogenicity (5, 6), it does not interact (directly) with these agents to affect SCE frequency (7, 8). Thus 3AB appears to be an ideal agent with which to probe SCE induction in the absence of other possibly confounding lesions.