Elwood P. Armour

Direct evidence that prostate tumors show high sensitivity to fractionation (low α/β ratio), similar to late-responding normal tissue

Abstract Purpose : A direct approach to the question of whether prostate tumors have an atypically high sensitivity to fractionation (low α/β ratio), more typical of the surrounding late-responding normal tissue. Methods and Materials : Earlier estimates of α/β for prostate cancer have relied on comparing results from external beam radiotherapy (EBRT) and brachytherapy, an approach with significant pitfalls due to the many differences between the treatments. To circumvent this, we analyze recent data from a single EBRT + high-dose-rate (HDR) brachytherapy protocol, in which the brachytherapy was given in either 2 or 3 implants, and at various doses. For the analysis, standard models of tumor cure based on Poisson statistics were used in conjunction with the linear-quadratic formalism. Biochemical control at 3 years was the clinical endpoint. Patients were matched between the 3 HDR vs. 2 HDR implants by clinical stage, pretreatment prostate-specific antigen (PSA), Gleason score, length of follow-up, and age. Results : The estimated value of α/β from the current analysis of 1.2 Gy (95% CI: 0.03, 4.1 Gy) is consistent with previous estimates for prostate tumor control. This α/β value is considerably less than typical values for tumors (≥8 Gy), and more comparable to values in surrounding late-responding normal tissues. Conclusions : This analysis provides strong supporting evidence that α/β values for prostate tumor control are atypically low, as indicated by previous analyses and radiobiological considerations. If true, hypofractionation or HDR regimens for prostate radiotherapy (with appropriate doses) should produce tumor control and late sequelae that are at least as good or even better than currently achieved, with the added possibility that early sequelae may be reduced.

Dose escalation using conformal high-dose-rate brachytherapy improves outcome in unfavorable prostate cancer

PURPOSEnTo overcome radioresistance for patients with unfavorable prostate cancer, a prospective trial of pelvic external beam irradiation (EBRT) interdigitated with dose-escalating conformal high-dose-rate (HDR) prostate brachytherapy was performed.nnnMETHODS AND MATERIALSnBetween November 1991 and August 2000, 207 patients were treated with 46 Gy pelvic EBRT and increasing HDR brachytherapy boost doses (5.50-11.5 Gy/fraction) during 5 weeks. The eligibility criteria were pretreatment prostate-specific antigen level >or=10.0 ng/mL, Gleason score >or=7, or clinical Stage T2b or higher. Patients were divided into 2 dose levels, low-dose biologically effective dose <93 Gy (58 patients) and high-dose biologically effective dose >93 Gy (149 patients). No patient received hormones. We used the American Society for Therapeutic Radiology and Oncology definition for biochemical failure.nnnRESULTSnThe median age was 69 years. The mean follow-up for the group was 4.4 years, and for the low and high-dose levels, it was 7.0 and 3.4 years, respectively. The actuarial 5-year biochemical control rate was 74%, and the overall, cause-specific, and disease-free survival rate was 92%, 98%, and 68%, respectively. The 5-year biochemical control rate for the low-dose group was 52%; the rate for the high-dose group was 87% (p <0.001). Improvement occurred in the cause-specific survival in favor of the brachytherapy high-dose level (p = 0.014). On multivariate analysis, a low-dose level, higher Gleason score, and higher nadir value were associated with increased biochemical failure. The Radiation Therapy Oncology Group Grade 3 gastrointestinal/genitourinary complications ranged from 0.5% to 9%. The actuarial 5-year impotency rate was 51%.nnnCONCLUSIONnPelvic EBRT interdigitated with transrectal ultrasound-guided real-time conformal HDR prostate brachytherapy boost is both a precise dose delivery system and a very effective treatment for unfavorable prostate cancer. We demonstrated an incremental beneficial effect on biochemical control and cause-specific survival with higher doses. These results, coupled with the low risk of complications, the advantage of not being radioactive after implantation, and the real-time interactive planning, define a new standard for treatment.

Human Cancer Treatment with Ultrasound

Absmct-Despite the interest in hyperthermia and the rather significant advantages that ultrasound possesses over other methods for localized heating, there remain only a few reports of human studies with welldocumented thermal dosimetry that permit the evaluation of the antitumor efficacy of ultrasound treatment. In this paper, these reports are discussed, and the biological basis for the application of ultrasound hyperthermia as an antitumor modality is presented. Further, clinical results involving the application of ultrasonic hyperthermia alone, and in conjuction with chemotherapy and radiation in 215 patients are reported. Overall objective response rates for ultrasoundalone,ultrasound with chemotherapy, and ultrasound with radiation therapy were 45 percent, 60 percent, and 66 percent, respectively. Of particular encouragement was the treatment of advanced primary breast cancer with ultrasoundcombined withchemotherapy, wherethe first seven wesexhibited a 100 percent overall response rate to therapy.

Cytotoxic Effects of Ultrasound in Vitro Dependence on Gas Content, Frequency, Radical Scavengers, and Attachment

CHO cells were exposed to therapeutic-intensity ultrasound under various conditions. Cell killing was dependent upon the amount of gas dissolved in the treatment medium. No decrease in survival was observed at 2.40 and 3.40 MHz under conditions which had produced killing at 1.70, 1.07, and 0.82 MHz. Cell death occurred primarily within 15 min of exposure and probably involved membrane damage. One radical scavenger, cysteamine, completely protected the cells from ultrasound-induced damage whereas another, cystamine, did not. Attachment of the cells to a Mylar membrane also protected them from damage. Under conditions most closely resembling in vivo ultrasound exposures no decrease in survival was observed for intensities as great as 14 W/cm2 and 30-min duration. The cell killing observed was apparently due to cavitation and may have involved formation of intracellular radicals. Although the role of radicals is not unequivocally demonstrated, a better understanding of the mechanisms of ultrasound-induced damage is needed before this modality can be considered to be without

Equivalence of continuous and pulse simulated low dose rate irradiation in 9L gliosarcoma cells at 37° and 41°C

Abstract The development of a brachytherapy technique that will use a scanning source to simulate continuous low dose rate irradiation holds the possibility of improving dose distributions and other clinically relevant factors as well as enhancing radiation safety. Rat 9L gliosarcoma cells growing in vitro have been used as a model to determine the role of fraction size when individual pulses of irradiation are given at appropriate intervals to result in an overall dose rate that is identical to currently applied continuous low dose rate irradiation. With an overall dose rate of 0.5 Gy/hr, cell killing was identical for fractionation schemes of 0.25 Gy every 0.5 hr, 1.00 Gy every 2.0 hr, and 3.00 Gy every 6.0 hr. The cell sensitivity of these schemes was also identical to continuous irradiation at the same overall dose rate. Increasing the fraction size to 6.0 Gy with intervals of 12 hr increased the cytotoxicity. This breaking point was above the D q (3.9 Gy) of acutely irradiated 9L cells. These data support the hypothesis that continuous low dose rate irradiation can be simulated by fractionated high dose rate irradiation as long as the fraction size remains less than the D q of the acute radiation response of the cells and the overall dose rate remains constant. The role of simultaneous heating at 41°C during pulsed and continuous low dose rate irradiation was also investigated. Substantial sensitization was observed for both continuous low dose rate irradiation and pulse simulated low dose rate irradiation. The D o thermal enhancement ratios were 1.98 and 1.92, respectively. The above results demonstrate that modalities utilizing intermittent high dose rate irradiation can be designed such that they will be equivalent to continuous low dose rate irradiation, and that in either case simultaneous extended low temperature heating can greatly enhance the cytotoxic effects of these irradiations.

Lack of radiosensitization after paclitaxel treatment of three human carcinoma cell lines

Background. Several recent studies have suggested radiosensitizing effects of paclitaxel, a microtubular inhibitor. To test the universality of this finding, the interaction between paclitaxel and radiation treatment of cell lines derived from three common human carcinomas MCF‐7 (breast cancer); DUT‐145 (prostate cancer); and HT‐29 (colon cancer) was evaluated. The study focused on the ability of paclitaxel to block cells at the G2‐M phase of the cell cycle and potentially enhance the radiation sensitivity of the cells.

Sublethal Damage Repair Times for a Late-Responding Tissue Relevant to Brachytherapy (and External-Beam Radiotherapy): Implications for New Brachytherapy Protocols

PURPOSEnData were analyzed from recent experiments with the end point of late rectal obstruction in rats, involving acute and various protracted radiation exposures. Because the end point is of direct relevance both for brachytherapy as well as external beam radiotherapy, the goal was to estimate the linear-quadratic (LQ) parameters alpha/beta and T1/2, which are of importance for designing improved protraction/fractionation schemes.nnnMETHODS AND MATERIALSnThe data were fit to the LQ model, both in its standard form and in a form in which two different components of sublethal damage repair-fast and slow-are assumed. The design of the experiments was such that both slow and reasonably fast sublethal damage repair components should be separately estimated, if they were contributing to a significant degree.nnnRESULTSnLQ parameter estimates were alpha/beta = 4.6 Gy [4.0, 5.5] and T1/2 = 70.2 min [59.1, 91.4]. Despite the experimental design facilitating detection of a rapid component of repair, no statistically robust evidence for a very fast repair component was found.nnnCONCLUSIONSnThe long estimated repair time for a late-responding normal-tissue end point with direct relevance to brachytherapy suggests a variety of possible brachytherapy protocols that may be more efficacious than continuous low dose rate irradiation. Just as a difference in alpha/beta ratios between early- and late-responding tissues are a central tenet in radiotherapy, so corresponding differences in T1/2 values have the potential to be exploited, particularly for brachytherapy.

Elimination of dose-rate effects by mild hyperthermia

PURPOSEnPreferential amplification of low dose-rate irradiation toxicity in tumor cells is one way of improving presently applied brachytherapy. Low temperature hyperthermia applied to a tumor volume during irradiation is one candidate for reaching this goal. The ranges of relevant temperatures and dose-rate have been determined in a tissue culture system. In addition, the role of inhibition of sublethal damage repair in inhibition of dose-rate sparing has been investigated.nnnMETHODS AND MATERIALSnDose-rate modification by long duration, mild hyperthermia was investigated in rat 9L gliosarcoma cells at dose-rates between 0.0833 and 132 Gy/hr. Enhancement of toxicity was measured using the colony formation technique.nnnRESULTSnA biphasic dose-rate effect curve was observed when cells were irradiated at 37 degrees C. The dose required to kill 99% of cells irradiated at 37 degrees C increased sharply between 20 and 5 Gy/hr and also below 1 Gy/hr. When cells were irradiated at 41 degrees C, dose-rate sparing disappeared from 132 to 0.0833 Gy/hr. Elimination of dose-rate sparing appeared to be caused by both inhibition of sublethal damage repair and blockage of cell proliferation. The temperature threshold for sensitizing low dose-rate irradiation was determined at temperatures between 24 degrees C and 41 degrees C during 0.5 Gy/hr irradiation. Temperature dependent sensitization occurred above 39 degrees C. The mechanisms by which low temperature hyperthermia sensitizes low dose-rate irradiation was investigated using split dose experiments. Survival curve shoulder recovery was inhibited when cells were incubated at 41 degrees C between acute irradiations. This effect appeared to be caused by both inhibition of recovery from sublethal damage from the first radiation and preheating sensitization of the second irradiation. In single acute dose experiments, sensitization from preheating at 41 degrees C increased gradually over a 6 hr period.nnnCONCLUSIONSnThe mechanism by which 41 degrees C hyperthermia sensitizes low dose-rate irradiation is inhibition of radiation repair at medium dose rates and inhibition of repair and proliferation at very low dose rates. If low temperature hyperthermia is able to sensitize human tumor cells to brachytherapy similar to what has been described with 9L gliosarcoma cells, the addition of this modality could potentially greatly improve presently applied therapy.

PULSED LOW DOSE RATE BRACHYTHERAPY IN A RAT MODEL: DEPENDENCE OF LATE RECTAL INJURY ON RADIATION PULSE SIZE

PURPOSEnClinical protocols utilizing pulsed low dose rate brachytherapy (PDR) to replace traditional continuous low dose rate brachytherapy (CLDR) employ irradiation in individual pulses given at intervals of a few hours. A critical factor in determining whether PDR will produce equivalent or greater late-occurring normal tissue toxicity is the dose per pulse. A rat rectal model was used to determine the role of pulse size in modifying dose effectiveness in producing late-occurring toxicity.nnnMETHODS AND MATERIALSnA rat model in which the rectum is irradiated with 192Ir sources was used in conjunction with an intracavitary applicator. A section of rectum 1.3 cm in length was irradiated with either 0.75 Gy/h CLDR or one of five schemes of PDR. The schemes applied 0.375, 0.75, 1.5, 3.0, or 6.0 Gy pulses at 0.5, 1.0, 2.0, 4.0, or 8.0 h intervals, respectively. Rats were observed for up to 300 days after completion of irradiation for rectal obstruction. Rectal specimens were taken at the time of sacrifice for obstruction or at the end of follow-up and analyzed histologically for injury.nnnRESULTSnEffectiveness of irradiation was analyzed by calculating the ED50 for incidence of obstruction and severe histological injury. The ED50 for obstruction after treatment with CLDR and pulse sizes of 0.375, 0.75, and 1.5 Gy were 70.5, 68.0, 68.6, and 68.8 Gy, respectively. These values were not significantly different. Compared to CLDR, the ED50 for obstruction after pulse sizes of 3.0 and 6.0 Gy were significantly different at 60.9 and 46.3 Gy, respectively. The relative changes in ED50 for the different radiation schemes in producing ulceration, fibrosis, and vascular sclerosis injury were similar to that observed for obstruction. The endpoints of colitis cystica profunda and atypical epithelial regeneration varied less with increasing pulse size.nnnCONCLUSIONSnWe have demonstrated that for late rat rectal injury, dose responses to PDR pulse sizes up to 1.5 Gy at 2-h intervals are not distinguishable from that seen with CLDR at a dose rate of 0.75 Gy/h.

Comparison of tumor growth between HSP25‐ and HSP27‐transfected murine L929 cells in nude mice

We have developed a novel system for examining the possible contribution of small heat shock proteins (hsp) to tumor growth. L929 fibrosarcoma cells, which do not express significant levels of endogenous hsp25, were stably transfected with either murine hsp25 or human hsp27. Both transfected genes were over‐expressed and the respective proteins were phosphorylated in L929 cells. L929 cells transfected with hsp25 exhibited enhanced tumor growth compared to control transfected L929 cells upon s.c. injection into nude mice. In contrast, cells transfected with hsp27 exhibited delayed tumor progression in comparison to controls. Although these 2 heat shock genes and respective proteins are structurally very similar, they apparently exhibit distinct effects on tumor growth in this system. Int. J. Cancer 72:871–877, 1997.