Soy isoflavones in conjunction with radiation therapy in patients with prostate cancer.

Soy isoflavones sensitize prostate cancer cells to radiation therapy by inhibiting cell survival pathways activated by radiation. At the same time, soy isoflavones have significant antioxidant and anti-inflammatory activity, which may help prevent the side effects of radiation. Therefore, we hypothesized that soy isoflavones could be useful when given in conjunction with curative radiation therapy in patients with localized prostate cancer. In addition to enhancing the efficacy of radiation therapy, soy isoflavones could prevent the adverse effects of radiation. We conducted a pilot study to investigate the effects of soy isoflavone supplementation on acute and subacute toxicity (≤6 mo) of external beam radiation therapy in patients with localized prostate cancer. Forty-two patients with prostate cancer were randomly assigned to receive 200 mg soy isoflavone (Group 1) or placebo (Group 2) daily for 6 mo beginning with the first day of radiation therapy, which was administered in 1.8 to 2.5 Gy fractions for a total of 73.8 to 77.5 Gy. Adverse effects of radiation therapy on bladder, bowel, and sexual function were assessed by a self-administered quality of life questionnaire at 3 and 6 mo. Only 26 and 27 patients returned completed questionnaires at 3 and 6 mo, respectively. At each time point, urinary, bowel, and sexual adverse symptoms induced by radiation therapy were decreased in the soy isoflavone group compared to placebo group. At 3 mo, soy-treated patients had less urinary incontinence, less urgency, and better erectile function as compared to the placebo group. At 6 mo, the symptoms in soy-treated patients were further improved as compared to the placebo group. These patients had less dripping/leakage of urine (7.7% in Group 1 vs. 28.4% in Group 2), less rectal cramping/diarrhea (7.7% vs. 21.4%), and less pain with bowel movements (0% vs. 14.8%) than placebo-treated patients. There was also a higher overall ability to have erections (77% vs. 57.1%). The results suggest that soy isoflavones taken in conjunction with radiation therapy could reduce the urinary, intestinal, and sexual adverse effects in patients with prostate cancer.

A Prospective Multi-Institutional Phase I/II Trial of Step-Wise Dose-per-Fraction Escalation in Low and Intermediate Risk Prostate Cancer.

PURPOSE: This phase I/II, multi-institutional trial explored the tolerance and efficacy of stepwise increasing hypofractionation (HPFX) radiation therapy regimens for fraction sizes up to 4.3 Gy in localized prostate cancer. METHODS AND MATERIALS: Three escalating dose-per-fraction schedules were designed to yield similar predicted tumor control while maintaining equivalent predicted late toxicity. HPFX levels I, II, and III were carried out sequentially and delivered schedules of 64.7 Gy/22 fx/2.94 Gy, 58.08 Gy/16 fx/3.63 Gy, and 51.6 Gy/12 fx/4.3 Gy, respectively with next level escalations contingent upon acceptable gastrointestinal (GI) toxicity. The primary endpoints were biochemical control and toxicity. RESULTS: A total of 347 patients were recruited by 5 institutions with 101, 111, and 135 patients treated on HPFX levels I, II, and III with median follow-ups of 100, 85.5, and 61.7 months, respectively (83.2 months combined). The National Comprehensive Cancer Network low- or intermediate-risk group distribution was 46% and 54%, respectively. Sixteen percent of patients, primarily intermediate risk, received 6 months of androgen deprivation therapy. The 8-year nadir + 2 actuarial biochemical control rates for HPFX levels I, II, and III were 91.1% ± 3.0%, 92.7% ± 2.7%, and 88.5% ± 4.6%, respectively (Kaplan-Meier log rank, 0.903). Among clinical covariates, only Gleason score reached near significance in multivariate analysis (P = .054). Twenty-six patients failed biochemically (crude incidence of 7.5%), and there were 5 cause-specific deaths. GI and genitourinary toxicities were acceptable and similar across the 3 HPFX levels. The combined actuarial cumulative incidence of grade 2+ GI and genitourinary toxicities at 7 years were 16.3% ± 2.1% and 22.1% ± 2.4%, respectively. CONCLUSIONS: HPFX employing fraction sizes extending into the 3.6 to 4.3 Gy/fraction range can be delivered with excellent oncologic outcomes. Such schedules, positioned between moderate and ultra-HPFX, may provide additional options for patients wishing to avoid prolonged treatment schedules associated with conventionally fractionated radiation therapy for prostate cancer.

The prognostic impact of seminal vesicle involvement found at prostatectomy and the effects of adjuvant radiation: data from Southwest Oncology Group 8794.

PURPOSE: From the randomized study Southwest Oncology Group 8794 we evaluated the effect of seminal vesicle involvement on outcomes and whether those patients benefited from post-prostatectomy adjuvant radiation therapy. MATERIALS AND METHODS: Southwest Oncology Group study 8794 randomized high risk patients (with seminal vesicle positive disease and/or capsular penetration and/or positive margins) to radiation vs observation after prostatectomy. A total of 431 subjects with pathologically advanced prostate cancer were randomized. RESULTS: Median followup was 12.2 years. Of the patients 139 had seminal vesicle involvement with or without capsular penetration and/or positive margins. Compared to the 286 patients with seminal vesicle negative disease there was poorer 10-year biochemical failure-free survival (33% for seminal vesicle negative and 22% for seminal vesicle positive, p = 0.04), metastasis-free survival (70% and 56%, respectively, p = 0.005) and overall survival (10-year overall survival 74% and 61%, respectively, p = 0.02) for those with seminal vesicle positive disease. Patients with seminal vesicle positive disease who received adjuvant radiation compared to observation realized an improvement in 10-year biochemical failure-free survival from 12% to 36% (p = 0.001), in 10-year overall survival from 51% to 71% (p = 0.08) and in metastasis-free survival from 47% to 66% (p = 0.09), respectively. CONCLUSIONS: Although seminal vesicle involvement is a negative prognostic factor, long-term control is possible especially if patients are given adjuvant radiation therapy. This therapy appears to be effective in patients with seminal vesicle involvement.

Intensity modulated neutron radiotherapy for the treatment of adenocarcinoma of the prostate.

PURPOSE: This study investigates the enhanced conformality of neutron dose distributions obtainable through the application of intensity modulated neutron radiotherapy (IMNRT) to the treatment of prostate adenocarcinoma. METHODS AND MATERIALS: An in-house algorithm was used to optimize individual segments for IMNRT generated using an organ-at-risk (OAR) avoidance approach. A number of beam orientation schemes were investigated in an attempt to approach an optimum solution. The IMNRT plans were created retrospectively for 5 patients previously treated for prostate adenocarcinoma using fast neutron therapy (FNT), and a comparison of these plans is presented. Dose distributions and dose-volume histograms (DVHs) were analyzed and plans were evaluated based on percentage volumes of rectum and bladder receiving 95%, 80%, and 50% (V(95), V(80), V(50)) of the prescription dose, and on V(60) for both the femoral heads and GM(muscle) group. RESULTS: Plans were normalized such that the IMNRT DVHs for prostate and seminal vesicles were nearly identical to those for conventional FNT plans. Use of IMNRT provided reductions in rectum V(95) and V(80) of 10% (2-27%) and 13% (5-28%), respectively, and reductions in bladder V(95) and V(80) of 12% (3-26%) and 4% (7-10%), respectively. The average decrease in V(60) for the femoral heads was 4.5% (1-18%), with no significant change in V(60) for the GM(muscle) group. CONCLUSIONS: This study provides the first analysis of the application of intensity modulation to neutron radiotherapy. The IMNRT technique provides a substantial reduction in normal tissue dose in the treatment of prostate cancer. This reduction should result in a significant clinical advantage for this and other treatment sites.

Clinical application of a repositioning scheme, using gold markers and electronic portal imaging.

BACKGROUND AND PURPOSE: To implement an on-line correction scheme based on implanted markers to reduce treatment margins in external beam radiation therapy (EBRT) of carcinoma of the prostate. In turn reduction in treatment margins reduces irradiated volumes and offers the possibility of reduced normal tissue complications or escalated target dose. PATIENTS AND METHODS: Five or six gold markers were implanted in 10 patients treated for prostate carcinoma using EBRT. All patients were enlisted in an IRB-approved protocol. Before each fraction two portal images were obtained using a low dose (2MU). Positions of the markers were calculated from these images using an in-house developed program. Corrections were applied with a threshold of 2mm displacement. After correction the procedure was repeated. RESULTS: Overall systematic errors were reduced from 7.45, 1.29, and 5.12 mm to 0.65, 0.11, and 0.46 mm in, respectively, the antero-posterior, lateral, and cranio-caudal directions. Likewise, the overall SD were reduced from 5.99, 5.34, and 4.44 mm to 2.82, 2.64, and 2.22 mm, respectively. All reductions were highly significant (P < 0.01) using a t-test for systematic and an F-test for random errors. On an individual level all but three patients showed significant improvements in all directions for the random errors. All patients improved in at least one direction. Systematic errors were significantly lower in all patients. Simulated correction schemes using this data suggest that margin reduction using off-line reduction does not benefit substantially from on-line corrections in the first few fractions. CONCLUSIONS: Use of marker-based correction improves the patient position. Factors influencing the accuracy were: (1) number of seeds usable for correction, (2) distribution of markers throughout the volume of interest, and (3) objective instructions for patient realignment.

Genistein inhibits radiation-induced activation of NF-kappaB in prostate cancer cells promoting apoptosis and G2/M cell cycle arrest.

BACKGROUND: New cancer therapeutic strategies must be investigated that enhance prostate cancer treatment while minimizing associated toxicities. We have previously shown that genistein, the major isoflavone found in soy, enhanced prostate cancer radiotherapy in vitro and in vivo. In this study, we investigated the cellular and molecular interaction between genistein and radiation using PC-3 human prostate cancer cells. METHODS: Tumor cell survival and progression was determined by clonogenic analysis, flow cytometry, EMSA analysis of NF-kappaB, and western blot analysis of cyclin B1, p21WAF1/Cip1, and cleaved PARP protein. RESULTS: Genistein combined with radiation caused greater inhibition in PC-3 colony formation compared to genistein or radiation alone. Treatment sequence of genistein followed by radiation and continuous exposure to genistein showed optimal effect. Cell cycle analysis demonstrated a significant dose- and time-dependent G2/M arrest induced by genistein and radiation that correlated with increased p21WAF1/Cip1 and decreased cyclin B1 expression. NF-kappaB activity was significantly decreased by genistein, yet increased by radiation. Radiation-induced activation of NF-kappaB activity was strongly inhibited by genistein pre-treatment. A significant and striking increase in cleaved PARP protein was measured following combined genistein and radiation treatment, indicating increased apoptosis. CONCLUSION: A mechanism of increased cell death by genistein and radiation is proposed to occur via inhibition of NF-kappaB, leading to altered expression of regulatory cell cycle proteins such as cyclin B and/or p21WAF1/Cip1, thus promoting G2/M arrest and increased radiosensitivity. These findings support the important and novel strategy of combining genistein with radiation for the treatment of prostate cancer.

Intermittent hormone therapy in nonmetastatic prostate cancer.

PURPOSE: The object of this study was to evaluate the duration of response to intermittent androgen deprivation (IAD) in patients with nonmetastatic recurrent or localized prostate cancer. PATIENTS AND METHODS: One hundred ten patients received IAD from February 1992 to February 2005. One hundred three patients were treated after failure of primary radiation therapy and/or prostatectomy, with the remaining 7 patients treated primarily with IAD. The median duration of treatment cycle was 6 months. Patients were considered resistant to hormone therapy if the prostate-specific antigen (PSA) level increased, with castrate levels of testosterone. At the time of initial diagnosis, the median Gleason score was 7 (range, 4-9), and tumor stages were as follows: T1/T2 (n = 73), T3 and T4 N1 (n = 34), and other (n = 3). The median PSA at the initiation of IAD was 8.25 ng/mL. RESULTS: The median follow-up after beginning IAD was 45.5 months. Patients received a median of 2 cycles (range, 1-9 cycles). Ninety-four of 110 patients (85.5%) remained responsive to IAD. Sixteen patients (14.5%) progressed to become refractory to primary hormone treatment. Patients with a higher tumor stage (T3 and T4) were significantly more likely to develop resistance. The median time to become refractory to hormone therapy was 47.9 months (range, 9.4-93.4 months). Five patients were put on secondary continuous hormone treatment, and 3 of them developed resistance at a median of 9 months. One patient was put on a secondary IAD and was still responding at the last follow-up. CONCLUSION: With 85.5% of the original patient population still responding to the primary hormone therapy at 45.5 months of follow-up, IAD appears to be a viable option for patients with biochemical failure after local radiation therapy. A pattern of shortening time between cycles and an increasing nadir PSA level with each successive cycle is consistent with the gradual development of hormone resistance.

Quality of life outcomes from a dose-per-fraction escalation trial of hypofractionation in prostate cancer.

OBJECTIVE: This multi-institutional phase I/II trial explored patient-assessed tolerance of increasingly hypofractionated (HPFX) radiation for low/intermediate risk prostate cancer. METHODS: 347 patients enrolled from 2002 to 2010. Three increasing dose-per-fraction schedules of 64.7 Gy/22 fx, 58.08 Gy/16 fx and 51.6 Gy/12 fx were each designed to yield equivalent predicted late toxicity. Three quality of life (QoL) surveys were administered prior to treatment and annually upto 3 years. RESULTS: Bowel QoL data at 3years revealed no significant difference among regimens (p=0.469). Bowel QoL for all regimens declined transiently, largely recovering by three years, with only the 22 fraction decrement reaching significance. Bladder outcomes at 3 years were comparable (p=0.343) although, for all patients combined, a significant decline was observed from the baseline (p=0.008). Spitzer quality of life data revealed similarly excellent, 3-year means (p=0.188). International erectile function data also revealed no significant differences at 3 years although all measures except intercourse satisfaction worsened post-treatment. CONCLUSIONS: Three-year QoL changes for bowel, bladder and SQLI were modest and similar for 3 HPFX regimens spanning 2.94-4.3 Gy per fraction. These favorable patient-scored outcomes demonstrate the safety and tolerability of such regimens and may be leveraged to support further implementation of mild to moderately hypofractionated radiotherapy in the setting of low and intermediate-risk prostate cancer.

Curative antitumor immune response is optimal with tumor irradiation followed by genetic induction of major histocompatibility complex class I and class II molecules and suppression of Ii protein.

Transfecting genes into tumors, to upregulate major histocompatibility complex (MHC) class I and class II molecules and inhibit MHC class II associated invariant chain (Ii), induces a potent anti-tumor immune response when preceded by tumor irradiation, in murine RM-9 prostate carcinoma. The transfected genes are cDNA plasmids for interferon-gamma (pIFN-gamma), MHC class II transactivator (pCIITA), an Ii reverse gene construct (pIi-RGC), and a subtherapeutic dose of adjuvant IL-2 (pIL-2). Responding mice rejected challenge with parental tumor and demonstrated tumor-specific cytotoxic T lymphocytes (CTLs). We have extended our investigation to determine the relative roles of each one of the four plasmids pIFN-gamma, pCIITA, pIi-RGC, and pIL-2 in conjunction with radiation for the induction of a curative immune response. Upregulation of MHC class I with pIFN-gamma or class II with pCIITA, separately, does not lead to a complete response even if supplemented with pIL-2 or pIi-RGC. An optimal and specific antitumor response is achieved in more than 50% of the mice when, after tumor irradiation, tumor cells are converted in situ to a MHC class I+/class II+/Ii- phenotype with pIFN-gamma, pCIITA, pIi-RGC, and pIL-2. We demonstrate further that both CD4+ helper T cells and CD8+ cytotoxic T cells are essential for induction of an antitumor response because in vivo depletion of either subset abrogates the response. The radiation contributes to the gene therapy by causing tumor debulking and increasing the permeability of tumors to infiltration of inflammatory cells.

Genistein potentiates inhibition of tumor growth by radiation in a prostate cancer orthotopic model.

OBJECTIVE: We have shown previously that pretreatment with genistein potentiated cell killing induced by radiation in human PC-3 prostate carcinoma cell line in vitro. We tested this approach in vivo using an orthotopic prostate carcinoma model of PC-3 cells in nude mice. METHODS: Established prostate tumors were pretreated with p.o. genistein at a dose of 5 mg/d for 2 days followed by tumor irradiation with 5 Gy photons. One day after radiation, genistein was resumed and given every other day for 4 weeks. RESULTS: Genistein combined with radiation caused a significantly greater inhibition of primary tumor growth (87%) compared with genistein (30%) or radiation (73%) alone. The number of metastatic lymph nodes was also significantly decreased following genistein and radiation. Paradoxically, genistein alone increased the size of lymph nodes associated with heavy tumor infiltration. Genistein-treated prostate tumors were large with necrosis, apoptotic cells, and giant cells and have a lower proliferation index than in control tumors. Following radiation, areas of tumor destruction replaced by fibrotic tissue and inflammatory cells as well as giant cells were observed, which are typical of radiation effect. After radiation and genistein treatment, an increase in giant cells, apoptosis, inflammatory cells, and fibrosis was observed with decreased tumor cell proliferation consistent with increased tumor cell destruction. Long-term therapy with genistein after prostate tumor irradiation significantly increased survival. CONCLUSIONS: Genistein combined with prostate tumor irradiation led to a greater control of the growth of the primary tumor and metastasis to lymph nodes than genistein or radiation alone, resulting in greater survival.

Radiation improves intratumoral gene therapy for induction of cancer vaccine in murine prostate carcinoma.

Our goal was to convert murine RM-9 prostate carcinoma cells in vivo into antigen-presenting cells capable of presenting endogenous tumor antigens and triggering a potent T-helper cell-mediated immune response essential for the generation of a specific antitumor response. We showed that generating the major histocompatibility complex (MHC) class I+/class II+/Ii- phenotype, within an established subcutaneous RM-9 tumor nodule, led to an effective immune response limiting tumor growth. This phenotype was created by intratumoral injection of plasmid cDNAs coding for interferon gamma, MHC class II transactivator, and an antisense reverse gene construct (RGC) for a segment of the gene for Ii protein (-92,97). While this protocol led to significant suppression of tumor growth, there were no disease-free survivors. Nevertheless, irradiation of the tumor nodule on the day preceding initiation of gene therapy yielded 7 of 16 mice that were disease-free in a long-term follow up of 57 days compared to 1 of 7 mice receiving radiotherapy alone. Mice receiving radiotherapy and gene therapy rejected challenge with parental RM-9 cells and demonstrated specific cytotoxic T-cell activity in their splenocytes but not the mouse cured by radiation alone. These data were reproduced in additional experiments and confirmed that tumor irradiation prior to gene therapy resulted in complete tumor regression and specific tumor immunity in more than 50% of the mice. Increasing the number of plasmid injections after tumor irradiation induced tumor regression in 70% of the mice. Administering radiation before this novel gene therapy approach, that creates an in situ tumor vaccine, holds promise for the treatment of human prostate carcinoma.

Turning tumor cells in situ into T-helper cell-stimulating, MHC class II tumor epitope-presenters: immuno-curing and immuno-consolidation.

Immunological control or cure of tumors depends on initiating a robust T helper cell response to MHC class II epitopes of tumor-associated antigens. T helper cells regulate the potency of cytotoxic T lymphocyte and antibody responses. We have developed a novel approach to stimulate T helper cells by converting tumor cells into MHC class II molecule-positive, antigen presenting cells. Furthermore, using antisense methods, we suppress expression of the Ii protein, that normally blocks the antigenic peptide binding site of MHC class II molecules during synthesis in the endoplasmic reticulum. In such gene-engineered tumor cells, the MHC class II molecules pick up antigenic peptides, which have been transported into the endoplasmic reticulum for binding to MHC class I molecules. All nucleated cells create such "surveys of self" to detect viral or malignant transformation. Our method extends that survey of self to MHC class II endogenous tumor-associated antigens. Simultaneous presentation of tumor antigens by both MHC class I and II generates a robust and long-lasting antitumor immune response. Injecting murine tumors with genes, which induce MHC class II molecules and suppress Ii protein, cures a significant number of animals with renal and prostate tumors. We have developed analogous human gene vectors that are suitable for most patients and cancers, because they are monomorphic and active in all HLA-DR alleles. We review our findings, and analyze remaining issues for preclinical study and the design of clinical trials.

Tumor irradiation followed by intratumoral cytokine gene therapy for murine renal adenocarcinoma.

To circumvent the toxicity caused by systemic injection of cytokines, cytokine cDNA genes encoding the human interleukin IL-2 cDNA (Ad-IL-2) and murine interferon IFN-gamma gene (Ad- IFN-gamma) were inserted into adenoviral vectors. These constructs were used for intratumoral gene therapy of murine renal adenocarcinoma Renca tumors. Treatment with three doses of Ad-IL-2 or Ad- IFN-gamma, given a day apart, was more effective than single-dose gene therapy. We found that tumor irradiation enhanced the therapeutic efficacy of Ad-IL-2 and Ad-IFN-gamma intratumoral gene therapy. Tumor irradiation, administered 1 day prior to three doses of Ad-IL-2 treatment, was more effective than radiation or Ad-IL-2 alone, resulting in tumor growth arrest in all mice, increased survival and a consistent increase in complete tumor regression response rate. Complete responders rejected Renca tumor challenge and demonstrated specific cytotoxic T-cell activity, indicative of specific tumor immunity. The effect of radiation combined with three doses of Ad-IFN-gamma was less pronounced and did not lead to tumor immunity. Histological observations showed that irradiation of the tumor prior to gene therapy increased tumor destruction and inflammatory infiltrates in the tumor nodules. These findings demonstrate that tumor irradiation improves the efficacy of Ad-IL-2 gene therapy for induction of antitumor immune response.

Responsiveness of experimental prostate carcinoma bone tumors to neutron or photon radiation combined with cytokine therapy.

PURPOSE: To improve the outcome of radiotherapy for prostate carcinoma bone tumors, we investigated bone tumor irradiation with photons or neutrons followed by interleukin 2 (IL-2) therapy in a tumor model. METHODS AND MATERIALS: Implantation of PC-3 cells in nude mouse femur cavity induced a bone tumor that progressed to the formation of a palpable tumor, at the hip joint, by Day 20. Established bone tumors were irradiated with photons or neutrons, and a day later, mice were treated with IL-2 therapy for 3 weekly cycles. RESULTS: PC-3 bone tumors responded to radiation with photons or neutrons in a dose-dependent manner. Combination of photon or neutron radiation with IL-2 therapy increased tumor growth delay, compared to that with photons or neutrons alone. Radiation alone or combined with IL-2 significantly increased mouse survival compared to that with IL-2 or no treatment. After combined therapy, a complete inhibition of bone tumor growth was observed in 45% to 50% of the mice. Histologically, the combined therapy resulted in greater tumor destruction associated with fibrosis, new bone formation, and inflammatory infiltrates than that observed with each modality alone. CONCLUSIONS: The efficacy of tumor irradiation with neutrons or photons was enhanced by IL-2 therapy for the treatment of prostate carcinoma bone tumors.

Therapeutic postprostatectomy irradiation.

The purpose of this study was to determine the outcome of patients receiving external beam radiation for an elevated postprostatectomy prostate-specific antigen (PSA) level. Between December 1991 and September 1998, 108 patients received definitive radiation therapy for elevated postprostatectomy PSA levels. The median dose of irradiation was 68 Gy (range, 48-74 Gy). During treatment, the PSA levels were checked an average of 5 times (range, 3-7 times). Prostate-specific antigen values were judged to decline or increase during treatment if they changed by more than 0.2 ng/mL. After treatment, biochemical failure was defined as a measurable or rising PSA > 0.2 ng/mL. Median follow-up was 51 months (range, 3-112 months). Fifty-eight patients (54%) had evidence of biochemical failure. The 3- and 5-year actuarial biochemical relapse-free (bNED) survivals for all patients were 55% and 39%, respectively. Upon univariate analysis, intratreatment PSA and preradiation PSA were significant predictors of bNED survival. Patients with a PSA level that decreased during treatment had a 5-year bNED survival of 43% compared to 10% in patients with an increasing PSA level (P = 0.0002). Using the preradiation therapy PSA value as a continuous variable, higher preradiation therapy PSA levels were associated with an increased risk of failure (P = 0.004). Cut points of pretreatment PSA were derived at 0.9 ng/mL and 4.2 ng/mL using the Michael Leblanc recursive partitioning algorithm. The 5-year bNED rate for patients with a preradiation therapy PSA < 0.9 ng/mL was 45% versus 42% for patients with preradiation therapy PSA between 0.9 and 4.2 ng/mL and 21% for patients > or = 4.2 ng/mL (P = 0.0003). Patients with a Gleason score of < or = 7 had a 5-year bNED rate of 38% compared to 37% for patients with a Gleason score > 7 (P = 0.27). Other factors examined individually that did not reach statistical significance included time from surgery to radiation therapy, race, seminal vesicle involvement, pathological stage, surgical margin, and perineural invasion. Upon multivariate analysis, only preradiation therapy PSA (P < 0.001) and the PSA trend during radiation therapy (P < 0.001) were significant factors. The results of therapeutic radiation for patients with elevated postprostatectomy PSA levels are sufficiently poor; other strategies should be explored as alternatives, including early adjuvant postprostatectomy irradiation or the use of combined hormonal and radiation therapy in the salvage situation.

Effect of MLC leaf width on the planning and delivery of SMLC IMRT using the CORVUS inverse treatment planning system.

This study investigates the influence of multileaf collimator (MLC) leaf width on intensity modulated radiation therapy (IMRT) plans delivered via the segmented multileaf collimator (SMLC) technique. IMRT plans were calculated using the Corvus treatment planning system for three brain, three prostate, and three pancreas cases using leaf widths of 0.5 and 1 cm. Resulting differences in plan quality and complexity are presented here. Plans calculated using a 1 cm leaf width were chosen over the 0.5 cm leaf width plans in seven out of nine cases based on clinical judgment. Conversely, optimization results revealed a superior objective function result for the 0.5 cm leaf width plans in seven out of the nine comparisons. The 1 cm leaf width objective function result was superior only for very large target volumes, indicating that expanding the solution space for plan optimization by using narrower leaves may result in a decreased probability of finding the global minimum. In the remaining cases, we can conclude that we are often not utilizing the objective function as proficiently as possible to meet our clinical goals. There was often no apparent clinically significant difference between the two plans, and in such cases the issue becomes one of plan complexity. A comparison of plan complexity revealed that the average 1 cm leaf width plan required roughly 60% fewer segments and over 40% fewer monitor units than required by 0.5 cm leaf width plans. This allows a significant decrease in whole body dose and total treatment time. For very complex IMRT plans, the treatment delivery time may affect the biologically effective dose. A clinically significant improvement in plan quality from using narrower leaves was evident only in cases with very small target volumes or those with concavities that are small with respect to the MLC leaf width. For the remaining cases investigated in this study, there was no clinical advantage to reducing the MLC leaf width from 1 to 0.5 cm. In such cases, there is no justification for the increased treatment time and whole body dose associated with the narrower MLC leaf width.

Independent verification of ultrasound based image-guided radiation treatment, using electronic portal imaging and implanted gold markers.

The aim of this paper is to study the correction of prostate motion and position during external beam therapy. The correction was performed using a commercially available ultrasound-based repositioning tool. Electronic portal imaging with the use of fiducial markers was used to assess efficacy and accuracy. Patients undergoing radiation treatment for adenocarcinoma of the prostate were enrolled in a positioning study. Fifteen patients had five to six gold fiducial markers implanted in their prostate. These patients were positioned daily in a standard manner and then were repositioned every other day using an ultrasound-based correction system. Every fraction of a patients' treatment was imaged. This yielded 156 image pairs with and 119 pairs without repositioning available for analysis. This group of patients with markers had the following residual positions measured after the use of ultrasound repositioning. A mean error of -0.4 mm (LL), -2.6 mm (CC), and +2.5 mm (AP) with a standard deviation of 4.3, 5.4, and 5.7 mm. In two directions the improvements of treatment using the ultrasound correction were smaller than the precision of this experiment. They were no larger than 0.81 mm (LAT), and 0.95 mm (CC). In the AP direction a significant improvement was found of 1.6 mm. A highly significant correlation (p < 0.001) was found between the residual errors in the cranio-caudal direction and the shifts performed on the basis of the ultrasound measurements (Spearman ranking R = 0.53). We presented a method to objectively estimate improvements by a correction scheme. This method applied to ultrasound-based adjustment showed significant improvement in one direction and no measurable improvement in two other directions.

Locally advanced adenocarcinoma of the prostate: how do different radiotherapy techniques compare?

Many men with prostate cancer will have locally advanced disease, either at presentation or later in their clinical course. Alternative treatment options for this stage of disease include locoregional radiation therapy, or systemic treatment. This article will present a discussion of the use of radiation therapy for locally advanced disease focusing on three methods of improving effectiveness of treatment: increasing the relative integral dose; decreasing the volume of tumor present by neoadjuvant hormonal therapy and radiobiologic optimization.

Adjuvant radiation therapy for pathologic T3 prostate cancer.

Locally invasive or T3 prostate cancer includes cases with intracapsular and extracapsular extension of tumor. For these men, adjuvant radiation therapy can improve long-term local control by eradicating microscopic tumor deposits in the prostatic bed, and may improve overall survival. Issues that generate debate include the timing of adjuvant radiation in relation to surgery, the volume to be treated, and techniques for minimizing morbidity. These issues will be discussed in this article.