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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.

Extraprostatic disease will be manifest in a third of men after radical prostatectomy. We present the long-term followup of a randomized clinical trial of radiotherapy to reduce the risk of subsequent metastatic disease and death.A total of 431 men with pT3N0M0 prostate cancer were randomized to 60 to 64 Gy adjuvant radiotherapy or observation. The primary study end point was metastasis-free survival.Of 425 eligible men 211 were randomized to observation and 214 to adjuvant radiation. Of those men under observation 70 ultimately received radiotherapy. Metastasis-free survival was significantly greater with radiotherapy (93 of 214 events on the radiotherapy arm vs 114 of 211 events on observation; HR 0.71; 95% CI 0.54, 0.94; p = 0.016). Survival improved significantly with adjuvant radiation (88 deaths of 214 on the radiotherapy arm vs 110 deaths of 211 on observation; HR 0.72; 95% CI 0.55, 0.96; p = 0.023).Adjuvant radiotherapy after radical prostatectomy for a man with pT3N0M0 prostate cancer significantly reduces the risk of metastasis and increases survival.

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...

Teletherapy with high linear energy transfer radiations (LET), perhaps more than with low LET types, requires careful beam collimation to limit effects to normal structures. Intensity modulated techniques may also hold promise in this regard. Accordingly, a remote computer-controlled, high-resolution multileaf collimator (MLC) is placed into service at the Gershenson Radiation Oncology Center's fast neutron therapy center of the Karmanos Cancer Institute, Detroit, Michigan. Prior to clinical application the basic radiological properties of the fast neutron MLC are studied. Complicating the evaluation is the mixed neutron and gamma radiation field environment encountered with fast neutron beams. As a reference the MLC performance is compared to an existing multirod collimator (MRC) used at the facility for more than ten years. The MLC aggregate transmission is found to be about 4%, slightly outperforming the MRC. The measured gamma component for a closed collimator is 1.5 times higher for the MLC, compared with the MRC. The different materials used for attenuation, steel and tungsten, respectively account for the difference. The geometry for the MRC is double focused whereas that for the MLC is single focused. The resulting penumbrae agree between the focused axis of the MLC and both axes of the MRC. Penumbra differences between the focused and unfocused axes were not observable at small field sizes and a maximum of about 1 cm for a 25 x 25 cm2 field at 2.5 cm depth in water. For a 10 x 10 cm2 field the focused penumbra is 9 mm, and the unfocused is 12 mm. The many benefits of the fully automatic MLC over the semimanual MRC are considered to justify this compromise.

Purpose An increasing serum prostate-specific antigen (PSA) level is the initial sign of recurrent prostate cancer among patients treated with radical prostatectomy. Salvage radiation therapy (SRT) may eradicate locally recurrent cancer, but studies to distinguish local from systemic recurrence lack adequate sensitivity and specificity. We developed a nomogram to predict the probability of cancer control at 6 years after SRT for PSA-defined recurrence. Patients and Methods Using multivariable Cox regression analysis, we constructed a model to predict the probability of disease progression after SRT in a multi-institutional cohort of 1,540 patients. Results The 6-year progression-free probability was 32% (95% CI, 28% to 35%) overall. Forty-eight percent (95% CI, 40% to 56%) of patients treated with SRT alone at PSA levels of 0.50 ng/mL or lower were disease free at 6 years, including 41% (95% CI, 31% to 51%) who also had a PSA doubling time of 10 months or less or poorly differentiated (Gleason grade 8 to 10) cancer. Significant variables in the model were PSA level before SRT (P < .001), prostatectomy Gleason grade (P < .001), PSA doubling time (P < .001), surgical margins (P < .001), androgen-deprivation therapy before or during SRT (P < .001), and lymph node metastasis (P = .019). The resultant nomogram was internally validated and had a concordance index of 0.69. Conclusion Nearly half of patients with recurrent prostate cancer after radical prostatectomy have a long-term PSA response to SRT when treatment is administered at the earliest sign of recurrence. The nomogram we developed predicts the outcome of SRT and should prove valuable for medical decision making for patients with a rising PSA level.

OBJECTIVE STAT3 participates in the regulation of cellular growth, survival, and oncogenesis. We evaluated the association between activated STAT3 expression and overall survival, disease-specific survival, distant metastasis, and local progression in a cohort of patients treated with either radiotherapy alone or radiotherapy plus short-term androgen blockade. METHODS A total of 456 assessable patients were included in the Radiation Therapy Oncology Group 86-10 trial. Of these, 62 patients had sufficient tissue for the analysis of STAT3 expression by immunohistochemistry. Nuclear staining was quantified by an image analysis system. RESULTS No significant difference was found in the distribution of clinical characteristics and assigned treatment between the patients available for STAT3 analysis (STAT3 cohort) and the others in the Radiation Therapy Oncology Group 86-10 trial (n = 394). Activated STAT3 correlated inversely with the development of distant metastasis (risk ratio [RR] = 0.81, P = 0.04) but not with overall survival, cause-specific survival, or local progression. Similar results were obtained when the data were dichotomized (ACIS index greater than 29%, RR = 0.41, P = 0.07). On multivariate analysis, activated STAT3 (continuous variable) was an independent predictor of distant metastasis (RR = 0.79, P = 0.04). CONCLUSIONS Activated STAT3 was inversely related to the development of distant metastasis in prostate cancer. This marker should be evaluated further in a larger cohort of patients.

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 64.7Gy/22fx, 58.08Gy/16fx and 51.6Gy/12fx were each designed to yield equivalent predicted late toxicity. Three quality of life (QoL) surveys were administered prior to treatment and annually upto 3years. 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 3years 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 3years 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 2.94–4.3Gy 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

The electromechanical properties of a 120-leaf, high-resolution, computer-controlled, fast neutronmultileaf collimator(MLC) are presented. The MLC replaces an aging, manually operated multirod collimator. The MLC leaves project 5 mm in the isocentric plane perpendicular to the beam axis. A taper is included on the leaves matching beam divergence along one axis. The 5 - mm leaf projection width is chosen to give high-resolution conformality across the entire field. The maximum field size provided is 30 × 30 cm 2 . To reduce the interleaf transmission a 0.254 - mm blocking step is included. End-leaf steps totaling 0.762 mm are also provided allowing opposing leaves to close off within the primary radiation beam. The neutronMLC also includes individual 45° and 60° automated universal tungsten wedges. The automated high-resolution neutroncollimation provides an increase in patient throughput capacity, enables a new modality, intensity modulated neutron therapy, and limits occupational radiation exposure by providing remote operation from a shielded console area.

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.

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.

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.

Epidemiological studies suggest an inverse association between soy intake and prostate cancer (Pca) risk. We have previously observed that soy isoflavone genistein induces apoptosis and inhibits growth of both androgen-sensitive and androgen-independent Pca cells in vitro. To determine the clinical effects of soy isoflavones on Pca we conducted a pilot study in patients with Pca who had rising serum prostate-specific antigen (PSA) levels. Patients with Pca were enrolled in the study if they had either newly diagnosed and untreated disease under watchful waiting with rising PSA (group I) or had increasing serum PSA following local therapy (group II) or while receiving hormone therapy (group III). The study intervention consisted of 100 mg of soy isoflavone (Novasoy) taken by mouth twice daily for a minimum of 3 or maximum of 6 mo. Forty-one patients were enrolled (4 in group I, 18 in group II, and 19 in group III) and had a median PSA level of 13.3 ng/ml. Thirty-nine patients could be assessed for response. Soy isoflavone supplementation was given for a median of 5.5 (range 0.8-6) mo per patient. Although there were no sustained decreases in PSA qualifying for a complete or partial response, stabilization of the PSA occurred in 83% of patients in hormone-sensitive (group II) and 35% of hormone-refractory (group III) patients. There was a decrease in the rate of the rise of serum PSA in the whole group (P = 0.01) with rates of rise decreasing from 14 to 6% in group II (P = 0.21) and from 31 to 9% in group III (P = 0.05) following the soy isoflavone intervention. Serum genistein and daidzein levels increased during supplementation from 0.11 to 0.65 microM (P = 0.00002) and from 0.11 to 0.51 microM (P = 0.00001), respectively. No significant changes were observed in serum levels of testosterone, IGF-1, IGFBP-3, or 5-OHmdU. These data suggest that soy isoflavones may benefit some patients with Pca.

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.

The d(48.5) + Be neutron beam from the Harper Hospital superconducting cyclotron is collimated using a unique multirod collimator (MRC). A computer controlled multileaf collimator (MLC) is being designed to improve efficiency and allow for the future development of intensity modulated radiation therapy with neutrons. For the current study the use of focused or unfocused collimator leaves has been studied. Since the engineering effort associated with the leaf design and materials choice impacts significantly on cost, it was desirable to determine the clinical impact of using unfocused leaves in the MLC design. The MRC is a useful tool for studying the effects of using focused versus unfocused beams on beam penumbra. The effects of the penumbra for the different leaf designs on tumor and normal tissue DVHs in two selected sites (prostate and head and neck) was investigated. The increase in the penumbra resulting from using unfocused beams was small (approximately 1.5 mm for a 5 x 5 cm2 field and approximately 7.6 mm for a 25 x 25 cm2 field at 10 cm depth) compared to the contribution of phantom scatter to the penumbra width (5.4 and 20 mm for the small and large fields at 10 cm depth, respectively). Comparison of DVHs for tumor and critical normal tissue in a prostate and head and neck case showed that the dosimetric disadvantages of using an unfocused rather than focused beam were minimal and only significant at shallow depths. For the rare cases, where optimum penumbra conditions are required, a MLC incorporating tapered leaves and, thus, providing focused collimation in one plane is necessary.

Purpose: Patients with locally advanced bladder cancer or who are not medically fit for surgery are a therapeutic dilemma. Radiotherapy with or without single agent cisplatin has been the major therapeutic modality. A phase II Southwest Oncology Group trial investigated the efficacy and feasibility of 5-fluorouracil, cisplatin and radiation in this patient subset.Materials and Methods: Eligible patients had muscle invasive bladder cancer (clinical stages T2-T4) with nodal involvement at or below the level of bifurcation of the iliac vessels, were medically or surgically inoperable, or refused cystectomy. Patients underwent pretreatment cystoscopy and detailed tumor mapping, and were treated with 75 mg./m.2 cisplatin on day 1 and 1 gm./m.2 daily, 5-fluorouracil on days 1 to 4 and definitive radiotherapy. Chemotherapy was repeated every 28 days, twice during and twice after radiation.Results: From October 1993 to April 1998, 60 patients were enrolled in study. Of the 56 eligible patients 34% had unresectabl...

PURPOSE: S8809 is a randomized phase III trial determining whether intensive cytoreductive treatment, followed by interferon consolidation at the time of minimal residual disease, prolongs the progression-free survival (PFS) or overall survival (OS) of indolent lymphoma patients. PATIENTS AND METHODS: Five hundred seventy-one patients with previously untreated stage III or IV low-grade non-Hodgkin’s lymphoma were registered. Patients received six to eight cycles of prednisone, methotrexate, doxorubicin, cyclophosphamide, and etoposide/mechlorethamine, vincristine, procarbazine, and prednisone (ProMACE[day 1]-MOPP[day 8]) chemotherapy or chemotherapy plus radiotherapy. Responding patients were randomized to observation alone or to interferon consolidation. Interferon alfa-2b 2 mU/m2 was given subcutaneously three times weekly for 2 years. RESULTS: Two hundred sixty-eight eligible patients were randomized to interferon alfa consolidation (n = 144) or observation alone (n = 124). With a median follow-up time from randomization among patients still alive of 6.2 years, the median PFS time was 4.1 years for patients who received interferon consolidation therapy and 3.2 years for patients who were observed after ProMACE-MOPP induction (P = .25). The adjusted hazard ratio for relapse for observation to interferon was 0.83 (95% confidence interval [CI], 0.61 to 1.13). The median OS has not been reached in either group. At 5 years, OS is 78% for the interferon group and 77% for the observation group (P = .65). The adjusted hazard ratio for survival for observation to interferon is 1.11 (95% CI, 0.69 to 1.79). CONCLUSION: Interferon alfa consolidation therapy after intensive treatment with anthracycline-containing combination chemotherapy and involved-field radiation therapy does not prolong the PFS or OS of patients with low-grade non-Hodgkin’s lymphoma.

Purpose: To assess the impact of race on biochemical freedom from recurrence in patients with early-stage prostate cancer treated either by radical prostatectomy or radiation therapy. Methods: Between July 1989 and December 1994, 693 patients with early-stage prostate cancer were treated with radiation (302 patients) or by radical prostatectomy (391 patients) at Barbara Ann Karmanos Cancer Institute/Wayne State University. Stage, Gleason score, race, pretreatment PSA, and follow-up PSA values were abstracted. There were 387 Caucasian males (CM) and 306 African-American males (AAM). None of the patients received hormone therapy. Radiation therapy was delivered using photon irradiation (249 patients, median dose 69 Gy) or mixed neutron/photon irradiation (53 patients, median dose 10 NGy + 38 PGy). Median follow-up was 36 months (range 2–70) for CM and 35 months (range 1–70) for AAM. Results: Thirty-seven percent of patients treated surgically were AAM, compared to 53% in the radiation group ( p = 0.0001). AAM had a higher median prostate-specific antigen (PSA) than CM (9.78 ng/ml vs. 8.0 ng/ml, p = 0.01). Thirty-three percent of AAM had a pretreatment PSA greater than 15 ng/ml compared to 20% of CM ( p = 0.00001). Disease-free survival (DFS) by race was equivalent at 36 months, 81% for CM and 77% for AAM ( p = NS). For patients with PSA ≤ 15, DFS rates were 87% and 85% for CM and AAM, respectively. DFS rates for patients with PSA > 15 were 61% for CM and 64% for AAM ( p = NS). Significant prognostic factors on multivariate analysis included pretreatment PSA ( p = 0.0001) and Gleason score ( p = 0.0001). Conclusion: Race does not appear to adversely affect biochemical disease-free survival in males treated for early-stage prostate cancer. African-American males with early-stage prostate cancer should expect similar biochemical disease-free survival rates to those seen in Caucasian males.

Objectives. To determine whether the response to hormonal therapy before radiation predicts the rate of biochemical relapse in patients with locally advanced prostate cancer. Methods. Between October 1991 and December 1997, 105 patients with locally advanced adenocarcinoma of the prostate received radiotherapy in two dose-escalation studies. Sixty-seven patients received neoadjuvant hormonal therapy. The mean and median duration of hormonal therapy before radiotherapy was 4 months each. All treatments were designed using three-dimensional conformal therapy. The total dose to the gross tumor volume ranged from 73 to 87 Gy in 2 Gy per fraction photon equivalent dose. The median follow-up time was 30 months (range 1 to 66). Results. The median prostate-specific antigen (PSA) nadir after neoadjuvant hormonal therapy but before radiotherapy was 1.7 ng/mL (range less than 0.05 to 71.2). The median nadir after radiation for patients who did and did not receive neoadjuvant androgen deprivation was 0.25 ng/mL (range less than 0.05 to 6.2) and 1.35 ng/mL (range 0.08 to 10), respectively. Median time to achieve nadir was 6 months (range 1 to 42) with and 12 months (range 1 to 48) without hormonal therapy. There was no significant difference in the rate of biochemical failure for patients with a posthormone (before irradiation) PSA nadir less than 1 ng/mL versus 1 ng/mL or greater (overall P = 0.9). However, there was a significant difference in biochemical no evidence of disease rates between those with a PSA nadir less than 1 ng/mL and those with a PSA nadir of 1 ng/mL or greater after radiation (63% versus 22% at 3 years, overall P

The design and construction of a unique superconducting cyclotron for use in fast neutron radiation therapy is described. The clinical results obtained in the treatment of adenocarcinoma of the prostate with this accelerator are presented. Future use of the boron neutron capture reaction as a means of enhancing fast neutron therapy in the treatment of patients with brain tumors (glioblastoma multiforme) is also discussed.

The results of clinical trials in the treatment of adenocarcinoma of the prostate using, mixed beam neutron/photon therapy, neutrons alone and photon therapy in combination with hormone treatment are compared. These trials indicate that neutron therapy is superior to photon/hormone therapy in achieving local control. The costs of delivering these two different therapies in a large US academic radiation oncology center at Wayne State University (WSU) are compared. The cost of a full course of mixed beam therapy is $20,142 compared to $18,871 for the photon/hormone treatment. Although the WSU neutron facility is a state-of-the-art installation, it is also a prototype device; it is estimated that a modern neutron facility based on this design would operate more cost effectively reducing the cost of a course of mixed beam therapy to $ 18,532.

Objectives. To evaluate the efficacy and toxicity of salvage radiation or surgery for locally recurrent tumor after initial treatment for clinically localized prostate cancer. Methods. The treatment records of 70 patients with local treatment failure after definitive therapy for clinically localized prostate cancer were reviewed. Initial treatment consisted of external beam radiation therapy (RT) in 27 patients and radical retropubic prostatectomy (RP) in 43 patients. Results. The mean serum PSA levels were similar in both groups before initial treatment: 8.5 and 10.5 ng/mL for the salvage RP and salvage RT groups, respectively (P = 0.09). However, at the time of salvage treatment, the mean serum PSA levels were 9.1 and 1.1 ng/mL for the salvage RP and salvage RT groups, respectively (P = 0.0001). The mean time from tumor recurrence to salvage treatment was 15.6 months for the salvage RP group and 4.9 months for the salvage RT group (P = 0.0001). Although there was no statistical difference in the disease-free survival rate (P = 0.38), a trend for better disease control in the salvage RT group was evident (74.4% versus 44.4%). Patients treated with salvage RP had a higher rate of urinary incontinence than those undergoing salvage RT: 63% and 32.6%, respectively (P = 0.01). Conclusions. The disease-free survival rate was similar between patients receiving salvage RP or RT, despite the significantly higher serum PSA levels at the time of treatment and the delay in time to treatment for the salvage RP patients. Salvage RP is associated with a high rate of urinary incontinence. Earlier identification of tumor recurrence after RT may improve the efficacy and safety of salvage RP.

Purpose: This study was initiated to determine the efficacy of post-prostatectomy therapeutic radiation for patients with elevated prostate specific antigen (PSA).Materials and Methods: A total of 47 patients received 66 Gy. therapeutic irradiation to the prostate bed for a PSA level greater than 0 ng./ml. postoperatively. Univariate and multivariate survival analyses were performed to identify prognostic variables.Results: At a median followup of 36 months (range 18 to 48) 83 and 33% of the patients with PSA 2 ng./ml. or less and 2 ng./ml. or greater, respectively, had no evidence of disease (p = 0.001). Pathological stage and a complete biochemical response (PSA less than 0.05 ng./ml.) were also significant prognostic variables.Conclusions: Therapeutic irradiation for patients with elevated PSA postoperatively is highly effective. At a median followup of 36 months 64% of the patients remain disease-free.

PURPOSE: To assess the impact of intravesical contrast during computed tomography (CT) simulation on prostate tumor volume definition and dose distribution. METHODS AND MATERIALS: Sixteen patients with localized adenocarcinoma of the prostate underwent CT-based virtual simulation in preparation for definitive radiotherapy. Patients were immobilized with a foam cradle and an initial CT was performed after oral but without intravesical contrast (noncontrast scan). A second scan was performed following administration of intravesical contrast (contrast scan). Beam apertures were designed on the noncontrast scans and digitized into the contrast scan file. Beam apertures were also designed on the contrast scans. Isodose plans were generated for several beam apertures and arrangements. RESULTS: There was enhanced visualization of the prostate at the cephalad portion of the field for 15 of the 16 cases. The mean differences between the noncontrast and contrast volumes was significant (p = 0.0001). The mean percent underdosage to the prostate ranged from 3.9% to 18.6%, depending upon the target volume and beam arrangement. CONCLUSION: This study demonstrates the necessity of using intravesical contrast for defining the location of the prostate during CT simulation. The underestimation of the extent of the prostate when omitting intravesical contrast leads to significant underdosage. The value of intravesical contrast is most evident when small (prostate only) conformal fields are used.

The p53 tumor suppressor gene (also known as TP53) is one of the most frequently mutated genes in human cancer. Several studies have shown that p53 mutations are infrequent in prostate cancer and are associated with advanced disease.We assessed the prognostic value of identifying abnormal p53 protein expression in the tumors of patients with locally advanced prostate cancer who were treated with either external-beam radiation therapy alone or total androgen blockade before and during the radiation therapy.The study population consisted of a subset of patients entered in Radiation Therapy Oncology Group protocol 8610 ("a phase III trial of Zoladex and flutamide used as cytoreductive agents in locally advanced carcinoma of the prostate treated with definitive radiotherapy"). Immunohistochemical detection of abnormal p53 protein in pretreatment specimens (i.e., needle biopsies or transurethral resections) was achieved by use of the monoclonal anti-p53 antibody DO7; specimens in which 20% or more of the tumor cell nuclei showed positive immunoreactivity were considered to have abnormal p53 protein expression. Associations between p53 protein expression status and the time to local progression, the incidence of distant metastases, progression-free survival, and overall survival were evaluated in univariate (logrank test) and multivariate (Cox proportional hazards model) analyses. Reported P values are two-sided.One hundred twenty-nine (27%) of the 471 patients entered in the trial had sufficient tumor material for analysis. Abnormal p53 protein expression was detected in the tumors of 23 (18%) of these 129 patients. Statistically significant associations were found between the presence of abnormal p53 protein expression and increased incidence of distant metastases (P = .04), decreased progression-free survival (P = .03), and decreased overall survival (P = .02); no association was found between abnormal p53 protein expression and the time to local progression (P = .58). These results were independent of the Gleason score and clinical stage. A significant treatment interaction was detected with respect to the development of distant metastases: Among patients receiving both radiation therapy and hormone therapy, those with tumors exhibiting abnormal p53 protein expression experienced a reduced time to the development of distant metastases (P = .001); for patients treated with radiation therapy alone, the time to distant metastases was unrelated to p53 protein expression status (P = .91).Determination of p53 protein expression status yield significant, independent prognostic information concerning the development of distant metastases, progression-free survival, and overall survival for patients with locally advanced prostate cancer who are treated primarily with radiation therapy.The interaction of radiation therapy plus hormone therapy and abnormal p53 protein expression may provide a clinical link to experimental evidence that radiation therapy and/or hormone therapy act, at least in part, by the induction of apoptosis (a cell death program) and suggests that this mechanism may be blocked in patients whose tumors have p53 mutations.

Although neutron irradiation for prostate cancer has been associated with significant morbidity, pilot data in patients with early stage disease suggested that conformal neutron and photon irradiation was well tolerated without severe complications. A self-assessment questionnaire was mailed to the first 83 patients treated with conformal neutron and photon irradiation to objectively evaluate the impact on quality of life of this regimen. In total, 75 patients (90%) returned the completed questionnaire. These patients had received either 9 neutron Gy (N Gy) plus 38 photon Gy (50 patients) or 10 N Gy plus 38 photon Gy (33 patients) for stage T1/T2 N0 M0 prostate cancer (Gleason score 1 tablespoon/day. One patient underwent surgery to dilate a urethral stricture. Although 55% of patients had gastrointestinal symptoms during radiation therapy, only 26% had persistent symptoms at the time of questioning. These included minor rectal bleeding in 20% and significant hematochezia in 3%. Of the 85% of patients able to obtain full or partial erections prior to irradiation, 87% maintained their potency. Fifteen percent sought treatment for impotence. Overall, at last follow-up, 84% felt little or no physical discomfort, 91% were very satisfied with their treatment, and 97% would choose radiation therapy again. This patient self-assessment questionnaire confirmed that this regimen of conformal neutron and photon irradiation resulted in levels of chronic toxicity acceptable to the patient.

The purpose of this study was to investigate the cause of hip complaints following conformal neutron therapy delivered by opposed lateral and oblique anterior ports to treat prostate cancer. Twenty-seven patients with hip complaints following neutron or mixed neutron and photon therapy for prostate cancer had 34 magnetic resonance imaging (MRI) studies 3–39 (mean 15.3) months following treatment; for comparison, 13 similarly treated patients without hip complaints were imaged 1–32 (mean 13.8) months post-treatment; 25/40 imaged patients received concurrent nonsteroidal hormone therapy. Coronal and axial images of the hips/pelvis were obtained utilizing T1 weighted spin echo and fat suppressed inversion recovery (STIR) sequences. Signal amplitude (SA) of involved muscles was measured on the STIR images and normalized to that of the psoas outside the treatment field. Hip complaints ranged from mild soreness or motion limitation to severe pain and limitation of ambulation; presence and severity of symptoms (sx) were significantly related to neutron dose (P = 0.020 and 0.0001) but not to hormone therapy (each P > 0.17). Normalized SA of the obturator muscles differed significantly with neutron dose (P = 0.013), the presence, and the severity, of sx (P = 0.0002 and 0.0007); estimated extent of abnormal muscle also differed significantly with neutron dose (P = 0.039), presence, and severity, of sx (P = 0.00004 and 0.0007); [hormone treatment had a profound effect on SA (P = 0.0001) and extent (P = 0.005) which was independent of sx (P = 0.10 and 0.14, respectively) and neutron dose (P = 0.33 and 0.32, respectively)]. Subcutaneous changes localized lateral to the greater trochanter were seen in all, and edema of the subjacent gluteus muscles in many, symptomatic hips; only 4/13 asymptomatic hips showed subcutaneous changes, 6 had mild gluteus edema. Avascular necrosis of the femoral head was seen in 5 symptomatic hips, with marked acetabular necrosis in 3 of these; small joint effusions were seen in 8 symptomatic hips; asymptomatic hips had no significant bone or joint abnormalities. Neutron therapy for prostate cancer designed to spare the rectum results in significant dose-dependent, musculoskeletal complications which are well demonstrated by MRI. SA abnormalities of irradiated muscle correlate significantly with neutron dose and both presence and severity of hip sx. Protocol modifications have been implemented to reduce these complications. MRI provides an objective means to assess both complications and the success of new protocols in ameliorating them. Concurrent hormone therapy has a profound effect on muscle changes on MRI which is independent of neutron dose and sx. Radiat. Oncol. Invest. 5:81–91, 1997. © 1997 Wiley-Liss, Inc.

In Part Three of this review, we begin with an analysis of prevention strategies for prostate cancer followed by a discussion of the clinical use of molecular techniques for the evaluation and treatment of patients with clinically localized prostate cancer. New developments in neutron and photon therapy of prostate cancer are addressed as well as the use of systemic radiotherapy for the treatment of bone metastases. Finally, we conclude with the role of hormonal therapy in the treatment of prostate cancer and the current status of development of chemo therapeutic regimens for the treatment of prostate cancer.

Diagnostic and prognostic markers for prostatic cancer (PCa) include conventional protein markers (e.g., PAP, PSA, PSMA, PIP, OA-519, Ki-67, PCNA, TF, collagenase, and TIMP 1), angiogenesis indicator (e.g., factor VIII), neuroendocrine differentiation status, adhesion molecules (E-cadherin, integrin), bone matrix degrading products (e.g., ICPT), as well as molecular markers (e.g., PSA, PSMA, p53, 12-LOX, and MSI). Currently, only PSA is used clinically for early diagnosis and monitoring of PCa. The histological differential diagnosis of prostatic adenocarcinoma includes normal tissues such as Cowper's gland, paraganglion tissue and seminal vesicle or ejaculatory duct as well as pathological conditions such as atypical adenomatous hyperplasia, atrophy, basal cell hyperplasia and sclerosing adenosis. A common PCa is characterized by a remarkable heterogeneity in terms of its differentiation, microscopic growth patterns and biological aggressiveness. Most PCa are multifocal with signi ficant variations in tumor grade between anatomically separated tumor foci. The Gleason grading system which recognizes five major grades defined by patterns of neoplastic growth has gained almost uniform acceptance. In predicting the biologic behavior of PCa clinical and pathological stages are used as the major prognostic indicators. Among the cell proliferation and death regulators androgens are critical survival factors for normal prostate epithelial cells as well as for the androgen-dependent human prostatic cancer cells. The androgen ablation has been shown to increase the apoptotic index in prostatic cancer patients and castration also promotes apoptotic death of human prostate carcinoma grown in mice. The progression of PCa, similarly to other malignancies, is a multistep process, accompanied by genetic and epigenetic changes, involving phenomenons as adhesion, invasion and angiogenesis (without prostate specific features).

Purpose: This study was initiated to assess the incidence of chronic complications and histologic and biochemical control following hyperfractioned conformal radiotherapy in patients with locally advanced prostate cancer. Methods and Materials: Between October 1991 and October 1994, 49 patients with locally advanced prostate cancer were entered on the first two dose levels of a prospective dose-escalation study using hyperfractionated three dimensional conformal radiotherapy. The first 25 patients received a minimum tumor dose of 78 Gy to the prostate and seminal vesicles in 6 weeks at 1.3 Gy, b.i.d. No increase in chronic toxicity compared with conventional radiotherapy was noted; therefore, an additional 24 patients were treated to a minimum tumor dose of 82.8 Gy to the prostate and seminal vesicles in 7 weeks at 1.15 Gy, b.i.d. Toxicity was scored according to the Radiation Therapy Oncology Group morbidity grading scale. Efficacy was assessed through scheduled postradiation prostate specific antigen values and ultrasound-guided biopsies. The median follow-up for the entire group was 20 months. Results: Thy hyperfractionated external radiation was well tolerated with minimal acute morbidity. At 30 months, the actuarial probability of Grade 2 gastrointestinal toxicity was 17%. At 30 months, the actuarial probability of Grade 2 genitourinary toxicity was 16%. There was no statistically significant difference between the two dose levels. No Grade 3 or 4 gastrointestinal or genitourinary toxicity was noted. At 12 months, 84% of patients had a prostate specific antigen ≤ 4; and 53%; ≤ 1 ng/ml. At 12 months, 71% of patients had post radiation biopsies that were either negative (55%) or showed a marked therapeutic effect (16%). Conclusion: The use of hyperfractionated conformal radiotherapy facilitated dose escalation with no increase in chronic toxicity compared to standard doses. The initial tumor response based on prostate specific antigen measurements adn postradiation biopsies is highly encouraging. Based on these results, an increase in dose to 87.4 Gy has been planned according to the schema of this ongoing dose escalation study.

Purpose: Accuracy of a patient treatment portal making device and computerized tomograph (CT) simulation have been clinically tested. Methods and Materials: A CT-based simulaor has been assembled based on a commercial CT scanner. This includes visualization software and a computer-controlled laser drawing device. This laser drawing devise is used to transfer the setup, central axis, and/or radiation portals from the CT simulator to the patient for appropriate patient skin marking. A protocol for clinical testing is reported. Twenty-five prospectively, sequentially accessioned patients have been analyzed. Results: The simulation process can be completed in an average time of 62 min. Under many cases, the treatment portals can be designed and the patient marked in one session. Mechanical accuracy of the system was found to be within ± 1 mm. The portal projection accuracy in clinical cases is observed to be better than ± 1.2 mm. Operating costs are equivalent to the conventional simulation process it replaces. Conclusion: Computed tomography simulation is a clinically accurate substitute for conventional simulation when used with an appropriate patient marking system and digitally reconstructured radiographs. Personnel time spent in CT simulation is equivalent to time in conventional simulation.

In an attempt to improve the probability of complication-free local control, a series of dose finding studies have been conducted at Wayne State University using either conformal neutron or hyperfractionated photon irradiation. In total, 96 patients with locally advanced prostate cancer (Stage T3/T4, N0/N1, M0, and/or Gleason score ≥8) were treated on two prospective dose-finding studies. Forty-seven patients received conformal neutron/photon irradiation (15NeutronGray + 18Gy). Forty-nine patients were treated on a dose escalation study using hyperfractionated conformal photon irradiation. Twenty-five patients received 78Gy and 24 patients received 83Gy. The median follow-up for both studies was 27 months (range 14–46). There was no significant difference in the rate of chronic gastrointestinal or genitourinary morbidity between the two groups. However, the neutron treated patients had a significantly higher rate of moderate (30%) and severe (12%) pelvic muscle fibrosis. The biochemical complete response rate and 12 month negative biopsy were comparable between the two groups. An estimated RBE for rectal and bladder injury of 3.3 was calculated. The RBE for tumor control was 3.9. Therefore, the therapeutic gain of neutron irradiation was estimated to be 1.2. In conclusion, a 2GY/fraction equivalent dose of 78Gy in conjunction with neoadjuvant hormones appears comparable to the mixed neutron-photon dose of 15NGy + 18Gy. Further efforts at comparing these regimens and assessing the potential benefits of neoadjuvant hormonal therapy should be undertaken. Radiat Oncol Invest 1996;4:129–134. © 1996 Wiley-Liss, Inc.

Purpose : To document the size and location of the prostate, seminal vesicles, bladder, and rectum throughout the course of external beam radiotherapy. The frequency and range of motion of these organs are quantified. Methods and Materials : Ten patients with localized carcinoma of the prostate had conventional simulation followed immediately by a treatment planning computed tomography scan (TPCT 0 ). Once treatment was initiated, each patient had a weekly CT (TPCT 1-N ) before or after his daily treatment. Anatomical structures from CT were delineated on a computer workstation for analysis. The serial CT sets were spatially registered to the initial scan using image correlation software that brings into congruence the bony pelvis of the different scans. The location of the prostate, seminal vesicles, bladder, and rectum on subsequent scans were compared to TPCT 0 , as well as to each other. Results : Prostate volumes were observed to vary by an average of ±10% during the course of radiation therapy, while the seminal vesicle volumes varied by as much as 100%. Bladder and rectal volumes varied by ±30%. Compared to TPCT 0 , movement of the prostate was demonstrated in all patients. Quantitation of the center-of-mass (CM) showed motion of less than 1 mm in the left-right direction, while motion ranging from 0 to ± 1 cm was observed in the anterior-posterior and superior-inferior directions. The individual standard deviations of these motions varied from approximately 1-5 mm. These variations were correlated to changes in the dimensions of the bladder and rectum. Conclusions : Changes in the location of the prostate, seminal vesicles, and normal tissue volumes during the course of radiation therapy occur and have dosimetric consequences that may impact tumor control and normal tissue complication probabilities. Conformal therapy for prostate cancer will require the incorporation of knowledge of the anatomic relationships of these structures as a function of time. Therefore, these uncertainties must be taken into account when designing treatment plans and in considering dose escalation trials.

29 Background: Recent publications questioned the survival impact of adjuvant radiotherapy (A-RT) in the treatment of DCIS. These reports had in common a short follow up. We wanted to know, in a disease where long term follow up is required, the magnitude of improvement in survival and assess any correlation with race and income. Methods: Search in the Surveillance, Epidemiology and End Results database, of patients diagnosed with DCIS between 1988 and 2012, younger than 70 years old. Analyses of age, race, hormonal receptors (HR), tumor size, surgery, ART and household income. Survival analyses with Kaplan-Meier and multifactorial with Cox proportional-hazard regression. Results: 125,805 patients. Mean follow-up 7.9 years. Patients treated with A-RT resulted in a mortality by breast cancer (DBC) significantly lower (-1.10%; HR: 0.54 [IC95%:0.48-0.59]; p < 0.0001). Based on the type of surgery, mastectomy resulted on a DBC significantly higher than those treated with tumorectomy and A-RT (+1.15%; HR: 2.08 [IC95%:1.84-2.36]; p < 0.0001). Patients with HR+ presented a significantly lower DBC. Black race was the one with the lowest household income (43% < 53900$) opposite to the Asian which was the one with the highest (47% > 71520$). Black race, also presented a DBC significantly higher than the other ones. In the multifactorial analyses (see table), the only variables which presented a significantly influence in DBC were -ART (it decreases DBC) and race (black race increases DBC). Conclusions: These results show blacks, which are the ones with lowest household income, have a significantly increase in cancer mortality than the other races, and that A-RT cuts mortality rates quite drastically in women with DCIS. [Table: see text]

111 Background: Randomized prospective clinical trials have demonstrated the benefit of adding postoperative radiotherapy (P-RT) for patients with prostate cancer with adverse pathological factors who underwent radical prostatectomy. Based on scientific evidence, the American Urological Association and American Society of Therapeutic Radiologists and Oncology, recommend offering P-RT to this type of patients. Methods: Retrospective analysis of 156,795 patients with prostate cancer diagnosed between 2004 and 2012, who underwent radical prostatectomy. The clinic-pathological information has been extracted from the database "Surveillance Epidemiology and End Results Program". Stage IV patients, and those with "Unknown" information on the type of surgery, radiotherapy, stage or grade, were excluded. Results: Stage II was the most common (81.9%), followed by stage III (18% of the patients). A 60% of the patients had Gleason > / = 8. Only 11.7% of the patients were > / = 70 years old. Treatment with P-RT decreased significantly between 2004 and 2012 (-0.44%; p = 0.0003). Analyzed by subgroups, P-RT decreased significantly in stage II (-0.72%; p < 0.0001) and III (-2.69%; p = 0.005), in patients with Gleason 6-7 (-1.05%; p = 0.0002) and > / = 8 (-1.79%; p = 0.0001) and < 70 years (-0.37%; p = 0.0001), whereas in > / = 70 years decreased but not significantly (-0.53%; p = 0.13). Conclusions: The use of P-RT in patients with prostate cancer who underwent radical prostatectomy is declining. What is most striking, is that the magnitude of this decline, is greatest in patients with higher risk factors, as the percentage of patients with Gleason score > / = 8 and/or Stage III (extracapsular invasion and/or involvement of seminal vesicles) receiving P-RT, declined more than the decline in the percentage of patients with Gleason 6-7 and/or stage II receiving P-RT, which clearly departs from the recommendations contained in the main treatment guidelines.

Objective The article explores the contemporary use of radiation therapy in the management of locally advanced prostate cancer. Methods The three main radiotherapeutic strategies that have been utilized in current clinical trials to optimize radiotherapy in the management of locally advanced prostate cancers are reviewed. These are to (1) increase the relative integral dose; (2) decrease the volume of tumor present; (3) optimize the biology. Results Results from the brachytherapy literature demonstrate that high doses may sterilize tumors more effectively. This concept has been taken into trials using conformal external beam radiation therapy. The Phase III trials conducted through the RTOG and in Canada are reviewed. These trials have demonstrated disease-free survival advantages of cytoreduction over conventional therapy alone. Neutron radiation therapy has also been evaluated in multicenter randomized studies, and the results there have demonstrated a superiority for neutron therapy over conventional photon therapy alone. Conclusion Although conventional photon radiation therapy may not be optimal inbulky prostate cancer, new techniques of optimizing radiation therapy by reducing the volume of tumor present or using techniques that give a biologically optimized dose or a physically increased dose may be of advantage in the future.

Background. Prostate brachytherapy represents one of the oldest techniques of using radiation therapy to treat prostate cancer. Over the past 10 years, there have been major changes in the types of prostate brachytherapy that can be performed with the introduction of new radioactive isotopes, new afterloading techniques, and an improved understanding of the radiobiology associated with differing dose rates. Methods. Prostate brachytherapy can be divided into temporary implantation using high activity sources such as iridium-192, or permanent brachytherapy using the interstitial implantation of iodine-125 or palladium-103 sources

The incidence of residual neoplastic cells on prostatic biopsy following conventional external beam radiotherapy is reported to range from 40–90%. As a result, it has been stated that current modalities of radiotherapy may carry an unacceptable local failure rate even in patients irradiated for low stage disease. In order to assess the potential benefits of threedimensional (3-D) treatment planning, an unselected, consecutive group of patients with localized adenocarcinoma of the prostate was evaluated. This study was designed to determine the frequency of residual cancer in the prostate two years following definitive external beam radiotherapy designed, using a 3-D planning system. Between February 1988 and February 1989, 30 consecutive patients with localized (Stage T1 -T3NxM0) adenocarcinoma of the prostate received definitive external beam radiotherapy. All treatment fields were designed with a computed tomography (CT)-based 3-D treatment planning system, resulting in a static conformal radiotherapy plan. The minimum dose delivered to the target volume, which included the prostate, periprostatic tissues, and a 1 cm margin, was between 65 and 69 cGy. Twenty-six patients had Stage T1, T2NxM0 primary tumors and four were T3NxM0. Two years following the completion of treatment, all patients underwent digital rectal examination, transrectal ultrasound examination of the prostate with multiple biopsies, bone scan, and serum prostate specific antigen (PSA) determinations. Residual prostate cancer was proven by biopsy in six of 30 patients (20%). Four of 26 (15%) with Stage T1 and T2 tumors had a positive biopsy. However, two of the four Stage T3 tumors had postradiation biopsies positive for cancer (50%). Only one patient with a positive biopsy had an abnormal rectal examination. Five of the eight patients with elevated serum PSA levels after two years had residual neoplasia identified on biopsy. One of six patients with an abnormal postradiation ultrasound had residual tumor. Only one of the 22 patients (5%) with a normal serum PSA at two years had a positive postradiation biopsy. In patients with localized prostate cancer, the use of 3-D static conformal radiotherapyfollowed by multiple ultrasound guided biopsies confirmed the efficacy of external beam radiotherapy in low stage disease. We believe that the low incidence of positive biopsies in this study resulted from the benefits of 3-D treatment planning as well as the fact that all patients were evaluated, whereas past studies have been in selected patient groups when suspicion of residual disease existed prior to biopsy. However, the 50% posttreatment positive biopsy rate in Stage T3 and T4 tumors underscores the unsatisfactory local control even with 3-D conformal radiotherapy. More aggressive treatment (e.g., neoadjuvant hormones, interstitial boost, hyperthermia, or dose escalation) may improve local control in these patients. It appears that routine postradiation biopsies may not be necessary in patients with normal serum PSA levels at two years following treatment. © 1993 Wiley-Liss, Inc.

PubMedID: 20924975 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. Copyright © 2010, Taylor & Francis Group, LLC.

SUMMARY Carcinoma of the urethra (male and female) is an unusual disease with insufficient clinical experience to be dogmatic about therapeutic recommendations. The onset is usually insidious, with a long interval from the first symptoms to diagnosis, yet lack of local and regional control remains the principal obstacle to cure. Treatment choices and results depend to a great degree on the exent, location, and stage of the lesion. Our conclusion is that good surgery and carefully planned irradiation are equally effective in the management of these tumors.

Purpose The possibility that prostate cancers have a low α/β ratio led to a schedule including a hypofractionated boost. The purpose of this study was to analyze the outcomes of this regimen. Patients and Methods Between 2002 and 2007, 125 patients with localized prostate cancer were treated. Median follow-up was 33 months. Radiation therapy was delivered to a planning target volume including the prostate and seminal vesicles with a 1-1.5 cm margin to block edge using a 6-field technique to 45 Gy in 25 fractions. This was followed by a 2.5-Gy/fraction intensity-modulated radiation therapy boost to the prostate alone to a total dose of 75 Gy in 61 low-risk patients and 77.5 Gy to the prostate and seminal vesicles in 64 high- and intermediate-risk patients. Results There have been 2 (1.6%) biochemical failures, 1 death from prostate cancer, and 1 death in a patient with no evidence of disease. Rates of acute genitourinary and gastrointestinal toxicity (grade 1 and 2) for the whole group were 31.2% and 16%, respectively. Rates of chronic genitourinary and gastrointestinal toxicity (grade 1 and 2) for the whole group were 30.4% and 27.2%, respectively. There were 2 patients (1.6%) with grade 3 gastrointestinal toxicity at 12 and 18 months' follow-up. They had radiation proctitis requiring laser cauterization. Conclusion The preliminary results of this novel schedule were excellent. Given that the α/β ratio is still in question, this technique addresses concerns regarding low and high ratios. This technique is a suitable alternative method of dose escalation in the treatment of localized prostate cancer.

Conventional simulation for patients with localized prostatic carcinoma often includes opacification of the dose limiting adjacent normal tissues. However, CT-based treatment planning is performed with the bladder and the rectum naturally filled or emptied. These latter conditions more closely approximate those in place at treatment. Comparison of these CT-based treatment plans to simulator films taken with the rectum and bladder opacified yielded indirect evidence of movement of the prostate gland by 0.5 cm or more in 31 of 50 consecutive patients. The range of motion was 0 to 2 cm with an average of 0.5 cm (1.0 cm in the 31 patients). Six additional patients (five with local recurrence following I-125 seed implantation) were analyzed separately using CT scans. Registered CT images (3 mm slices) taken with the rectum and bladder full and/or empty provided direct evidence of prostate movement in 3 of the 6 patients. The dosimetric consequences of this movement are demonstrated using 3-dimensional dose distributions.

Objectives It is unclear whether postoperative salvage radiation therapy (SRT) and early adjuvant radiotherapy (ART) after radical prostatectomy lead to equivalent long-term tumor control. We studied a group of patients undergoing ART by comparing them with a matched control group undergoing SRT after biochemical failure. Methods Using a multi-institutional database of 2299 patients, 449 patients with pT3-4N0 disease were eligible for inclusion, including 211 patients receiving ART and 238 patients receiving SRT. Patients were matched in a 1:1 ratio according to preoperative prostate-specific antigen Gleason score, seminal vesicle invasion, surgical margin status, and follow-up from date of surgery. Results A total of 192 patients were matched (96:96). The median follow-up was 94 months from surgery and 73 months from RT completion. There was a significant reduction in biochemical failure with ART compared with SRT. The 5-year freedom from biochemical failure (FFBF) from surgery was 75% after ART, compared with 66% for SRT (hazard ratio [HR] = 1.6, P = .049). The 5-year FFBF from the end of RT was 73% after ART, compared with 50% after SRT (HR = 2.3, log rank [LR] P = .0007). From the end of RT, SRT and Gleason score ≥8 were independent predictors of diminished FFBF. From the date of surgery, Gleason score ≥8 was a significant predictor of FFBF. Conclusions Early ART for pT3-4N0 prostate cancer significantly reduces the risk of long-term biochemical progression after radical prostatectomy compared with SRT. Gleason score ≥8 was the only factor on multivariate analysis associated with metastasic progression.

Radiation necrosis of the brain is a well documented adverse effect of radiation therapy. The authors report an unusual case of relapsing multifocal radiation necrosis following whole brain radiation therapy (WBRT) for brain metastases from a systemic germ cell tumor. Anticoagulation with warfarin may have had therapeutic benefit. The patient is alive without a neurological deficit 10 years after the diagnosis of radiation necrosis.

Few intervention studies have been conducted to help couples manage the effects of prostate cancer and maintain their quality of life. The objective of this study was to determine whether a family-based intervention could improve appraisal variables (appraisal of illness or caregiving, uncertainty, hopelessness), coping resources (coping strategies, self-efficacy, communication), symptom distress, and quality of life in men with prostate cancer and their spouses.For this clinical trial, 263 patient-spouse dyads were stratified by research site, phase of illness, and treatment; then, they were randomized to the control group (standard care) or the experimental group (standard care plus a 5-session family intervention). The intervention targeted couples' communication, hope, coping, uncertainty, and symptom management. The final sample consisted of 235 couples: 123 couples in the control group and 112 couples in the experimental group. Data collection occurred at baseline before randomization and at 4 months, 8 months, and 12 months.At 4-month follow-up, intervention patients reported less uncertainty and better communication with spouses than control patients, but they reported no other effects. Intervention spouses reported higher quality of life, more self-efficacy, better communication, and less negative appraisal of caregiving, uncertainty, hopelessness, and symptom distress at 4 months compared with controls, and some effects were sustained to 8 months and 12 months.Men with prostate cancer and their spouses reported positive outcomes from a family intervention that offered them information and support. Programs of care need to be extended to spouses who likely will experience multiple benefits from intervention.

Dietary intake of lycopene and soy has been associated with a lower risk of prostate cancer. In vitro studies with lycopene and genistein, a soy isoflavone, have shown induction of apoptosis and inhibition of cell growth in androgen-sensitive (LNCaP) and androgen-independent (PC3 and VeCaP) prostate cancer cell lines. In a previous Phase II clinical trial in prostate cancer patients, we observed prostate-specific antigen (PSA) stabilization with soy isoflavone intake. In this Phase II clinical trial, we investigated the efficacy of lycopene alone or in combination with soy isoflavones on serum PSA levels in men with prostate cancer. To be eligible for the study, men with prostate cancer had to have rising serum PSA following local therapy or while on hormone therapy. Study population included 71 eligible patients who had 3 successive rising PSA levels or a minimum PSA of 10 ng/ml at 2 successive evaluations prior to starting therapy. Subjects were randomly assigned to receive a tomato extract capsule containing 15 mg of lycopene alone (n = 38) or together with a capsule containing 40 mg of a soy isoflavone mixture (n = 33) twice daily orally for a maximum of 6 mo. One patient on the lycopene arm did not receive therapy due to his inability to ingest the study pill. There was no decline in serum PSA in either group qualifying for a partial or complete response. However, 35 of 37 (95%) evaluable patients in the lycopene group and 22 of 33 (67%) evaluable patients in the lycopene plus soy isoflavone group achieved stable disease described as stabilization in serum PSA level. The data suggest that lycopene and soy isoflavones have activity in prostate cancer patients with PSA relapse disease and may delay progression of both hormone-refractory and hormone-sensitive prostate cancer. However, there may not be an additive effect between the 2 compounds when taken together. Future studies are warranted to further investigate the efficacy of lycopene and soy isoflavones in prostate cancer as well as the mechanism of potential negative interaction between them.

Purpose Despite the high prevalence of prostate cancer, little information is available on the quality of life of men and their spouses during the phases of illness. This study assessed patients' and spouses' quality of life, appraisal of illness, resources, symptoms, and risk for distress across three phases of prostate cancer: newly diagnosed, biochemical recurrence, and advanced. Patients and Methods The sample consisted of 263 patient/spouse dyads. A stress-appraisal conceptual model guided the selection of variables which were then assessed with established instruments. Study variables were examined for phase effects (differences in dyads across three phases), role effects (patients v spouses), and phase-by-role interactions (differences within dyads across phases) using analysis of variance (ANOVA). Results More phase effects than role effects were found, indicating that the psychosocial experiences of patients and their spouses were similar, but differed from dyads in other phases. Dyads in the advanced phase were at highest risk for distress. These patients had the lowest physical quality of life, and their spouses had the lowest emotional quality of life of all participants. Dyads in the biochemical recurrence and advanced phases had more negative appraisals of illness and caregiving, greater uncertainty, and more hopelessness compared with dyads in the newly diagnosed phase. Spouses, in contrast to patients, had less confidence in their ability to manage the illness and perceived less support across all phases of illness. Conclusion Phase-specific programs of care are needed to assist both men with prostate cancer and their spouses to manage the effects of illness.