Patients\u27 Preferences for Androgen Deprivation Therapy in the Treatment of Intermediate-Risk Prostate Cancer

Background. For men with intermediate-risk prostate cancer (IRPC), adding short-term androgen deprivation therapy (ADT) to external beam radiation therapy (EBRT) has shown efficacy, but men are often reluctant to accept it because of its impact on quality of life. Methods. We conducted time tradeoffs (score of 1 = perfect health and 0 = death) and probability tradeoffs with patients aged 51 to 78 y who had received EBRT for IRPC within the past 2 y. Of 40 patients, 20 had received 6 mo of ADT and 20 had declined. Utility assessments explored 4 ADT-related side effects: hot flashes, fatigue, loss of libido/erectile dysfunction, and weight gain. Results. The most commonly reported “worst” treatment-related complication of ADT was fatigue (50% in both cohorts) followed by reduced libido/erectile dysfunction (40% in both cohorts). The utilities for fatigue were mean = 0.71 and median = 0.92 and for reduced libido/erectile dysfunction were mean = 0.81 and median = 0.92. Utilities did not differ significantly between cohorts. Assuming a 6-mo course of ADT, men reported being willing to trade 3 mo of life expectancy to avoid fatigue due to ADT and 1.8 mo to avoid sexual side effects. Patients in the ADT cohort were willing to accept the side effects of ADT in exchange for a mean 8% absolute increase in survival, whereas patients in the no ADT cohort required a 16% increase (P \u3c 0.001). Conclusions. When considering treatment with ADT, men with IRPC identified fatigue and sexual dysfunction as the most bothersome side effects. Patients who declined ADT expected a larger survival benefit than those who opted for treatment. Both groups expected a survival benefit exceeding that shown by recent trials, suggesting some men may be selecting treatments inconsistent with their preferences. Highlights This study demonstrates that prostate cancer patients receiving radiation therapy are reluctant to receive androgen deprivation therapy (ADT) most commonly due to anticipated fatigue and loss of libido/erectile dysfunction. Men who had received ADT reported they would require an average 8% absolute increase in survival to tolerate its side effects, whereas those who declined ADT would require an average 16% increase. Required thresholds are well above the estimated absolute survival benefit for ADT demonstrated in recent clinical trials, suggesting an unmet need for improved patient education regarding the risks and benefits of ADT

Effect of anatomic motion on proton therapy dose distributions in prostate cancer treatment

Purpose: To determine the dosimetric impact of interfraction anatomic movements in prostate cancer patients receiving proton therapy. Methods and Materials: For each of the 10 patients studied, 8 computed tomography (CT) scans were selected from sets of daily setup CT images that were acquired from a cohort of prostate cancer patients. The images were acquired in the treatment room using the CT-on-rails system. First, standard proton therapy and intensity-modulated radiation therapy (IMRT) plans were designed for each patient using standard modality-specific methods. The images, the proton plan, and the IMRT plan were then aligned to the eight CT images based on skin marks. The doses were recalculated on these eight CT images using beam from the standard plans. Second, the plans were redesigned and evaluated assuming a smaller clinical target volume to planning target volume margin (3 mm). The images and the corresponding plans were then realigned based on the center of volume of the prostate. Dose distributions were evaluated using isodose displays, dose-volume histograms, and target coverage. Results: For the skin-marker alignment method, 4 of the 10 IMRT plans were deficient, whereas 3 of 10 proton plans were compromised. For the alignment method based on the center of volume of the prostate, only the proton plan for 1 patient was deficient, whereas 3 of the 10 IMRT plans were suboptimal. Conclusion: A comparison of passively scattered proton therapy and highly conformal IMRT plans for prostate cancer revealed that the dosimetric impact of interfractional anatomic motions was similar for both modalities. © 2007 Elsevier Inc. All rights reserved

Is a 3-mm intrafractional margin sufficient for daily image-guided intensity-modulated radiation therapy of prostate cancer?

PURPOSE: To determine whether a 3-mm isotropic target margin adequately covers the prostate and seminal vesicles (SVs) during administration of an intensity-modulated radiation therapy (IMRT) treatment fraction, assuming that daily image-guided setup is performed just before each fraction. MATERIALS AND METHODS: In-room computed tomographic (CT) scans were acquired immediately before and after a daily treatment fraction in 46 patients with prostate cancer. An eight-field IMRT plan was designed using the pre-fraction CT with a 3-mm margin and subsequently recalculated on the post-fraction CT. For convenience of comparison, dose plans were scaled to full course of treatment (75.6 Gy). Dose coverage was assessed on the post-treatment CT image set. RESULTS: During one treatment fraction (21.4+/-5.5 min), there were reductions in the volumes of the prostate and SVs receiving the prescribed dose (median reduction 0.1% and 1.0%, respectively, p\u3c0.001) and in the minimum dose to 0.1 cm(3) of their volumes (median reduction 0.5 and 1.5 Gy, p\u3c0.001). Of the 46 patients, three patients\u27 prostates and eight patients\u27 SVs did not maintain dose coverage above 70 Gy. Rectal filling correlated with decreased percentage-volume of SV receiving 75.6, 70, and 60 Gy (p\u3c0.02). CONCLUSIONS: The 3-mm intrafractional margin was adequate for prostate dose coverage. However, a significant subset of patients lost SV dose coverage. The rectal volume change significantly affected SV dose coverage. For advanced-stage prostate cancers, we recommend to use larger margins or improve organ immobilization (such as with a rectal balloon) to ensure SV coverage

A Phase 3 Trial of 2 Years of Androgen Suppression and Radiation Therapy With or Without Adjuvant Chemotherapy for High-Risk Prostate Cancer: Final Results of Radiation Therapy Oncology Group Phase 3 Randomized Trial NRG Oncology RTOG 9902.

PURPOSE: Long-term (LT) androgen suppression (AS) with radiation therapy (RT) is a standard treatment of high-risk, localized prostate cancer (PCa). Radiation Therapy Oncology Group 9902 was a randomized trial testing the hypothesis that adjuvant combination chemotherapy (CT) with paclitaxel, estramustine, and oral etoposide plus LT AS plus RT would improve overall survival (OS). METHODS AND MATERIALS: Patients with high-risk PCa (prostate-specific antigen 20-100 ng/mL and Gleason score [GS] ≥ 7 or clinical stage ≥ T2 and GS ≥ 8) were randomized to RT and AS (AS + RT) alone or with adjuvant CT (AS + RT + CT). CT was given as four 21-day cycles, delivered beginning 28 days after 70.2 Gy of RT. AS was given as luteinizing hormone-releasing hormone for 24 months, beginning 2 months before RT plus an oral antiandrogen for 4 months before and during RT. The study was designed based on a 6% improvement in OS from 79% to 85% at 5 years, with 90% power and a 2-sided alpha of 0.05. RESULTS: A total of 397 patients (380 eligible) were randomized. The patients had high-risk PCa, 68% with GS 8 to 10 and 34% T3 to T4 tumors, and median prostate-specific antigen of 22.6 ng/mL. The median follow-up period was 9.2 years. The trial closed early because of excess thromboembolic toxicity in the CT arm. The 10-year results for all randomized patients revealed no significant difference between the AS + RT and AS + RT + CT arms in OS (65% vs 63%; P=.81), biochemical failure (58% vs 54%; P=.82), local progression (11% vs 7%; P=.09), distant metastases (16% vs 14%; P=.42), or disease-free survival (22% vs 26%; P=.61). CONCLUSIONS: NRG Oncology RTOG 9902 showed no significant differences in OS, biochemical failure, local progression, distant metastases, or disease-free survival with the addition of adjuvant CT to LT AS + RT. The trial results provide valuable data regarding the natural history of high-risk PCa treated with LT AS + RT and have implications for the feasibility of clinical trial accrual and tolerability using CT for PCa

Girls and Boys Born before 28 Weeks Gestation: Risks of Cognitive, Behavioral, and Neurologic Outcomes at Age 10 Years

To compare the prevalence of cognitive, neurological, and behavioral outcomes at 10 years of age in 428 girls and 446 boys who were born extremely preterm (EP)

Extremely low gestational age and very low birthweight for gestational age are risk factors for autism spectrum disorder in a large cohort study of 10-year-old children born at 23-27 weeks’ gestation

No prospective cohort study of high-risk children has used rigorous exposure assessment and optimal diagnostic procedures to examine the perinatal antecedents of autism spectrum disorder (ASD), separately among those with and without cognitive impairment

Elevated protein concentrations in newborn blood and the risks of autism spectrum disorder, and of social impairment, at age 10 years among infants born before the 28th week of gestation

Among the 1 of 10 children who are born preterm annually in the United States, 6% are born before the third trimester. Among children who survive birth before the 28th week of gestation, the risks of autism spectrum disorder (ASD) and non-autistic social impairment are severalfold higher than in the general population. We examined the relationship between top quartile inflammation-related protein concentrations among children born extremely preterm and ASD or, separately, a high score on the Social Responsiveness Scale (SRS total score ≥65) among those who did not meet ASD criteria, using information only from the subset of children whose DAS-II verbal or non-verbal IQ was ≥70, who were assessed for ASD, and who had proteins measured in blood collected on ≥2 days (N = 763). ASD (N = 36) assessed at age 10 years is associated with recurrent top quartile concentrations of inflammation-related proteins during the first post-natal month (e.g., SAA odds ratio (OR); 95% confidence interval (CI): 2.5; 1.2–5.3) and IL-6 (OR; 95% CI: 2.6; 1.03–6.4)). Top quartile concentrations of neurotrophic proteins appear to moderate the increased risk of ASD associated with repeated top quartile concentrations of inflammation-related proteins. High (top quartile) concentrations of SAA are associated with elevated risk of ASD (2.8; 1.2–6.7) when Ang-1 concentrations are below the top quartile, but not when Ang-1 concentrations are high (1.3; 0.3–5.8). Similarly, high concentrations of TNF-α are associated with heightened risk of SRS-defined social impairment (N = 130) (2.0; 1.1–3.8) when ANG-1 concentrations are not high, but not when ANG-1 concentrations are elevated (0.5; 0.1–4.2)

Impact of androgen deprivation therapy on survival in men treated with radiation for prostate cancer

A number of retrospective and randomized trials have studied the effect of external-beam radiation therapy (EBRT) plus androgen deprivation therapy (ADT) on locally advanced/high-risk prostate cancer. Of 6 published randomized trials that have compared EBRT plus ADT with EBRT alone, 2 have shown a highly significant overall survival benefit for EBRT plus ADT, and 2 have demonstrated an advantage for the combination in patient subsets based on Gleason score. The results from the positive trials of EBRT plus ADT versus EBRT alone, as well as a recent report of a comparison of short-term (6 months) ADT plus EBRT versus long-term (>6 months) ADT plus EBRT, suggest that short-term ADT plus EBRT preferentially lengthens the survival of patients with Gleason score 2 to 6 disease, whereas for Gleason score 8 to 10 disease, prolongation of survival requires long-term ADT plus EBRT. These data are far from clear-cut because there are factors that confound interpretation of the subgroup analyses. Retrospective data on patients with positive lymph node status support the assertion that EBRT plus ADT prolongs survival to a greater degree than either treatment given individually. The weight of the available investigations on the survival effect of EBRT plus ADT supports its use on a routine basis for patients with high-risk prostate cancer. The results with long-term ADT are much more convincing than short-term ADT, and, as a consequence, 2 to 3 years are recommended

Prostate biopsy status and PSA nadir level as early surrogates for treatment failure: analysis of a prostate cancer randomized radiation dose escalation trial

Purpose : A positive biopsy after external beam radiotherapy in patients free of any evidence of treatment failure is not synonymous with eventual recurrence. Although biopsy positivity is a predictor of outcome, the utility of biopsy status as a surrogate end point, the effect of radiation dose on biopsy status, and the interrelationships of these associations to prostate-specific antigen (PSA) nadir level are not well-defined. These issues were investigated in a cohort of men with Stage T1-T3 prostate cancer who were randomized to receive between 70 Gy and 78 Gy and were prospectively biopsied at about 2 years after the completion of radiotherapy (RT). Methods and Materials : Of the 301 assessable patients in the trial, 168 underwent planned sextant or greater prostate post-RT biopsies in the absence of biochemical or clinical failure; this group constituted the study cohort. Of the 168 patients, 87 were in the 70-Gy arm and 81 in the 78-Gy arm. Biopsies were classified into four groups: negative (no tumor), atypical/suspicious cells (not diagnostic of carcinoma), carcinoma with treatment effect (CaTxEffect), and carcinoma without treatment effect (CaNoTxEffect). Any diagnosis of carcinoma in the specimen was classified as biopsy positive. Freedom from failure (FFF) included biochemical failure and/or clinical failure. Kaplan-Meier curves were calculated from the completion of RT. For those alive in the study cohort, the median follow-up was 65 months. Results : The rate of biopsy without tumor was 42%; with atypical cells, it was 28%, with CaTxEffect 21%, and with CaNoTxEffect 9%. The overall biopsy positivity rate (CaTxEffect + CaNoTxEffect) was 30%; 28% in the 70-Gy group and 32% in the 78-Gy group ( p = 0.52). The distribution of PSA nadir levels was 73% ≤0.5, 20% >0.5–1.0, 5% >1.0–2.0, and 1% >2.0 ng/mL. Significantly more patients randomized to 78 Gy had a PSA nadir of ≤0.5 ng/mL (80% vs. 67%; p = 0.02). No relationship was found between PSA nadir level and prostate biopsy status. The 5-year FFF rate for those classified as biopsy negative was 84% and for those biopsy positive was 60% ( p = 0.0002). Radiation dose did not significantly alter FFF rates by prostate biopsy status. Nadir PSA level correlated with FFF, although this was dependent on the inclusion of the 2 patients with a PSA nadir >2.0 ng/mL. Conclusion : For patients free of treatment failure at the time of prostate biopsy 2 years after RT, the prognosis of no tumor cells was the same as that of atypical/suspicious cells and CaTxEffect was the same as CaNoTxEffect. The biopsy positivity rate was not altered by dose, suggesting that most of the outcome differences between the 70-Gy and 78-Gy groups were due to events occurring before prostate biopsy at 2 years and/or were not entirely dependent on biopsy status. Biopsy status is a strong prognostic factor, but, as an early end point, it may be misleading. PSA nadir appears to have little clinical value in patients treated to doses of ≥70 Gy who are failure free 2 years after RT