Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial.

BACKGROUND: Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. METHODS: RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. FINDINGS: Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60-69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0-10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612-0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6-75·7) in the short-course ADT group and 78·1% (74·2-81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. INTERPRETATION: Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. FUNDING: Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society.

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial.

BACKGROUND: Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. METHODS: RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. FINDINGS: Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61-69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1-10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688-1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4-82·5) in the no ADT group and 80·4% (76·6-83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. INTERPRETATION: Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population. FUNDING: Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society.

A review of stereotactic ablative radiotherapy for nonmetastatic renal cell carcinoma.

Renal cell carcinoma (RCC) is an uncommon malignancy whose incidence has been increasing over the past few decades, posing treatment challenges for elderly or infirm patients who are not surgical candidates. Stereotactic ablative radiotherapy (SABR) has emerged as a promising non-invasive treatment modality for RCC. The high dose-per-fraction used in SABR overcomes some of the mechanisms of radioresistance that has hindered the effective treatment of RCC with conventional radiotherapy. For primary RCC, local control rates for SABR exceed 90%, with typically minimal grade 3 or higher toxicities, offering a viable alternative for inoperable patients and those not eligible for or unable to tolerate radiofrequency or cryotherapy ablation. SABR can also be used in patients with a solitary kidney as a strategy for renal preservation to avoid need for dialysis. Given its excellent local control rates, low toxicity and preservation of renal function, SABR offers an attractive alternative to more invasive modalities for treatment of localized RCC.

Understanding Oral PrEP Interest, Uptake, Persistence, and Experience of Use Among Heterosexual Men in Johannesburg, South Africa: An Exploratory Pilot Study.

South Africa's PrEP programming has primarily focused on men who have sex with men and other key populations through dedicated clinical and outreach services. However, data shows that the pool of men vulnerable to contracting HIV extends beyond this group, including men who have sex only with women and who do not identify as gay. The aim of this pilot study was to assess acceptability of PrEP among this subset of men who are at risk of HIV acquisition in South Africa and to describe the demographic and behavioral characteristics of male PrEP users as well as their experience of PrEP use. We employed a mixed-methods study design consisting of in-depth interviews and quantitative analysis of routine clinic data collected between September 2021 and February 2022 from 10 private health facilities. Men who enrolled in the study and initiated PrEP had low consistent condom use and nearly three quarters reported more than one sexual partner in the past three months. Despite minimal follow-up support, PrEP persistence was relatively high and similar to other populations. 57% of men returned for their 1-month visit, 40% returned for their 4-month visit, and 16% returned for their 7-month visit. The greatest barriers to ongoing use were the need to take a daily pill and low perceived HIV risk. To improve uptake and continuation, programs should increase awareness of PrEP, leverage trusted sources to build credibility, make access more convenient, and accommodate flexible use through event-driven PrEP.

RESUMEN: La programación de la PrEP en Sudáfrica se ha centrado principalmente en los hombres que tienen sexo con hombres a través de servicios clínicos y de servicio de alcance comunitario específicos. Sin embargo, los datos muestran que el grupo de hombres vulnerables a contraer el VIH se extiende más allá de este grupo, e incluye a hombres que sólo tienen relaciones sexuales con mujeres y que no se identifican como homosexuales. El objetivo de este estudio piloto fue evaluar la aceptabilidad de la PrEP en este subgrupo de hombres en riesgo de contraer el VIH en Sudáfrica y describir las características demográficas y de comportamiento de los usuarios masculinos de la PrEP, así como su experiencia con el uso de la PrEP. Se empleó un diseño de estudio de métodos mixtos que consistió en entrevistas a profundidad y análisis cuantitativos de datos clínicos rutinarios recolectados entre septiembre de 2021 y febrero de 2022, en 10 centros sanitarios privados. Los hombres que se inscribieron en el estudio e iniciaron la PrEP tenían un bajo uso consistente de condón y casi tres cuartas partes declararon haber tenido más de una pareja sexual en los últimos tres meses. A pesar de tener un apoyo de seguimiento mínimo, la continuidad de la PrEP fue relativamente alta y similar a la de otras poblaciones. El 57% de los hombres volvieron a su visita de 1 mes, el 40% volvieron a su visita de 4 meses y el 16% volvieron a su visita de 7 meses. Las mayores barreras para el uso continuo fueron la necesidad de tomar una pastilla diaria y la baja percepción del riesgo de VIH. Para mejorar la aceptación y la continuidad, los programas deben aumentar la conciencia sobre la PrEP, aprovechar las fuentes de confianza para aumentar la credibilidad, hacer que el acceso sea más cómodo y permitir un uso flexible mediante la PrEP a demanda.

Dosimetric impact of rotational errors in trigeminal neuralgia radiosurgery using CyberKnife.

PURPOSE: Trigeminal neuralgia (TN) can be treated on the CyberKnife system using two different treatment delivery paths: the general-purpose full path corrects small rotations, while the dedicated trigeminal path improves dose fall-off but does not allow rotational corrections. The study evaluates the impact of uncorrected rotations on brainstem dose and the length of CN5 (denoted as Leff) covered by the prescription dose. METHODS AND MATERIALS: A proposed model estimates the delivered dose considering translational and rotational delivery errors for TN treatments on the CyberKnife system. The model is validated using radiochromic film measurements with and without rotational setup error for both paths. Leff and the brainstem dose is retrospectively assessed for 24 cases planned using the trigeminal path. For 15 cases, plans generated using both paths are compared for the target coverage and toxicity to the brainstem. RESULTS: In experimental validations, measured and estimated doses agree at 1%/1 mm level. For 24 cases, the treated Leff is 5.3 ± 1.7 mm, reduced from 5.9 ± 1.8 mm in the planned dose. Constraints for the brainstem are met in 23 cases for the treated dose but require frequent treatment interruption to maintain rotational corrections <0.5° using the trigeminal path. The treated length of CN5, and plan quality metrics are similar for the two paths, favoring the full path where rotations are corrected. CONCLUSIONS: We validated an analytical model that can provide patient-specific tolerances on rotations to meet plan objectives. Treatment using the full path can reduce treatment time and allow for rotational corrections.

Implications of metastatic stage at presentation in docetaxel naïve metastatic castrate resistant prostate cancer.

BACKGROUND: We performed a secondary analysis of ACIS study to determine if synchronous versus metachronous metastatic presentation has any association with survival and treatment response to dual androgen receptor axis-targeted therapy (ARAT) in docetaxel naïve metastatic castrate resistant prostate cancer (mCRPC). METHODOLOGY: In this phase III randomized controlled trial, docetaxel naïve mCRPC patients were randomized to either apalutamide or placebo combined with abiraterone and prednisone. Multivariable Cox regression models were applied to determine the adjusted association of M-stage with radiographic progression-free survival (rPFS) and overall survival (OS). To determine the heterogeneity of treatment effect based on metastatic stage (M-stage) at presentation, Cox regression was applied with interaction terms between M-stage and treatment. RESULTS: Among 972 patients, 432 had M0, 334 had M1, while M-stage at presentation was unknown in 206. There was no association of M-stage at presentation with rPFS in patients with prior local therapy (LT) (hazard ratio for M1-stage: 1.22 [95% confidence interval: 0.82-1.82]; unknown: 1.03 [0.77-1.38]) or without prior LT (M1-stage: 0.87 [0.64-1.19]; unknown: 1.15 [0.77-1.72]) with no significant heterogeneity. Similarly, there was no association of M-stage with OS in patients with prior LT (M1-stage: 1.04 [0.81-1.33]; unknown: 0.98 [0.79-1.21]) or without prior LT (M1-stage: 0.95 [0.70-1.29]; unknown: 1.17 [0.80-1.71]) with no significant heterogeneity. Based on M-stage at presentation, we did not find any significant heterogeneity in treatment effect on rPFS (interaction p = 0.13), and OS (interaction p = 0.87). CONCLUSION: M-stage at presentation had no association with survival in chemotherapy-naïve mCRPC. We did not find any statistically significant heterogeneity in efficacy of dual ARAT based on synchronous versus metachronous presentation.

Association of PSA kinetics after testosterone recovery with subsequent recurrence: secondary analysis of a phase III randomized controlled trial.

PURPOSE: After cessation of androgen deprivation therapy (ADT), testosterone gradually recovers to supracastrate levels (> 50 ng/dL). After this, rises in prostate-specific antigen (PSA) are often seen. However, it remains unknown whether early PSA kinetics after testosterone recovery are associated with subsequent biochemical recurrence (BCR). METHODS: We performed a secondary analysis of a phase III randomized controlled trial in which newly diagnosed localized prostate cancer patients were randomly allocated to ADT for 6 months starting 4 months prior to or simultaneously with prostate RT. We calculated the PSA doubling time (PSADT) based on PSA values up to 18 months after supracastrate testosterone recovery. Competing risk regression was used to evaluate the association of PSADT with relative incidence of BCR, considering deaths as competing events. RESULTS: Overall, 313 patients were eligible. Median PSADT was 8 months. Cumulative incidence of BCR at 10 years from supracastrate testosterone recovery was 19% and 11% in patients with PSADT < 8 months and ≥ 8 months (p = 0.03). Compared to patients with PSADT of < 4 months, patients with higher PSADT (sHR for PSADT 4 to < 8 months: 0.36 [95% CI 0.16-0.82]; 8 to < 12 months: 0.26 [0.08-0.91]; ≥ 12 months: 0.20 [0.07-0.56]) had lower risk of relative incidence of BCR. CONCLUSIONS: Early PSA kinetics, within 18 months of recovery of testosterone to a supracastrate level, can predict for subsequent BCR. Taking account of early changes in PSA after testosterone recovery may allow for recognition of potential failures earlier in the disease course and thereby permit superior personalization of treatment.

Impact of sequencing of androgen receptor-signaling inhibition and radiotherapy in prostate cancer: importance of homologous recombination disruption.

PURPOSE: The synergy of combining androgen receptor-signaling inhibition (ARSI) to radiotherapy (RT) in prostate cancer has been largely attributed to non-homologous end joining (NHEJ) inhibition. However, this mechanism is unlikely to explain recently observed trial results that demonstrated the sequencing of ARSI and RT significantly impacts clinical outcomes, with adjuvant ARSI following RT yielding superior outcomes to neoadjuvant/concurrent therapy. We hypothesized this is driven by differential effects on AR-signaling and alternative DNA repair pathway engagement based on ARSI/RT sequencing. METHODS: We explored the effects of ARSI sequencing with RT (neoadjuvant vs concurrent vs adjuvant) in multiple prostate cancer cell lines using androgen-deprived media and validation with the anti-androgen enzalutamide. The effects of ARSI sequencing were measured with clonogenic assays, AR-target gene transcription and translation quantification, cell cycle analysis, DNA damage and repair assays, and xenograft animal validation studies. RESULTS: Adjuvant ARSI after RT was significantly more effective at killing colony forming cells and decreasing the transcription and translation of downstream AR-target genes across all prostate cancer models evaluated. These results were reproduced in xenograft studies. The differential effects of ARSI sequencing were not fully explained by NHEJ inhibition alone, but by the additional disruption of homologous recombination specifically with adjuvant sequencing of ARSI. CONCLUSION: We demonstrate that altered sequencing of ARSI and RT mediates differential anti-AR-signaling and anti-cancer effects, with the greatest benefit from adjuvant ARSI following RT. These results, combined with our prior clinical findings, support the superiority of an adjuvant-based sequencing approach when using ARSI with RT.

The plasma peptides of breast versus ovarian cancer.

BACKGROUND: There is a need to demonstrate a proof of principle that proteomics has the capacity to analyze plasma from breast cancer versus other diseases and controls in a multisite clinical trial design. The peptides or proteins that show a high observation frequency, and/or precursor intensity, specific to breast cancer plasma might be discovered by comparison to other diseases and matched controls. The endogenous tryptic peptides of breast cancer plasma were compared to ovarian cancer, female normal, sepsis, heart attack, Alzheimer's and multiple sclerosis along with the institution-matched normal and control samples collected directly onto ice. METHODS: Endogenous tryptic peptides were extracted from individual breast cancer and control EDTA plasma samples in a step gradient of acetonitrile, and collected over preparative C18 for LC-ESI-MS/MS with a set of LTQ XL linear quadrupole ion traps working together in parallel to randomly and independently sample clinical populations. The MS/MS spectra were fit to fully tryptic peptides or phosphopeptides within proteins using the X!TANDEM algorithm. The protein observation frequency was counted using the SEQUEST algorithm after selecting the single best charge state and peptide sequence for each MS/MS spectra. The observation frequency was subsequently tested by Chi Square analysis. The log10 precursor intensity was compared by ANOVA in the R statistical system. RESULTS: Peptides and/or phosphopeptides of common plasma proteins such as APOE, C4A, C4B, C3, APOA1, APOC2, APOC4, ITIH3 and ITIH4 showed increased observation frequency and/or precursor intensity in breast cancer. Many cellular proteins also showed large changes in frequency by Chi Square (χ2 > 100, p < 0.0001) in the breast cancer samples such as CPEB1, LTBP4, HIF-1A, IGHE, RAB44, NEFM, C19orf82, SLC35B1, 1D12A, C8orf34, HIF1A, OCLN, EYA1, HLA-DRB1, LARS, PTPDC1, WWC1, ZNF562, PTMA, MGAT1, NDUFA1, NOGOC, OR1E1, OR1E2, CFI, HSA12, GCSH, ELTD1, TBX15, NR2C2, FLJ00045, PDLIM1, GALNT9, ASH2L, PPFIBP1, LRRC4B, SLCO3A1, BHMT2, CS, FAM188B2, LGALS7, SAT2, SFRS8, SLC22A12, WNT9B, SLC2A4, ZNF101, WT1, CCDC47, ERLIN1, SPFH1, EID2, THOC1, DDX47, MREG, PTPRE, EMILIN1, DKFZp779G1236 and MAP3K8 among others. The protein gene symbols with large Chi Square values were significantly enriched in proteins that showed a complex set of previously established functional and structural relationships by STRING analysis. An increase in mean precursor intensity of peptides was observed for QSER1 as well as SLC35B1, IQCJ-SCHIP1, MREG, BHMT2, LGALS7, THOC1, ANXA4, DHDDS, SAT2, PTMA and FYCO1 among others. In contrast, the QSER1 peptide QPKVKAEPPPK was apparently specific to ovarian cancer. CONCLUSION: There was striking agreement between the breast cancer plasma peptides and proteins discovered by LC-ESI-MS/MS with previous biomarkers from tumors, cells lines or body fluids by genetic or biochemical methods. The results indicate that variation in plasma peptides from breast cancer versus ovarian cancer may be directly discovered by LC-ESI-MS/MS that will be a powerful tool for clinical research. It may be possible to use a battery of sensitive and robust linear quadrupole ion traps for random and independent sampling of plasma from a multisite clinical trial.

The plasma peptides of ovarian cancer.

BACKGROUND: It may be possible to discover new diagnostic or therapeutic peptides or proteins from blood plasma by using liquid chromatography and tandem mass spectrometry to identify, quantify and compare the peptides cleaved ex vivo from different clinical populations. The endogenous tryptic peptides of ovarian cancer plasma were compared to breast cancer and female cancer normal controls, other diseases with their matched or normal controls, plus ice cold plasma to control for pre-analytical variation. METHODS: The endogenous tryptic peptides or tryptic phospho peptides (i.e. without exogenous digestion) were analyzed from 200 µl of EDTA plasma. The plasma peptides were extracted by a step gradient of organic/water with differential centrifugation, dried, and collected over C18 for analytical HPLC nano electrospray ionization and tandem mass spectrometry (LC-ESI-MS/MS) with a linear quadrupole ion trap. The endogenous peptides of ovarian cancer were compared to multiple disease and normal samples from different institutions alongside ice cold controls. Peptides were randomly and independently sampled by LC-ESI-MS/MS. Precursor ions from peptides > E4 counts were identified by the SEQUEST and X!TANDEM algorithms, filtered in SQL Server, before testing of frequency counts by Chi Square (χ2), for analysis with the STRING algorithm, and comparison of precursor intensity by ANOVA in the R statistical system with the Tukey-Kramer Honestly Significant Difference (HSD) test. RESULTS: Peptides and/or phosphopeptides of common plasma proteins such as HPR, HP, HPX, and SERPINA1 showed increased observation frequency and/or precursor intensity in ovarian cancer. Many cellular proteins showed large changes in frequency by Chi Square (χ2 > 60, p < 0.0001) in the ovarian cancer samples such as ZNF91, ZNF254, F13A1, LOC102723511, ZNF253, QSER1, P4HA1, GPC6, LMNB2, PYGB, NBR1, CCNI2, LOC101930455, TRPM5, IGSF1, ITGB1, CHD6, SIRT1, NEFM, SKOR2, SUPT20HL1, PLCE1, CCDC148, CPSF3, MORN3, NMI, XTP11, LOC101927572, SMC5, SEMA6B, LOXL3, SEZ6L2, and DHCR24. The protein gene symbols with large Chi Square values were significantly enriched in proteins that showed a complex set of previously established functional and structural relationships by STRING analysis. Analysis of the frequently observed proteins by ANOVA confirmed increases in mean precursor intensity in ZFN91, TRPM5, SIRT1, CHD6, RIMS1, LOC101930455 (XP_005275896), CCDC37 and GIMAP4 between ovarian cancer versus normal female and other diseases or controls by the Tukey-Kramer HSD test. CONCLUSION: Here we show that separation of endogenous peptides with a step gradient of organic/water and differential centrifugation followed by random and independent sampling by LC-ESI-MS/MS with analysis of peptide frequency and intensity by SQL Server and R revealed significant difference in the ex vivo cleavage of peptides between ovarian cancer and other clinical treatments. There was striking agreement between the proteins discovered from cancer plasma versus previous biomarkers discovered in tumors by genetic or biochemical methods. The results indicate that variation in plasma proteins from ovarian cancer may be directly discovered by LC-ESI-MS/MS that will be a powerful tool for clinical research.

The plasma peptidome.

BACKGROUND: It may be possible to discover new diagnostic or therapeutic peptides or proteins from blood plasma using LC-ESI-MS/MS to identify, with a linear quadrupole ion trap to identify, quantify and compare the statistical distributions of peptides cleaved ex vivo from plasma samples from different clinical populations. METHODS: A systematic method for the organic fractionation of plasma peptides was applied to identify and quantify the endogenous tryptic peptides from human plasma from multiple institutions by C18 HPLC followed nano electrospray ionization and tandem mass spectrometry (LC-ESI-MS/MS) with a linear quadrupole ion trap. The endogenous tryptic peptides, or tryptic phospho peptides (i.e. without exogenous digestion), were extracted in a mixture of organic solvent and water, dried and collected by preparative C18. The tryptic peptides from 6 institutions with 12 different disease and normal EDTA plasma populations, alongside ice cold controls for pre-analytical variation, were characterized by mass spectrometry. Each patient plasma was precipitated in 90% acetonitrile and the endogenous tryptic peptides extracted by a stepwise gradient of increasing water and then formic acid resulting in 10 sub-fractions. The fractionated peptides were manually collected over preparative C18 and injected for 1508 LC-ESI-MS/MS experiments analyzed in SQL Server R. RESULTS: Peptides that were cleaved in human plasma by a tryptic activity ex vivo provided convenient and sensitive access to most human proteins in plasma that show differences in the frequency or intensity of proteins observed across populations that may have clinical significance. Combination of step wise organic extraction of 200 µL of plasma with nano electrospray resulted in the confident identification and quantification ~ 14,000 gene symbols by X!TANDEM that is the largest number of blood proteins identified to date and shows that you can monitor the ex vivo proteolysis of most human proteins, including interleukins, from blood. A total of 15,968,550 MS/MS spectra ≥ E4 intensity counts were correlated by the SEQUEST and X!TANDEM algorithms to a federated library of 157,478 protein sequences that were filtered for best charge state (2+ or 3+) and peptide sequence in SQL Server resulting in 1,916,672 distinct best-fit peptide correlations for analysis with the R statistical system. SEQUEST identified some 140,054 protein accessions, or some ~ 26,000 gene symbols, proteins or loci, with at least 5 independent correlations. The X!TANDEM algorithm made at least 5 best fit correlations to more than 14,000 protein gene symbols with p-values and FDR corrected q-values of ~ 0.001 or less. Log10 peptide intensity values showed a Gaussian distribution from E8 to E4 arbitrary counts by quantile plot, and significant variation in average precursor intensity across the disease and controls treatments by ANOVA with means compared by the Tukey-Kramer test. STRING analysis of the top 2000 gene symbols showed a tight association of cellular proteins that were apparently present in the plasma as protein complexes with related cellular components, molecular functions and biological processes. CONCLUSIONS: The random and independent sampling of pre-fractionated blood peptides by LC-ESI-MS/MS with SQL Server-R analysis revealed the largest plasma proteome to date and was a practical method to quantify and compare the frequency or log10 intensity of individual proteins cleaved ex vivo across populations of plasma samples from multiple clinical locations to discover treatment-specific variation using classical statistics suitable for clinical science. It was possible to identify and quantify nearly all human proteins from EDTA plasma and compare the results of thousands of LC-ESI-MS/MS experiments from multiple clinical populations using standard database methods in SQL Server and classical statistical strategies in the R data analysis system.

Comparison of four techniques for spine stereotactic body radiotherapy: Dosimetric and efficiency analysis.

PURPOSE: The aim of this study is to compare the dosimetric differences between four techniques for spine stereotactic body radiotherapy (SBRT): CyberKnife (CK), volumetric modulated arc therapy (VMAT), and helical tomotherapy (HT) with dynamic jaws (HT-D) and fixed jaws (HT-F). MATERIALS/METHODS: Data from 10 patients were utilized. All patients were planned for 24 Gy in two fractions, with the primary objectives being: (a) restricting the maximum dose to the cord to ≤ 17 Gy and/or cauda equina to ≤ 20 Gy, and (b) to maximize the clinical target volume (CTV) to receive the prescribed dose. Treatment plans were generated by separate dosimetrists and then compared using velocity AI. Parameters of comparison include target volume coverage, conformity index (CI), gradient index (GI), homogeneity index (HI), treatment time (TT) per fraction, and monitor units (MU) per fraction. RESULTS: PTV D2 and D5 were significantly higher for CK compared to VMAT, HT-F, and HT-D (P < 0.001). The average volume of CTV receiving the prescription dose (CTV D95) was significantly less for VMAT compared to CK, HT-F and HT-D (P = 0.036). CI improved for CK (0.69), HT-F (0.66), and HT-D (0.67) compared to VMAT (0.52) (P = 0.013). CK (41.86) had the largest HI compared to VMAT (26.99), HT-F (20.69), and HT-D (21.17) (P < 0.001). GI was significantly less for CK (3.96) compared to VMAT (6.76) (P = 0.001). Likewise, CK (62.4 min, 14059 MU) had the longest treatment time and MU per fraction compared to VMAT (8.5 min, 9764 MU), HT-F (13 min, 10822 MU), and HT-D (13.5 min, 11418 MU) (P < 0.001). CONCLUSION: Both CK and HT plans achieved conformal target coverage while respecting cord tolerance. Dose heterogeneity was significantly larger in CK. VMAT required the least treatment time and MU output, but had the least steep GI, CI, and target coverage.

Health-related quality of life for immediate versus delayed androgen-deprivation therapy in patients with asymptomatic, non-curable prostate cancer (TROG 03.06 and VCOG PR 01-03 [TOAD]): a randomised, multicentre, non-blinded, phase 3 trial.

BACKGROUND: Androgen-deprivation therapy in patients with prostate cancer who have relapsed with rising prostate-specific antigen concentration only (PSA-only relapse), or with non-curable but asymptomatic disease at diagnosis, could adversely affect quality of life at a time when the disease itself does not. We aimed to compare the effect of immediate versus delayed androgen-deprivation therapy on health-related quality of life over 5 years in men enrolled in the TOAD (Timing of Androgen Deprivation) trial. METHODS: This randomised, multicentre, open-label, phase 3 trial done in 29 public and private cancer centres across Australia, New Zealand, and Canada compared immediate with delayed androgen-deprivation therapy in men with PSA-only relapse after definitive treatment, or de-novo non-curable disease. Patients were randomly assigned (1:1) with a database-embedded, dynamically balanced algorithm to immediate androgen-deprivation therapy (immediate therapy group) or to delayed androgen-deprivation therapy (delayed therapy group). Any type of androgen-deprivation therapy was permitted, as were intermittent or continuous schedules. The European Organisation for Research and Treatment of Cancer (EORTC) quality-of-life questionnaires QLQ-C30 and PR25 were completed before randomisation, every 6 months for 2 years, and annually for a further 3 years. The primary outcome of the trial, reported previously, was overall survival, with global health-related quality of life at 2 years as a secondary endpoint. Here we report prespecified secondary objectives of the quality-of-life endpoint. Analysis was by intention to treat. Statistical significance was set at p=0·0036. The trial was registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12606000301561, and ClinicalTrials.gov, number NCT00110162. FINDINGS: Between Sept 3, 2004, and July 13, 2012, 293 men were recruited and randomly assigned; 151 to the delayed therapy group and 142 to the immediate therapy group. There was no difference between the two groups in global health-related quality of life over 2 years from randomisation. There were no statistically significant differences in global quality of life, physical functioning, role functioning, or emotional functioning, fatigue, dyspnoea, insomnia, or feeling less masculine over the entire 5 years after randomisation. Sexual activity was lower in the immediate therapy group than in the delayed group at 6 and 12 months (at 6 months mean score 29·20 [95% CI 24·59-33·80] in the delayed group vs 10·40 [6·87-13·93] in the immediate group, difference 18·80 [95% CI 13·00-24·59], p<0·0001; at 12 months 28·63 [24·07-33·18] vs 13·76 [9·94-17·59], 14·86 [8·95-20·78], p<0·0001), with the differences exceeding the clinically significant threshold of 10 points until beyond 2 years. The immediate therapy group also had more hormone-treatment-related symptoms at 6 and 12 months (at 6 months mean score 8·48 [95% CI 6·89-10·07] in the delayed group vs 15·97 [13·92-18·02] in the immediate group, difference -7·49 [-10·06 to -4·93], p<0·0001; at 12 months 9·32 [7·59-11·05] vs 17·07 [14·75-19·39], -7·75 [-10·62 to -4·89], p<0·0001), but with differences below the threshold of clinical significance. For the individual symptoms, hot flushes were clinically significantly higher in the immediate group (adjusted proportion 0·31 for delayed therapy vs 0·55 for immediate therapy, adjusted odds ratio 2·87 [1·96-4·21], p<0·0001) over the 5-year period, as were nipple or breast symptoms (0·06 vs 0·14, 2·64 [1·61-4·34], p=0·00013). INTERPRETATION: Immediate use of androgen-deprivation therapy was associated with early detriments in specific hormone-treatment-related symptoms, but with no other demonstrable effect on overall functioning or health-related quality of life. This evidence can be used to help decision making about treatment initiation for men at this disease stage. FUNDING: Australian National Health and Medical Research Council and Cancer Councils, The Royal Australian and New Zealand College of Radiologists, Mayne Pharma Australia, Tolmar Australia.

Timing of androgen-deprivation therapy in patients with prostate cancer with a rising PSA (TROG 03.06 and VCOG PR 01-03 [TOAD]): a randomised, multicentre, non-blinded, phase 3 trial.

BACKGROUND: Androgen-deprivation therapy is offered to men with prostate cancer who have a rising prostate-specific antigen after curative therapy (PSA relapse) or who are considered not suitable for curative treatment; however, the optimal timing for its introduction is uncertain. We aimed to assess whether immediate androgen-deprivation therapy improves overall survival compared with delayed therapy. METHODS: In this randomised, multicentre, phase 3, non-blinded trial, we recruited men through 29 oncology centres in Australia, New Zealand, and Canada. Men with prostate cancer were eligible if they had a PSA relapse after previous attempted curative therapy (radiotherapy or surgery, with or without postoperative radiotherapy) or if they were not considered suitable for curative treatment (because of age, comorbidity, or locally advanced disease). We used a database-embedded, dynamically balanced, randomisation algorithm, coordinated by the Cancer Council Victoria, to randomly assign participants (1:1) to immediate androgen-deprivation therapy (immediate therapy arm) or to delayed androgen-deprivation therapy (delayed therapy arm) with a recommended interval of at least 2 years unless clinically contraindicated. Randomisation for participants with PSA relapse was stratified by type of previous therapy, relapse-free interval, and PSA doubling time; randomisation for those with non-curative disease was stratified by metastatic status; and randomisation in both groups was stratified by planned treatment schedule (continuous or intermittent) and treatment centre. Clinicians could prescribe any form and schedule of androgen-deprivation therapy and group assignment was not masked. The primary outcome was overall survival in the intention-to-treat population. The trial closed to accrual in 2012 after review by the independent data monitoring committee, but data collection continued for 18 months until Feb 26, 2014. It is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12606000301561) and ClinicalTrials.gov (NCT00110162). FINDINGS: Between Sept 3, 2004, and July 13, 2012, we recruited 293 men (261 with PSA relapse and 32 with non-curable disease). We randomly assigned 142 men to the immediate therapy arm and 151 to the delayed therapy arm. Median follow-up was 5 years (IQR 3·3-6·2) from the date of randomisation. 16 (11%) men died in the immediate therapy arm and 30 (20%) died in the delayed therapy arm. 5-year overall survival was 86·4% (95% CI 78·5-91·5) in the delayed therapy arm versus 91·2% (84·2-95·2) in the immediate therapy arm (log-rank p=0·047). After Cox regression, the unadjusted HR for overall survival for immediate versus delayed arm assignment was 0·55 (95% CI 0·30-1·00; p=0·050). 23 patients had grade 3 treatment-related adverse events. 105 (36%) men had adverse events requiring hospital admission; none of these events were attributable to treatment or differed between treatment-timing groups. The most common serious adverse events were cardiovascular, which occurred in nine (6%) patients in the delayed therapy arm and 13 (9%) in the immediate therapy arm. INTERPRETATION: Immediate receipt of androgen-deprivation therapy significantly improved overall survival compared with delayed intervention in men with PSA-relapsed or non-curable prostate cancer. The results provide benchmark evidence of survival rates and morbidity to discuss with men when considering their treatment options. FUNDING: Australian National Health and Medical Research Council and Cancer Councils, The Royal Australian and New Zealand College of Radiologists, Mayne Pharma Australia.

Intermittent androgen suppression for rising PSA level after radiotherapy.

BACKGROUND: Intermittent androgen deprivation for prostate-specific antigen (PSA) elevation after radiotherapy may improve quality of life and delay hormone resistance. We assessed overall survival with intermittent versus continuous androgen deprivation in a noninferiority randomized trial. METHODS: We enrolled patients with a PSA level greater than 3 ng per milliliter more than 1 year after primary or salvage radiotherapy for localized prostate cancer. Intermittent treatment was provided in 8-month cycles, with nontreatment periods determined according to the PSA level. The primary end point was overall survival. Secondary end points included quality of life, time to castration-resistant disease, and duration of nontreatment intervals. RESULTS: Of 1386 enrolled patients, 690 were randomly assigned to intermittent therapy and 696 to continuous therapy. Median follow-up was 6.9 years. There were no significant between-group differences in adverse events. In the intermittent-therapy group, full testosterone recovery occurred in 35% of patients, and testosterone recovery to the trial-entry threshold occurred in 79%. Intermittent therapy provided potential benefits with respect to physical function, fatigue, urinary problems, hot flashes, libido, and erectile function. There were 268 deaths in the intermittent-therapy group and 256 in the continuous-therapy group. Median overall survival was 8.8 years in the intermittent-therapy group versus 9.1 years in the continuous-therapy group (hazard ratio for death, 1.02; 95% confidence interval, 0.86 to 1.21). The estimated 7-year cumulative rates of disease-related death were 18% and 15% in the two groups, respectively (P=0.24). CONCLUSIONS: Intermittent androgen deprivation was noninferior to continuous therapy with respect to overall survival. Some quality-of-life factors improved with intermittent therapy. (Funded by the Canadian Cancer Society Research Institute and others; ClinicalTrials.gov number, NCT00003653.).

Multi-echo gradient recalled echo imaging of the pelvis for improved depiction of brachytherapy seeds and fiducial markers facilitating radiotherapy planning and treatment of prostatic carcinoma.

PURPOSE: MR localization of implanted devices for radiotherapy (RT) in prostatic carcinoma is critical for treatment planning. This clinical note studies the application of a multi-echo gradient recalled echo (GRE) pulse sequence with sum of squares echo combination (ME GRE) to enhance detection of seeds and fiducials. MATERIALS AND METHODS: Fifteen patients who underwent MRI using fast spin echo (FSE), single-echo and ME GRE over a 9-month period were retrospectively evaluated by two readers who assessed overall image quality, depiction of seeds/fiducials and image sharpness using a 5-point scale (1 = poor, 2 = suboptimal, 3 = adequate, 4 = above average, 5 = excellent). Image scores were compared using the Wilcoxon sign rank test. RESULTS: In all 15 patients, both readers rated the depiction of seeds/fiducials with ME GRE as excellent. In all 15 patients, overall image quality and image sharpness with ME GRE was rated as excellent by reader 1. In 12/15 patients, overall image quality and image sharpness with ME GRE was rated as excellent and in the other patients above average by reader 2. There was a difference in depiction of seeds/fiducials comparing GRE to FSE (P < 0.001) and ME to single echo GRE (P < 0.001). Overall image quality and sharpness was higher with ME compared with single echo GRE (P < 0.001) and similar to FSE (P = 0.26 and P = 0.16). CONCLUSION: Multi-echo GRE provides better detection of implanted seeds and fiducial markers when compared with both FSE and single-echo GRE potentially improving RT treatment planning for prostate carcinoma.

Dynamic CT angiography for cyberknife radiosurgery planning of intracranial arteriovenous malformations: a technical/feasibility report.

BACKGROUND: Successful radiosurgery for arteriovenous malformations (AVMs) requires accurate nidus delineation in the 3D treatment planning system (TPS). The catheter biplane digital subtraction angiogram (DSA) has traditionally been the gold standard for evaluation of the AVM nidus, but its 2D nature limits its value for contouring and it cannot be imported into the Cyberknife TPS. We describe a technique for acquisition and integration of 3D dynamic CT angiograms (dCTA) into the Cyberknife TPS for intracranial AVMs and review the feasibility of using this technique in the first patient cohort. PATIENTS AND METHODS: Dynamic continuous whole brain CT images were acquired in a Toshiba 320 volume CT scanner with data reconstruction every 0.5 sec. This multi-time-point acquisition enabled us to choose the CT data-set with the clearest nidus without significant enhancement of surrounding blood vessels. This was imported to the Cyberknife TPS and co-registered with planning CT and T2 MRI (2D DSA adjacent for reference). The feasibility of using dCTA was evaluated in the first thirteen patients with outcome evaluation from patient records. RESULTS: dCTA data was accurately co-registered in the Cyberknife TPS and appeared to assist in nidus contouring for all patients. Imaging modalities were complementary. 85% of patients had complete (6/13) or continuing partial nidus obliteration (5/13) at 37 months median follow-up. CONCLUSIONS: dCTA is a promising imaging technique that can be successfully imported into the Cyberknife TPS and appears to assist in radiosurgery nidus definition. Further study to validate its role is warranted.

Clinical and radiographic response of a paravertebral hemangioma to radiotherapy.

Hemangiomas can arise anywhere in the body. While vertebral hemangiomas are common, atypical hemangiomas with paraspinal and epidural extension are rare. We present a case of a patient who presented with persistent cough and anorexia from a paravertebral hemangioma that invaded the adjacent vertebrae and neural foramen causing moderate spinal canal stenosis. She was treated with stereotactic body radiotherapy to prevent the development of symptomatic spinal cord compression. The hemangioma underwent significant shrinkage and her cough resolved. This case demonstrates impressive and sustained clinical and radiographic response of a paraspinal hemangioma to stereotactic body radiotherapy.

Effect of Concomitant Medications on Treatment Response and Survival in De Novo Metastatic Prostate Cancer: Secondary Analysis of the LATITUDE Study.

PURPOSE: It is unclear whether exposure to commonly prescribed medications influences survival and treatment response in patients with de novo high-risk metastatic prostate cancer (mPCa) treated with androgen receptor pathway inhibitors (ARPIs). METHODS: We performed a secondary analysis of the LATITUDE trial to determine whether receipt of concomitant medications influenced the effect of abiraterone acetate and prednisone, in addition to androgen deprivation therapy (ADT), on overall survival (OS) and prostate cancer-specific mortality (PCSM) in patients with de novo mPCa. We focused on 7 commonly prescribed classes of medications: metformin, statins, proton pump inhibitors (PPIs), cyclooxygenase 2 (COX-2) inhibitors, aspirin, acetaminophen, and NSAIDs (nonselective COX inhibitors). To account for multiple testing, a two-sided p < 0.0024 was set as the threshold for statistical significance. RESULTS: Overall, 1135 patients were eligible. There was some evidence of a differential treatment effect from abiraterone among patients who received concomitant NSAIDs (hazard ratio [HR] for OS: 0.54; 95% CI: 0.42-0.70) versus those who did not (HR: 0.74; 95% CI: 0.60-0.91), though this did not reach significance (interaction p = 0.05). A similar non-significant finding of heterogeneity of effect from abiraterone was noted among patients who received concomitant aspirin (HR for OS: 0.93 [0.63-1.36]) versus those who did not (HR: 0.61 [0.51-0.73]) (interaction p = 0.04). Receipt of NSAIDs was independently associated with a significantly inferior OS (HR: 1.37 [1.15-1.62]; p < 0.001) and higher relative incidence of PCSM (sHR: 1.47 [1.21-1.78]; p < 0.001). CONCLUSIONS: This exploratory analysis did not find statistically significant evidence of differences in treatment effects from ADT plus abiraterone in de novo high-risk mPCa based on the receipt of concurrent medications. The receipt of NSAIDs was independently associated with increased PCSM and inferior OS.

Effect of Pelvic External Beam Radiation Therapy on Bone Mineral Density: A Secondary Analysis of a Phase 3 Randomized Controlled Trial.

PURPOSE: Pelvic radiation therapy may lead to decreased bone mineral density (BMD) and increased risk of fracture that could be of particular concern in patients with prostate cancer who also receive androgen deprivation therapy (ADT). We performed an exploratory analysis of a randomized, double-masked, placebo-controlled trial to determine whether exposure to prior pelvic external beam radiation therapy (XRT) affects BMD and risk of fracture in patients with prostate cancer treated with ADT. METHODS AND MATERIALS: Patients with nonmetastatic prostate cancer aged ≥70 years or <70 years with low BMD (T-score < -1) or osteoporotic fracture who had been receiving ADT for ≥12 months were randomly assigned to receive densoumab or placebo every 6 months for 3 years. BMD was measured at baseline and at months 1, 3, 6, 12, 24, and 36. We applied multivariable linear mixed-effects models with an interaction term between the treatment arm and exposure to prior pelvic XRT to evaluate differential XRT effect on percent BMD change between the 2 treatment arms. RESULTS: Among 1407 eligible patients, 31% (n = 447) received prior pelvic XRT. There was no significant difference in any clinical fractures among patients with (5.8%, 26 of 447) or without (5.2%, 50 of 960) prior pelvic XRT (P = .42). Prior pelvic XRT was associated with a significant (0.54%) improvement in BMD (95% CI, 0.05-1.02) in the placebo group and a nonsignificant (0.04%) decline in BMD (95% CI, -0.47 to -0.35) in the denosumab group (interaction P = .007). There was no significant difference in pelvic XRT effect on percent BMD change in the lumbar spine (P = .65) or total hip (P = .39) between the 2 treatment groups. CONCLUSIONS: We did not find sufficient evidence to suggest any detrimental effect of pelvic XRT on the treatment effect from denosumab on percent BMD change, with only an approximately 5% incidence of clinical fractures.