Genitourinary quality-of-life comparison between urethral sparing prostate stereotactic body radiation therapy monotherapy and virtual high-dose-rate brachytherapy boost

Purpose: Although radiation dose escalation improves prostate cancer disease control, it can cause increased toxicity. Genitourinary (GU) symptoms after prostate radiation therapy affect patient health-related quality of life (QoL). We compared patient-reported GU QoL outcomes following 2 alternative urethral sparing stereotactic body radiation therapy regimens. Methods and Materials: Expanded Prostate Cancer Index Composite (EPIC)–26 GU scores were compared between 2 urethral sparing stereotactic body radiation therapy trials. The SPARK trial prescribed a “Monotherapy” dose of 36.25 Gy in 5 fractions to the prostate. The PROMETHEUS trial prescribed 2 phases: a 19- to 21-Gy in 2 fractions “Boost” to the prostate, followed by 46 Gy in 23 fractions or 36 Gy in 12 fractions. The biological effective dose (BED) for urethral toxicity was 123.9 Gy for Monotherapy and 155.8 to 171.2 Gy for Boost. Mixed effects logistic regression models were utilized to estimate the difference in the odds of a minimal clinically important change from baseline EPIC-26 GU score between regimens at each follow-up. Results: 46 Monotherapy and 149 Boost patients completed baseline EPIC-26 scoring. Mean EPIC-26 GU scores revealed statistically superior urinary incontinence outcomes for Monotherapy at 12 months (mean difference, 6.9; 95% confidence interval [CI], 1.6-12.1; P = .01) and 36 months (mean difference, 9.6; 95% CI, 4.1-15.1; P < .01). Monotherapy also revealed superior mean urinary irritative/obstructive outcomes at 12 months (mean difference, 6.9; 95% CI, 2.0-12.9; P < .01) and 36 months (mean difference, 6.3; 95% CI, 1.9-10.8; P < .01). For both domains and at all time points, the absolute differences were <10%. There were no significant differences in the odds of reporting a minimal clinically important change between regimens at any time point. Conclusions: Even in the presence of urethral sparing, the higher BED delivered in the Boost schedule may have a small adverse effect on GU QoL compared with Monotherapy. However, this did not translate to statistically significant differences in minimal clinically important changes. Whether the higher BED of the boost arm offers an efficacy advantage is being investigated in the Trans Tasman Radiation Oncology Group 18.01 NINJA randomized trial

Artificial intelligence and imaging biomarkers for prostate radiation therapy during and after treatment

Magnetic resonance imaging (MRI) is increasingly used in the management of prostate cancer (PCa). Quantitative MRI (qMRI) parameters, derived from multi-parametric MRI, provide indirect measures of tumour characteristics such as cellularity, angiogenesis and hypoxia. Using Artificial Intelligence (AI), relevant information and patterns can be efficiently identified in these complex data to develop quantitative imaging biomarkers (QIBs) of tumour function and biology. Such QIBs have already demonstrated potential in the diagnosis and staging of PCa. In this review, we explore the role of these QIBs in monitoring treatment response during and after PCa radiotherapy (RT). Recurrence of PCa after RT is not uncommon, and early detection prior to development of metastases provides an opportunity for salvage treatments with curative intent. However, the current method of monitoring treatment response using prostate-specific antigen levels lacks specificity. QIBs, derived from qMRI and developed using AI techniques, can be used to monitor biological changes post-RT providing the potential for accurate and early diagnosis of recurrent disease

Long term patient reported urinary function following external beam radiotherapy for prostate cancer

Introduction This study reports long-term patient reported urinary function and urinary-related quality of life (uQoL) after external beam radiotherapy (EBRT) for localized prostate cancer. Methods 574 men underwent definitive prostate EBRT to 70–78 Gy ± androgen deprivation therapy between 2000 and 2009. The median follow-up from EBRT was 44 months. Patients were evaluated at baseline (pre-EBRT) and at intervals post-treatment using the International Prostate Symptom Score (IPSS) instrument. Results Patients with mild IPSS at baseline (total 0–7) reported median total scores of 3, 4 and 3 at baseline, 6 and 48 months respectively post-EBRT. For patients with moderate IPSS at baseline (total 8–19), median total IPSS was 12 at baseline and 9 at both 6 and 48 months. For the severe IPSS group at baseline (total 20–35), the median total IPSS was 24, 12 and 14 at baseline, 6 and 48 months post-EBRT. The cumulative risk of persistent IPSS increase (greater than 5 points above baseline) at 48 months was 16%, 10% and 6% for patients with mild, moderate and severe baseline IPSS respectively. 94%, 54% and 11% of patients with mild, moderate and severe baseline IPSS reported good uQoL at baseline respectively, with these proportions increasing to 95%, 83% and 69% at 48 months. Conclusion Urinary symptoms and uQoL as measured by the IPSS instrument remained stable or improved for the majority of men after definitive EBRT with or without ADT for prostate cancer. This was especially notable for the group of men with worse baseline symptoms or uQoL, with risk of persistent worsening of urinary symptoms decreasing with higher baseline IPSS category. Understanding the expected pattern of urinary symptoms and related uQoL in the months and years following EBRT taking into account baseline urinary function is highly valuable for counselling men as part of the therapeutic decision-making process

A predictive model for determining rectum and bladder dose constraints in prostate volumetric modulated arc therapy

Generic dose-volume constraints of the rectum/bladder (R/B) are used in inverse planning to reduce doses to these organs for patients undergoing prostate radiotherapy. A retrospective study was undertaken to assess correlations between the overlap of the R/B with the planning target volume (PTV) and the dose received during planning to organs at risk (OARs). Data for 105 prostate cancer patients who had volumetric modulated arc therapy (VMAT) to the intact prostate and proximal seminal vesicles at Nepean Cancer Care Centre from 2011 to 2015 were analyzed. R/B volume, R/B-PTV overlap volume, and R/B-PTV overlap percent metrics were collected with VMAT planning objectives. Characteristics were evaluated for correlation with different planning outcomes. The percentage overlap between the R/B and PTV were highly correlated to the doses to the relevant OAR, with a coefficient of determination (R2) of 0.63 for the rectum volume percentage receiving more than 75 Gy (RV75Gy) and R2 of 0.91 for the bladder volume percentage receiving more than 70 Gy (BV70Gy). We identified a cut-off value of 10.14% (sensitivity 84.62%, specificity 80.43%) as predictive of RV75Gy &lt; 10% and a cut-off of 7.95% (sensitivity 97.62%, specificity 92.06%) as predictive of BV70Gy &lt; 15%. A 95% prediction interval assisted in identifying individualized R/B planning goals. The R/B-PTV percentage overlap has a high reliability in estimating sparing of the R/B. This prediction model can be used to improve planning efficiency and create customised automated OAR planning goals in prostate VMAT plans. By doing this, the radiation doses received by these OARs can be minimized

Dual-energy x-ray absorptiometry assessment of bone health in Australian men with prostate cancer commencing androgen deprivation therapy

Objective: To determine the prevalence in Australia of bone health assessment of men with prostate cancer by dual-energy x-ray absorptiometry (DXA), from six months before to twelve months after initiation of androgen deprivation therapy (ADT). Design, setting: Cross-sectional national study; linkage of de-identified Medicare Benefits Schedule (MBS) and Pharmaceutical Benefits Scheme (PBS) data. Participants: Men (18 years or older) first dispensed PBS-subsidised ADT during 1 May 2017 – 31 July 2020. Main outcome measures: Prevalence of MBS-subsidised DXA assessments undertaken from six months before to twelve months after first ADT prescription. Results: Of 33 836 men with prostate cancer commencing ADT therapy during 2017–20, 6683 (19.8%) underwent DXA bone heath assessments between six months before and twelve months after commencing ADT; the mean time from first ADT dispensing to DXA scanning was +90 days (standard deviation, 134 days). The proportion of men aged 54 years or younger who had scans (66 of 639, 10%) was smaller than that of men aged 70–84 years (4528 of 19 378, 23.4%; adjusted odds ratio, 0.36; 95% CI, 0.28–0.47). Conclusions: For about 80% of men with prostate cancer commencing ADT in Australia, therapy initiation was not accompanied by DXA assessment of bone health. Given the excellent long term prognosis for men with prostate cancer and the availability of bone protective therapy, bone health monitoring should be a routine component of prostate cancer care for men receiving ADT

Long-term outcomes in 1121 Australian prostate cancer patients treated with definitive radiotherapy

Introduction: Optimal definitive treatment of prostate cancer is controversial, especially in high-risk patients. We report the largest prospective cohort of Australian patients treated with radiotherapy for localised prostate cancer. Methods: One thousand, one hundred and twenty-one patients with prostate cancer were prospectively registered and treated to a dose of 70–74 Gy. Patients were classified as low, intermediate or high risk based on PSA, clinical staging and Gleason score. Intermediate-risk patients were treated with 0–6 months of hormonal therapy (ADT) and high-risk patients were offered neoadjuvant and adjuvant ADT. Overall survival (OS) and biochemical relapse-free survival (bNED) were calculated using the Kaplan–Meier method. Results: Median follow-up was 92 months. Eight-year OS and bNED were 78.4% and 68.1% respectively in the entire cohort. OS for the low, intermediate and high-risk groups was 84.5%, 78.4% and 68% respectively. For these risk groups, bNED was 80.3%, 65.7% and 53.7% respectively. In the intermediate and high-risk group, OS and bNED decreased with increasing number of risk factors. Conclusion: Definitive radiotherapy is an effective treatment for prostate cancer, including in high-risk cases

[In Press] Insulin-like growth factor role in determining the anti-cancer effect of metformin : RCT in prostate cancer patients

Objective: Androgen deprivation therapy (ADT), a principal therapy in patients with prostate cancer, is associated with the development of obesity, insulin resistance and hyperinsulinemia. Recent evidence indicates that metformin may slow cancer progression and improves survival in prostate cancer patients, but the mechanism is not well understood. Circulating insulin-like growth factors (IGFs) are bound to high affinity binding proteins, which not only modulate the bioavailability and signalling of IGFs, but also have independent actions on cell growth and survival. The aim of this study was to investigate whether metformin modulates IGFs, IGF-binding proteins (IGFBPs), and the pregnancy-associated plasma protein-A (PAPP-A) – stanniocalcin-2 (STC2) axis. Design and methods: In a blinded randomized cross-over design, fifteen patients with prostate cancer on stable ADT received metformin and placebo treatment for 6 weeks each. Glucose metabolism along with circulating IGFs and IGFBPs were assessed. Results: Metformin significantly reduced the homeostasis model assessment as an index of insulin resistance (HOMA IR) and hepatic insulin resistance. Metformin also reduced circulating IGF-2 (p<0.05) and IGFBP-3 (p<0.01), but increased IGF bioactivity (p<0.05). At baseline, IGF-2 correlated significantly with the hepatic insulin resistance (r2=0.28, p<0.05). PAPP-A remained unchanged but STC2 declined significantly (p<0.05) following metformin administration. During metformin treatment, change in HOMA IR correlated with the change in STC2 (r2=0.35, p<0.05). Conclusion: Metformin administration alters many components of the circulating IGF-system, either directly or indirectly via an improved insulin sensitivity. Reduction in IGF-2 and STC2 may provide a novel mechanism for a potential metformin-induced antineoplastic effect

Is multileaf collimator tracking or gating a better intrafraction motion adaptation strategy? An analysis of the TROG 15.01 stereotactic prostate ablative radiotherapy with KIM (SPARK) trial

Purpose: Stereotactic Ablative Radiotherapy (SABR) has recently emerged as a favourable treatment option for prostate cancer patients. With higher doses delivered over fewer fractions, motion adaptation is a requirement for accurate delivery of SABR. This study compared the efficacy of multileaf collimator (MLC) tracking vs. gating as a real-time motion adaptation strategy for prostate SABR patients enrolled in a clinical trial. Methods: Forty-four prostate cancer patients treated over five fractions in the TROG 15.01 SPARK trial were analysed in this study. Forty-nine fractions were treated using MLC tracking and 166 fractions were treated using beam gating and couch shifts. A time-resolved motion-encoded dose reconstruction method was used to evaluate the dose delivered using each motion adaptation strategy and compared to an estimation of what would have been delivered with no motion adaptation strategy implemented. Results: MLC tracking and gating both delivered doses closer to the plan compared to when no motion adaptation strategy was used. Differences between MLC tracking and gating were small with differences in the mean discrepancy from the plan of -0.3% (CTV D98%), 1.4% (CTV D2%), 0.4% (PTV D95%), 0.2% (rectum V30Gy) and 0.0% (bladder V30Gy). On average, 0.5 couch shifts were required per gated fractions with a mean interruption duration of 1.8 ± 2.6 min per fraction treated using gating. Conclusion: Both MLC tracking and gating were effective strategies at improving the accuracy of the dose delivered to the target and organs at risk. While dosimetric performance was comparable, gating resulted in interruptions to treatment

The dosimetric error due to uncorrected tumor rotation during real-time adaptive prostate stereotactic body radiation therapy

Background: During prostate stereotactic body radiation therapy (SBRT), prostate tumor translational motion may deteriorate the planned dose distribution. Most of the major advances in motion management to date have focused on correcting this one aspect of the tumor motion, translation. However, large prostate rotation up to 30° has been measured. As the technological innovation evolves toward delivering increasingly precise radiotherapy, it is important to quantify the clinical benefit of translational and rotational motion correction over translational motion correction alone. Purpose: The purpose of this work was to quantify the dosimetric impact of intrafractional dynamic rotation of the prostate measured with a six degrees-of-freedom tumor motion monitoring technology. Methods: The delivered dose was reconstructed including (a) translational and rotational motion and (b) only translational motion of the tumor for 32 prostate cancer patients recruited on a 5-fraction prostate SBRT clinical trial. Patients on the trial received 7.25 Gy in a treatment fraction. A 5 mm clinical target volume (CTV) to planning target volume (PTV) margin was applied in all directions except the posterior direction where a 3 mm expansion was used. Prostate intrafractional translational motion was managed using a gating strategy, and any translation above the gating threshold was corrected by applying an equivalent couch shift. The residual translational motion is denoted as (Formula presented.). Prostate intrafractional rotational motion (Formula presented.) was recorded but not corrected. The dose differences from the planned dose due to (Formula presented.) + (Formula presented.), ΔD((Formula presented.) + (Formula presented.)) and due to (Formula presented.) alone, ΔD((Formula presented.)), were then determined for CTV D98, PTV D95, bladder V6Gy, and rectum V6Gy. The residual dose error due to uncorrected rotation, (Formula presented.) was then quantified: (Formula presented.) = ΔD((Formula presented.) + (Formula presented.)) - ΔD((Formula presented.)). Results: Fractional data analysis shows that the dose differences from the plan (both ΔD((Formula presented.) + (Formula presented.)) and ΔD((Formula presented.))) for CTV D98 was less than 5% in all treatment fractions. ΔD((Formula presented.) + (Formula presented.)) was larger than 5% in one fraction for PTV D95, in one fraction for bladder V6Gy, and in five fractions for rectum V6Gy. Uncorrected rotation, (Formula presented.) induced residual dose error, (Formula presented.), resulted in less dose to CTV and PTV in 43% and 59% treatment fractions, respectively, and more dose to bladder and rectum in 51% and 53% treatment fractions, respectively. The cumulative dose over five fractions, ∑D((Formula presented.) + (Formula presented.)) and ∑D((Formula presented.)), was always within 5% of the planned dose for all four structures for every patient. Conclusions: The dosimetric impact of tumor rotation on a large prostate cancer patient cohort was quantified in this study. These results suggest that the standard 3–5 mm CTV-PTV margin was sufficient to account for the intrafraction prostate rotation observed for this cohort of patients, provided an appropriate gating threshold was applied to correct for translational motion. Residual dose errors due to uncorrected prostate rotation were small in magnitude, which may be corrected using different treatment adaptation strategies to further improve the dosimetric accuracy