Abstract Background and purpose Dose planning requires a CT scan which provides the electron density distribution for dose calculation. MR provides superior soft tissue contrast compared to CT and ...the use of MR-alone for prostate planning would provide further benefits such as lower cost to the patient. This study compares the accuracy of MR-alone based dose calculations with bulk electron density assignment to CT-based dose calculations for prostate radiotherapy. Materials and methods CT and whole pelvis MR images were contoured for 39 prostate patients. Plans with uniform density and plans with bulk density values assigned to bone and tissue were compared to the patient’s gold standard full density CT plan. The optimal bulk density for bone was calculated using effective depth measurements. The plans were evaluated using ICRU point doses, dose volume histograms, and Chi comparisons. Differences in spatial uniformity were investigated for the CT and MR scans. Results The calculated dose for CT bulk bone and tissue density plans was 0.1 ± 0.6% (mean ± 1 SD) higher than the corresponding full density CT plan. MR bulk bone and tissue density plans were 1.3 ± 0.8% lower than the full density CT plan. CT uniform density plans and MR uniform density plans were 1.4 ± 0.9% and 2.6 ± 0.9% lower, respectively. Paired t -tests performed on specific points on the DVH graphs showed that points on DVHs for all bulk electron density plans were equivalent with two exceptions. There was no significant difference between doses calculated on Pinnacle and Eclipse. The dose distributions of six patients produced Chi values outside the acceptable range of values when MR-based plans were compared to the full density plan. Conclusions MR-alone bulk density planning is feasible provided bone is assigned a density, however, manual segmentation of bone on MR images will have to be replaced with automatic methods. The major dose differences for MR bulk density plans are due to differences in patient external contours introduced by the MR couch-top and pelvic coil.
Summary Background Androgen suppression therapy and radiotherapy are used to treat locally advanced prostate cancer. 3 years of androgen suppression confers a small survival benefit compared with 6 ...months of therapy in this setting, but is associated with more toxic effects. Early identification of men in whom radiotherapy and 6 months of androgen suppression is insufficient for cure is important. Thus, we assessed whether prostate-specific antigen (PSA) values can act as an early surrogate for prostate cancer-specific mortality (PCSM). Methods We systematically reviewed randomised controlled trials that showed improved overall and prostate cancer-specific survival with radiotherapy and 6 months of androgen suppression compared with radiotherapy alone and measured lowest PSA concentrations (PSA nadir) and those immediately after treatment (PSA end). We assessed a cohort of 734 men with localised or locally advanced prostate cancer from two eligible trials in the USA and Australasia that randomly allocated participants between Feb 2, 1996, and Dec 27, 2001. We used Prentice criteria to assess whether reported PSA nadir or PSA end concentrations of more than 0·5 ng/mL were surrogates for PCSM. Findings Men treated with radiotherapy and 6 months of androgen suppression in both trials were significantly less likely to have PSA end and PSA nadir values of more than 0·5 ng/mL than were those treated with radiotherapy alone (p<0·0001). Presence of candidate surrogates (ie, PSA end and PSA nadir values >0·5 ng/mL) alone and when assessed in conjunction with the randomised treatment group increased risk of PCSM in the US trial (PSA nadir p=0·0016; PSA end p=0·017) and Australasian trial (PSA nadir p<0·0001; PSA end p=0·0012). In both trials, the randomised treatment group was no longer associated with PCSM (p≥0·20) when the candidate surrogates were included in the model. Therefore, both PSA metrics satisfied Prentice criteria for surrogacy. Interpretation After radiotherapy and 6 months of androgen suppression, men with PSA end values exceeding 0·5 ng/mL should be considered for long-term androgen suppression and those with localised or locally advanced prostate cancer with PSA nadir values exceeding 0·5 ng/mL should be considered for inclusion in randomised trials investigating the use of drugs that have extended survival in castration-resistant metastatic prostate cancer. Funding None.
Purpose:
For prostate cancer treatment, comparable or superior biochemical control was reported when using External-Beam-Radiotherapy (EBRT) with High-Dose-Rate-Brachytherapy (HDRB)-boost, compared ...to dose-escalation with EBRT alone. The conformal doses produced by HDRB could allow further beneficial prostate dose-escalation, but increase in dose is limited by normal tissue toxicity. Previous works showed correlation between urethral dose and incidence of urinary toxicity, but there is a lack of established guidelines on the dose constraints to this organ. This work aimed at fitting a Normal-Tissue-Complication-Probability model to urethral stricture data collected at one institution and validating it with an external cohort, looking at neo-adjuvant androgen deprivation as dose-modifying factor.
Materials and Methods:
Clinical and dosimetric data of 258 patients, with a toxicity rate of 12.8%, treated at a single institution with a variety of prescription doses, were collected to fit the Lyman–Kutcher–Burman (LKB) model using the maximum likelihood method. Due to the different fractionations, doses were converted into 2 Gy-equivalent doses (α/β = 5 Gy), and urethral stricture was used as an end-point. For validation, an external cohort of 187 patients treated as part of the TROG (Trans Tasman Radiation Oncology Group) 03.04 RADAR trial with a toxicity rate of 8.7%, was used. The goodness of fit was assessed using calibration plots. The effect of neo-adjuvant androgen deprivation (AD) was analyzed separating patients who had received it prior to treatment from those who did not receive it.
Results:
The obtained LKB parameters were TD50 = 116.7 Gy and
m
= 0.23;
n
was fixed to 0.3, based on numerical optimization of the likelihood. The calibration plot showed a good agreement between the observed toxicity and the probability predicted by the model, confirmed by bootstrapping. For the external validation, the calibration plot showed that the observed toxicity obtained with the RADAR patients was well-represented by the fitted LKB model parameters. When patients were stratified by the use of AD TD50 decreased when AD was not present.
Conclusions:
Lyman–Kutcher–Burman model parameters were fitted to the risk of urethral stricture and externally validated with an independent cohort, to provide guidance on urethral tolerance doses for patients treated with a HDRB boost. For patients that did not receive AD, model fitting provided a lower TD50 suggesting a protective effect on urethra toxicity.
Background: In 1991, a National Institutes of Health Consensus Panel stated that preoperative localization for primary hyperparathyroidism is not cost effective. Since then, the sestamibi scan has ...been applied to parathyroid disease with excellent results, even allowing unilateral exploration under local anesthesia.
Study Design: A metaanalysis of the English literature over the past 10 years was performed to determine the collective sensitivity and specificity of sestamibi scanning to establish its utility in directing a unilateral procedure. The cost effectiveness of scanning all patients with sporadic primary hyperparathyroidism was examined by determining the costs of seven operative technique–dependent variables that could be reduced with a limited procedure.
Results: The average sensitivity and specificity of sestamibi were 90.7% and 98.8%, respectively, indicating its ability to guide an accurate unilateral exploration. The analysis of 6,331 patients showed that 87% had solitary adenomas. An average cost savings of $650 was demonstrated for a unilateral operation, which could be realized in as many as 90% (sestamibi sensitivity) of those with solitary adenomas.
Conclusions: A preoperative sestamibi scan is specific enough in identifying solitary adenomas to allow unilateral exploration with a < 1% failure rate. The sensitivity of this scan suggests that 78% of all patients with sporadic primary hyperparathyroidism (90% of the 87% with solitary adenomas) are candidates for unilateral exploration. This rate is significantly higher than the 51% rate at which scanning all patients becomes cost effective.
Nonsteroidal anti-inflammatory drugs (NSAIDs) can produce adverse effects by inhibiting prostaglandin (PG) synthesis. A PGE1 analogue, misoprostol, is often utilized to alleviate NSAID-related ...gastrointestinal side effects. This study examined the effect of misoprostol on celecoxib renal toxicity. Additionally, the effects of these drugs on cardiovascular parameters were evaluated. Four randomized rat groups were orally gavaged for 9 days, two groups receiving vehicle and two groups receiving misoprostol (100 µg/kg) twice daily. Celecoxib (40 mg/kg) was co-administered once daily to one vehicle and one misoprostol group from days 3 to 9. Urine and blood samples were collected and blood pressure parameters were measured during the study period. Hearts and kidneys were harvested on final day. Day 2 urinary electrolyte samples revealed significant reductions in sodium excretion in misoprostol (0.12 ± 0.05 µmol/min/100 g) and misoprostol+celecoxib groups (0.07 ± 0.02 µmol/min/100 g). At day 3, all treatment groups showed significantly reduced sodium excretion. Potassium excretion diminished significantly in vehicle+celecoxib and misoprostol+celecoxib groups from day 3 onward. Urinary kidney injury molecule-1 levels were significantly increased in vehicle+celecoxib (0.65 ± 0.02 vs. 0.35 ± 0.07 ng/mL, p = 0.0002) and misoprostol+celecoxib (0.61 ± 0.06 vs. 0.37 ± 0.06 ng/mL, p = 0.0015) groups when compared to baseline; while plasma levels of cardiac troponin I increased significantly in vehicle+celecoxib (p = 0.0040) and misoprostol+misoprostol (p = 0.0078) groups when compared to vehicle+vehicle. Blood pressure parameters increased significantly in all misoprostol treated groups. Significant elevation in diastolic (p = 0.0071) and mean blood pressure (p = 0.0153) was noted in misoprostol+celecoxib compared to vehicle+celecoxib. All treatments produced significant tubular dilatation/necrosis compared to control. No significant myocardial changes were noticed; however, three animals presented with pericarditis. Kidney, heart, and plasma celecoxib levels revealed no significant change between vehicle+celecoxib and misoprostol+celecoxib. Concomitant misoprostol administration did not prevent celecoxib renal toxicity, and instead exacerbated renal side effects. Misoprostol did not alter plasma or tissue celecoxib concentrations suggesting no pharmacokinetic interaction between celecoxib and misoprostol.
Previous reports have shown that quantification of high tumour grade is of prognostic significance for patients with prostate cancer. In particular, percent Gleason pattern 4 (GP4) has been shown to ...predict outcome in several studies, although conflicting results have also been reported. A major issue with these studies is that they rely on surrogate markers of outcome rather than patient survival. We have investigated the prognostic predictive value of quantifying GP4 in a series of prostatic biopsies containing Gleason score 3+4=7 and 4+3=7 tumours. It was found that the length of GP4 tumour determined from the measurement of all biopsy cores from a single patient, percent GP4 present and absolute GP4 were all significantly associated with distant progression of tumour, all-cause mortality and cancer-specific mortality over a 10-year follow-up period. Assessment of the relative prognostic significance showed that these parameters outperformed division of cases according to Gleason score (3+4=7 versus 4+3=7). International Society of Urological Pathology (ISUP) Grade Groups currently divide these tumours, according to Gleason grading guidelines, into grade 2 (3+4=7) and grade 3 (4+3=7). Our results indicate that this simple classification results in the loss of important prognostic information. In view of this we would recommend that ISUP Grade Groups 2 and 3 be amalgamated as grade 2 tumour with the percentage of GP4 carcinoma being appended to the final grade, e.g., 3+4=7 carcinoma with 40% pattern 4 tumour would be classified as ISUP Grade Group 2 (40%).
To use a high-quality multicenter trial dataset to determine dose-volume effects for gastrointestinal (GI) toxicity following radiation therapy for prostate carcinoma. Influential dose-volume ...histogram regions were to be determined as functions of dose, anatomical location, toxicity, and clinical endpoint.
Planning datasets for 754 participants in the TROG 03.04 RADAR trial were available, with Late Effects of Normal Tissues (LENT) Subjective, Objective, Management, and Analytic (SOMA) toxicity assessment to a median of 72 months. A rank sum method was used to define dose-volume cut-points as near-continuous functions of dose to 3 GI anatomical regions, together with a comprehensive assessment of significance. Univariate and multivariate ordinal regression was used to assess the importance of cut-points at each dose.
Dose ranges providing significant cut-points tended to be consistent with those showing significant univariate regression odds-ratios (representing the probability of a unitary increase in toxicity grade per percent relative volume). Ranges of significant cut-points for rectal bleeding validated previously published results. Separation of the lower GI anatomy into complete anorectum, rectum, and anal canal showed the impact of mid-low doses to the anal canal on urgency and tenesmus, completeness of evacuation and stool frequency, and mid-high doses to the anorectum on bleeding and stool frequency. Derived multivariate models emphasized the importance of the high-dose region of the anorectum and rectum for rectal bleeding and mid- to low-dose regions for diarrhea and urgency and tenesmus, and low-to-mid doses to the anal canal for stool frequency, diarrhea, evacuation, and bleeding.
Results confirm anatomical dependence of specific GI toxicities. They provide an atlas summarizing dose-histogram effects and derived constraints as functions of anatomical region, dose, toxicity, and endpoint for informing future radiation therapy planning.
Dose information from organ sub-regions has been shown to be more predictive of genitourinary toxicity than whole organ dose volume histogram information. This study aimed to identify ...anatomically-localized regions where 3D dose is associated with genitourinary toxicities in healthy tissues throughout the pelvic anatomy.
Dose distributions for up to 656 patients of the Trans-Tasman Radiation Oncology Group 03.04 RADAR trial were deformably registered onto a single exemplar CT dataset. Voxel- based multiple comparison permutation dose difference testing, Cox regression modeling and LASSO feature selection were used to identify regions where 3D dose-increase was associated with late grade ≥ 2 genitourinary dysuria, incontinence and frequency, and late grade ≥ 1 haematuria. This was externally validated by registering dose distributions from the RT01 (up to
= 388) and CHHiP (up to
= 247) trials onto the same exemplar and repeating the voxel-based tests on each of these data sets. All three datasets were then combined, and the tests repeated.
Voxel-based Cox regression and multiple comparison permutation dose difference testing revealed regions where increased dose was correlated with genitourinary toxicity. Increased dose in the vicinity of the membranous and spongy urethra was associated with dysuria for all datasets. Haematuria was similarly correlated with increased dose at the membranous and spongy urethra, for the RADAR, CHHiP, and combined datasets. Some evidence was found for the association between incontinence and increased dose at the internal and external urethral sphincter for RADAR and the internal sphincter alone for the combined dataset. Incontinence was also strongly correlated with dose from posterior oblique beams. Patients with fields extending inferiorly and posteriorly to the CTV, adjacent to the membranous and spongy urethra, were found to experience increased frequency.
Anatomically-localized dose-toxicity relationships were determined for late genitourinary symptoms in the urethra and urinary sphincters. Low-intermediate doses to the extraprostatic urethra were associated with risk of late dysuria and haematuria, while dose to the urinary sphincters was associated with incontinence.
Androgen deprivation is an established treatment regimen for disseminated prostate cancer; however, its role in patients with localised cancer is less clear. We did a large randomised controlled ...trial to determine whether 3 months or 6 months of androgen deprivation given before and during radiotherapy improves outcomes for patients with locally advanced prostate cancer.
818 men with locally advanced prostate cancer were randomly assigned to: no androgen deprivation (ie, radiotherapy alone: 66 Gy in 33 fractions of 2 Gy per day over 6·5–7·0 weeks to the prostate and seminal vesicles); 3 months' androgen deprivation with 3·6 mg goserelin given subcutaneously every month and 250 mg flutamide given orally three times a day starting 2 months before radiotherapy (same regimen as control group); or 6 months' androgen deprivation, with the same regimen, starting 5 months before radiotherapy (same regimen as control group). Primary endpoints were time to local failure and prostate-cancer-specific survival; secondary endpoints were distant failure, disease-free survival, and freedom from salvage treatment. Analyses were done by intention to treat.
802 (98%) patients were eligible for analysis. Median follow-up was 5·9 years (range 0·1–8·5). Compared with patients assigned no androgen deprivation, those assigned 3 months' treatment had significantly improved local failure (hazard ratio HR 0·56 95% CI 0·39–0·79, p=0·001), biochemical failure-free survival (0·70 0·56–0·88, p=0·002), disease-free survival (0·65 0·52–0·80, p=0·0001), and freedom from salvage treatment (0·73 0·56–0·96, p=0·025). 6 months' androgen deprivation significantly improved local failure (0·42 0·28–0·62, p<0·0001), biochemical failure-free survival (0·58 0·46–0·74, p<0·0001), disease-free survival (0·56 0·45–0·69, p<0·0001), freedom from salvage treatment (0·53 0·40–0·71, p<0·0001), distant failure (0·67 0·45–0·99, p=0·046) and prostate-cancer-specific survival (0·56 0·32–0·98, p=0·04) compared with no androgen deprivation.
6 months' androgen deprivation given before and during radiotherapy improves the outlook of patients with locally advanced prostate cancer. Further follow-up is needed to estimate precisely the size of survival benefits. Increased radiation doses and additional periods of androgen deprivation might lead to further benefit.
PDF
