Abstract
Background
Multiparametric magnetic resonance imaging (mpMRI) and positron emission tomography (PET) are widely used for the management of prostate cancer (PCa). However, how these ...modalities complement each other in PCa risk stratification is still largely unknown. We aim to provide insights into the potential of mpMRI and PET for PCa risk stratification.
Methods
We analyzed data from 55 consecutive patients with elevated prostate-specific antigen and biopsy-proven PCa enrolled in a prospective study between December 2016 and December 2019.
68
GaPSMA-11 PET (PSMA-PET),
11
CAcetate PET (Acetate-PET) and mpMRI were co-registered with whole-mount histopathology. Lower- and higher-grade lesions were defined by International Society of Urological Pathology (ISUP) grade groups (IGG). We used PET and mpMRI data to differentiate between grades in two cases: IGG 3 vs. IGG 2 (case 1) and IGG ≥ 3 vs. IGG ≤ 2 (case 2). The performance was evaluated by receiver operating characteristic (ROC) analysis.
Results
We find that the maximum standardized uptake value (SUV
max
) for PSMA-PET achieves the highest area under the ROC curve (AUC), with AUCs of 0.72 (case 1) and 0.79 (case 2). Combining the volume transfer constant, apparent diffusion coefficient and T2-weighted images (each normalized to non-malignant prostatic tissue) results in AUCs of 0.70 (case 1) and 0.70 (case 2). Adding PSMA-SUV
max
increases the AUCs by 0.09 (
p
< 0.01) and 0.12 (
p
< 0.01), respectively.
Conclusions
By co-registering whole-mount histopathology and in-vivo imaging we show that mpMRI and PET can distinguish between lower- and higher-grade prostate cancer, using partially discriminative cut-off values.
Hypofractionated radiotherapy for prostate cancer has gained increased attention due to its proposed high radiation-fraction sensitivity. Recent reports from studies comparing moderately ...hypofractionated and conventionally fractionated radiotherapy support the clinical use of moderate hypofractionation. To date, there are no published randomised studies on ultra-hypofractionated radiotherapy. Here, we report the outcomes of the Scandinavian HYPO-RT-PC phase 3 trial with the aim to show non-inferiority of ultra-hypofractionation compared with conventional fractionation.
In this open-label, randomised, phase 3 non-inferiority trial done in 12 centres in Sweden and Denmark, we recruited men up to 75 years of age with intermediate-to-high-risk prostate cancer and a WHO performance status between 0 and 2. Patients were randomly assigned to ultra-hypofractionation (42·7 Gy in seven fractions, 3 days per week for 2·5 weeks) or conventional fractionated radiotherapy (78·0 Gy in 39 fractions, 5 days per week for 8 weeks). No androgen deprivation therapy was allowed. The primary endpoint was time to biochemical or clinical failure, analysed in the per-protocol population. The prespecified non-inferiority margin was 4% at 5 years, corresponding to a critical hazard ratio (HR) limit of 1·338. Physician-recorded toxicity was measured according to the Radiation Therapy Oncology Group (RTOG) morbidity scale and patient-reported outcome measurements with the Prostate Cancer Symptom Scale (PCSS) questionnaire. This trial is registered with the ISRCTN registry, number ISRCTN45905321.
Between July 1, 2005, and Nov 4, 2015, 1200 patients were randomly assigned to conventional fractionation (n=602) or ultra-hypofractionation (n=598), of whom 1180 (591 conventional fractionation and 589 ultra-hypofractionation) constituted the per-protocol population. 1054 (89%) participants were intermediate risk and 126 (11%) were high risk. Median follow-up time was 5·0 years (IQR 3·1–7·0). The estimated failure-free survival at 5 years was 84% (95% CI 80–87) in both treatment groups, with an adjusted HR of 1·002 (95% CI 0·758–1·325; log-rank p=0·99). There was weak evidence of an increased frequency of acute physician-reported RTOG grade 2 or worse urinary toxicity in the ultra-hypofractionation group at end of radiotherapy (158 28% of 569 patients vs 132 23% of 578 patients; p=0·057). There were no significant differences in grade 2 or worse urinary or bowel late toxicity between the two treatment groups at any point after radiotherapy, except for an increase in urinary toxicity in the ultra-hypofractionation group compared to the conventional fractionation group at 1-year follow-up (32 6% of 528 patients vs 13 2% of 529 patients; (p=0·0037). We observed no differences between groups in frequencies at 5 years of RTOG grade 2 or worse urinary toxicity (11 5% of 243 patients for the ultra-hypofractionation group vs 12 5% of 249 for the conventional fractionation group; p=1·00) and bowel toxicity (three 1% of 244 patients vs nine 4% of 249 patients; p=0·14). Patient-reported outcomes revealed significantly higher levels of acute urinary and bowel symptoms in the ultra-hypofractionation group compared with the conventional fractionation group but no significant increases in late symptoms were found, except for increased urinary symptoms at 1-year follow-up, consistent with the physician-evaluated toxicity.
Ultra-hypofractionated radiotherapy is non-inferior to conventionally fractionated radiotherapy for intermediate-to-high risk prostate cancer regarding failure-free survival. Early side-effects are more pronounced with ultra-hypofractionation compared with conventional fractionation whereas late toxicity is similar in both treatment groups. The results support the use of ultra-hypofractionation for radiotherapy of prostate cancer.
The Nordic Cancer Union, the Swedish Cancer Society, and the Swedish Research Council.
Background
Attenuation correction of PET/MRI is a remaining problem for whole-body PET/MRI. The statistical decomposition algorithm (SDA) is a probabilistic atlas-based method that calculates ...synthetic CTs from T2-weighted MRI scans. In this study, we evaluated the application of SDA for attenuation correction of PET images in the pelvic region.
Materials and method
Twelve patients were retrospectively selected from an ongoing prostate cancer research study. The patients had same-day scans of 11Cacetate PET/MRI and CT. The CT images were non-rigidly registered to the PET/MRI geometry, and PET images were reconstructed with attenuation correction employing CT, SDA-generated CT, and the built-in Dixon sequence-based method of the scanner. The PET images reconstructed using CT-based attenuation correction were used as ground truth.
Results
The mean whole-image PET uptake error was reduced from − 5.4% for Dixon-PET to − 0.9% for SDA-PET. The prostate standardized uptake value (SUV) quantification error was significantly reduced from − 5.6% for Dixon-PET to − 2.3% for SDA-PET.
Conclusion
Attenuation correction with SDA improves quantification of PET/MR images in the pelvic region compared to the Dixon-based method.
Local and regional recurrence after radical prostatectomy (RP) can be treated using salvage radiotherapy (SRT). If the recurrence can be delineated on diagnostic imaging, this could allow for ...increasingly individualized SRT.
This systematic review aimed at evaluating the evidence regarding the usefulness of positron emission tomography (PET) and magnetic resonance imaging (MRI) in identifying local and regional recurrences, with the aim to further individualize the SRT treatment.
A systematic PubMed/Medline search was conducted in December 2015. Studies included were imaging studies of post-RP patients focusing on local and/or regional recurrence where sensitivity and specificity of MRI or PET were the primary end points. Only studies using biopsy, other histological analysis, and/or treatment follow-up as reference standard were included. Quality Assessment of Diagnostic Accuracy Studies-2 was used to score the study quality. Twenty-five articles were deemed of sufficient quality and included in the review.
11CAcetate had the highest pooled sensitivity (92%), while 11Ccholine and 18Fcholine had pooled sensitivities of 71% and 84%, respectively. The PET tracer with highest pooled specificity was 11Ccholine (86%). Regarding MRI, MR spectroscopy combined with dynamic contrast enhanced (DCE) MRI showed the highest pooled sensitivity (89%). High pooled sensitivities were also seen using multiparametric MRI (84%), diffusion-weighted MRI combined with T2-weigthed (T2w) imaging (82%), and DCE MRI combined with T2w imaging (82%). These also showed high pooled specificities (85%, 89%, and 92%, respectively).
Both MRI and PET have adequate sensitivity and specificity for the detection of prostate cancer recurrences post-RP. Multiparametric MRI, using diffusion-weighted and/or DCE imaging, and the choline-labeled tracers showed high pooled sensitivity and specificity, although their ranges were broad.
After reviewing imaging studies of recurrent prostate cancer after prostatectomy, we concluded that choline positron emission tomography and diffusion-weighted magnetic resonance imaging can be proposed as the current standard, with high sensitivity and specificity.
Both magnetic resonance imaging and positron emission tomography (PET) have adequate sensitivity and specificity for the detection of prostate cancer recurrences after radical prostatectomy. Regrettably, no prostate-specific membrane antigen (PSMA) PET articles were of sufficient quality to be included, but this review provides a possible point of comparison for future PSMA trials.
A fundamental requirement for safe use of magnetic resonance imaging (MRI) in radiotherapy is geometrical accuracy. One factor that can introduce geometrical distortion is patient-induced ...susceptibility effects. This work aims at developing a method for simulating these distortions. The specific goal being to help objectively identifying a balanced acquisition bandwidth, keeping these distortions within acceptable limits for radiotherapy.
A simulation algorithm was implemented in Medical Interactive Creative Environment (MICE). The algorithm was validated by comparison between simulations and analytical solutions for a cylinder and a sphere. Simulations were performed for four body regions; neck, lungs, thorax with the lungs excluded, and the pelvic region. This was done using digital phantoms created from patient CT images, after converting the CT Hounsfield units to magnetic susceptibility values through interpolation between known values.
The simulations showed good agreement with analytical solutions, with only small discrepancies due to pixelation of the phantoms. The calculated distortions in digital phantoms based on patient CT data showed maximal 95th percentile distortions of 39%, 32%, 28%, and 25% of the fat-water shift for the neck, lungs, thorax with the lungs excluded, and pelvic region, respectively.
The presented results show the expected pixel distortions for various body parts, and how they scale with bandwidth and field strength. This information can be used to determine which bandwidth is required to keep the patient-induced susceptibility distortions within an acceptable range for a given field strength.
The treatment of metastatic prostate cancer has seen drastic changes in the recent years with more intense treatment at initial diagnose. The new standard is combination therapy with castration as ...the backbone and the addition of new hormonal therapies with or without chemotherapy. For patients with minimal metastatic spread it is also recommended to give radiotherapy to the primary tumour. Since many patients now can look forward to longer survival it is paramount to take care of the side-effects of the treatments, where focus is on cardiovascular disease and bone health management. Precision medicine has started also in prostate cancer; testing of BRCA1/2 mutation is mandatory for treatment with PARP inhibitors.
Background The HYPO-RT-PC trial compared conventionally fractionated radiotherapy with ultra-hypofractionated radiotherapy in patients with localised prostate cancer. Ultra-hypofractionation was ...non-inferior to conventional fractionation regarding 5-year failure-free survival and toxicity. We aimed to assess whether patient-reported quality of life (QOL) differs between conventional fractionation and ultra-hypofractionation up to 6 years after treatment in the HYPO-RT-PC trial. Methods HYPO-RT-PC is a multicentre, open-label, randomised, controlled, non-inferiority, phase 3 trial done in 12 centres (seven university hospitals and five county hospitals) in Sweden and Denmark. Inclusion criteria were histologically verified intermediate-to-high-risk prostate cancer (defined as T1c-T3a with one or two of the following risk factors: stage T3a; Gleason score &gt;= 7; and prostate-specific antigen 10-20 ng/mL with no evidence of lymph node involvement or distant metastases), age up to 75 years, and WHO performance status 0-2. Participants were randomly assigned (1:1) to conventional fractionation (78.0 Gy in 39 fractions, 5 days per week for 8 weeks) or ultra-hypofractionation (42.7 Gy in seven fractions, 3 days per week for 2.5 weeks) via a minimisation algorithm with stratification by trial centre, T-stage, Gleason score, and prostate-specific antigen. QOL was measured using the validated Prostate Cancer Symptom Scale (PCSS) and European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ-C30) at baseline, the end of radiotherapy, months 3, 6, 12, and 24 after radiotherapy, every other year thereafter up to 10 years, and at 15 years. The primary endpoint (failure-free survival) has been reported elsewhere. Here we report QOL, a secondary endpoint analysed in the perprotocol population, up to 6 years after radiotherapy. The HYPO-RT-PC trial is registered with the ISRCTN registry, ISRCTN45905321. Findings Between July 1, 2005, and Nov 4, 2015, 1200 patients were enrolled and 1180 were randomly assigned (conventional fractionation n=591, ultra-hypofractionation n=589); 1165 patients (conventional fractionation n=582, ultra-hypofractionation n=583) were included in this QOL analysis. 158 (71%) of 223 patients in the conventional fractionation group and 146 (66%) of 220 in the ultra-hypofractionation group completed questionnaires at 6 years. The median follow-up was 48 months (IQR 25-72). In seven of ten bowel symptoms or problems the proportion of patients with clinically relevant deteriorations at the end of radiotherapy was significantly higher in the ultra-hypofractionation group than in the conventional fractionation group (stool frequency p&lt;0.0001, rush to toilet p=0.0013, flatulence p=0.0013, bowel cramp p&lt;0.0001, mucus p=0.0014, blood in stool p&lt;0.0001, and limitation in daily activity p=0.0014). There were no statistically significant differences in the proportions of patients with clinically relevant acute urinary symptoms or problems (total 14 items) and sexual functioning between the two treatment groups at end of radiotherapy. Thereafter, there were no clinically relevant differences in urinary, bowel, or sexual functioning between the groups. At the 6-year followup there was no difference in the incidence of clinically relevant deterioration between the groups for overall urinary bother (43 33% of 132 for conventional fractionation vs 33 28% of 120 for ultra-hypofractionation; mean difference 5.1% 95% CI -4.4 to 14.6; p=0.38), overall bowel bother (43 33% of 129 vs 34 28% of 123; 5.7% -3.8 to 15.2; p=0.33), overall sexual bother (75 60% of 126 vs 59 50% of 117; 9.1% -1.4 to 19.6; p=0.15), or global health/QOL (56 42% of 134 vs 46 37% of 125; 5.0% -5.0 to 15.0; p=0.41). Interpretation Although acute toxicity was higher for ultra-hypofractionation than conventional fractionation, this long-term patient-reported QOL analysis shows that ultra-hypofractionation was as well tolerated as conventional fractionation up to 6 years after completion of treatment. These findings support the use of ultra-hypofractionation radiotherapy for intermediate-to-high-risk prostate cancer.
Increasing evidence indicates calcium-binding S100 protein involvement in inflammation and tumor progression. In this prospective study, we evaluated the mRNA levels of two members of this family, ...S100A9 and S100A12, in peripheral blood mononuclear cells (PBMCs) in a cohort of 121 prostate cancer patients using RT-PCR. Furthermore, monocyte count was determined by flow cytometry. By stratifying patients into different risk groups, according to TNM stage, Gleason score and PSA concentration at diagnosis, expression of S100A9 and S100A12 was found to be significantly higher in patients with metastases compared to patients without clinically detectable metastases. In line with this, we observed that the protein levels of S100A9 and S100A12 in plasma were higher in patients with advanced disease. Importantly, in patients with metastases at diagnosis, high monocyte count and high levels of S100A9 and S100A12 were significantly associated with short progression free survival (PFS) after androgen deprivation therapy (ADT). High monocyte count and S100A9 levels were also associated with short cancer-specific survival, with monocyte count providing independent prognostic information. These findings indicate that circulating levels of monocytes, as well as S100A9 and S100A12, could be biomarkers for metastatic prostate cancer associated with particularly poor prognosis.
After cloning of the second estrogen receptor, estrogen receptor beta (ERbeta) in 1996, increasing evidence of its importance in prostate cancer development has been obtained. ERbeta is thought to ...exert an antiproliferative and proapoptotic effect. We examined whether sequence variants in the ERbeta gene are associated with prostate cancer risk.
We conducted a large population-based case-control study (CAncer Prostate in Sweden, CAPS) consisting of 1,415 incident cases of prostate cancer and 801 controls. We evaluated 28 single nucleotide polymorphisms (SNP) spanning the entire ERbeta gene from the promoter to the 3'-untranslated region in 94 subjects of the control group. From this, we constructed gene-specific haplotypes and selected four haplotype-tagging SNPs (htSNP: rs2987983, rs1887994, rs1256040, and rs1256062). These four htSNPs were then genotyped in the total study population of 2,216 subjects.
There was a statistically significant difference in allele frequency between cases and controls for one of the typed htSNPs (rs2987983), 27% in cases and 24% in controls (P = 0.03). Unconditional logistics regression showed an odds ratio of 1.22 (95% confidence interval, 1.02-1.46) for men carrying the variant allele TC or CC versus the wild-type TT, and an odds ratio of 1.33 (95% confidence interval, 1.08-1.64) for localized cancer. No association of prostate cancer risk with any of the other SNPs or with any haplotypes were seen.
We found an association with a SNP located in the promoter region of the ERbeta gene and risk of developing prostate cancer. The biological significance of this finding is unclear, but it supports the hypothesis that sequence variation in the promoter region of ERbeta is of importance for risk of prostate cancer.
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