The Clinical Significance of Bone Mineral Density Changes Following Long-Term Androgen Deprivation Therapy in Localized Prostate Cancer Patients.

PURPOSE: Long-term androgen deprivation therapy has been associated with decreased bone mineral density in men with prostate cancer. Some evidence suggests that there is no impact on fracture risk despite this bone mineral density loss. Our study aimed to quantify changes in bone mineral density in men with high risk prostate cancer on long-term androgen deprivation therapy and calcium and vitamin D supplementation. MATERIALS AND METHODS: Bone mineral density analysis was conducted for localized high risk prostate cancer patients enrolled in the phase III randomized trial PCS-V (Prostate Cancer Study 5), comparing conventional and hypofractionated radiation therapy. Patients received 28 months of luteinizing hormone-releasing hormone agonist and calcium and vitamin D supplementation (500 mg calcium BID+400 IU vitamin D3 BID). The areal density and T-scores (spine, femoral neck and total femur) at baseline and 30 months of followup were extracted, and the absolute change was calculated. Clinical bone density status (normal, osteopenia, osteoporosis) was monitored. RESULTS: The lumbar spine, femoral neck and total femoral bone mineral density were measured for 226, 231, and 173 patients, respectively. The mean percent change in bone mineral density was -2.65%, -2.76% and -4.27% for these respective sites (p <0.001 for all). The average decrease in bone mineral density across all sites was -3.2%, with no decline in bone mineral density category in most patients (83%). Eight patients (4%) became osteoporotic. CONCLUSIONS: Despite a mild decline in bone mineral density, the change in clinical bone mineral density category remained low with long-term androgen deprivation therapy. Consequently, calcium and vitamin D supplementation alone may suffice for most localized prostate cancer patients on long-term androgen deprivation therapy.

Ablative Therapies in Metastatic Breast Cancer: A Systematic Review.

PURPOSE: Patients with oligometastatic breast cancer are being increasingly offered ablative therapies, yet it is unclear which subpopulations may derive long-term benefit. This study sought to explore factors that could define a clinically relevant oligometastatic breast cancer population that benefits from ablative therapies. METHODS: A systematic review using MEDLINE for English language articles published between 1985 and April 2014 was undertaken. Criteria for review included studies that reported overall survival (OS) or progression-free survival (PFS) in breast cancer patients with distant metastases which also: quantified the extent of disease, had metachronous presentation of metastases, and reported on at least 5 patients. RESULTS: Of 59 674 screened studies, 41 studies of 1813 individual patients were identified. All studies were observational cohort studies (level 2B or 4 evidence) and underwent critical review. All outcomes pertaining to OS and PFS were extracted. Extracted data were too heterogeneous to facilitate a meta-analysis. The only factor that suggested worse outcomes was positive margins post-metastasectomy. There was no clear signal for improved outcomes in regards to age, disease extent, disease-free interval, or receptor status. CONCLUSION: Existing evidence does not provide meaningful direction on which metastatic breast cancer patients should have ablation of their residual disease due to heterogeneous reporting of disease factors, patient factors, and outcomes. Thorough demonstration of the absence of high- or moderate-level evidence and the absence of clinical data to guide patient selection suggests that metastatic breast cancer patients being treated with ablative modalities should be placed on clinical trial.

Effectiveness of radiotherapy for local control in T3N0 rectal cancer managed with total mesorectal excision: a meta-analysis.

INTRODUCTION: The total mesorectal excision (TME) significantly improved rectal cancer outcomes. Radiotherapy's benefit in T3N0 rectal cancer patients managed with TME has not been clearly demonstrated. A systematic review and meta-analysis were undertaken to determine whether radiotherapy altered the risk of locoregional recurrence (LR) in T3N0 rectal cancer patients managed with a TME. MATERIALS AND METHODS: Studies indexed on PubMed or Embase were systematically searched from inception to October 18, 2020. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were observed for the literature search, study screening, and data extraction; the Newcastle Ottawa Scale evaluated bias; Grades of Recommendation, Assessment, Development, and Evaluation Working Group system evaluated certainty; and all were performed independently by at least two investigators. Studies that reported LR data specific to T3N0 rectal cancer patients managed with TME, treated with and without radiotherapy, were included. Data was pooled using a random-effects model. Meta-analyses of the relative risk of local recurrence were conducted. RESULTS: Five retrospective cohort studies involving 932 unique patients reported LR outcomes; no prospective studies met eligibility criteria. Median follow-up ranged from 38.4-78 months. Adjuvant radiotherapy was provided in 3 studies. Chemotherapy was delivered and reported in 4 studies, providing both concurrent and adjuvant chemotherapy. A non-significant LR reduction with radiotherapy alongside TME was estimated, mean relative risk (RR) 0.63 (95% Confidence Interval 0.31-1.29; I2 = 41.8%). CONCLUSIONS: A non-significant LR benefit with radiotherapy's addition was estimated. Meta-analysis of exclusively retrospective cohort studies was concerning for biased results. Adequately powered randomized trials are warranted.

Combined Long-Term Androgen Deprivation and Pelvic Radiotherapy in the Post-operative Management of Pathologically Defined High-Risk Prostate Cancer Patients: Results of the Prospective Phase II McGill 0913 Study.

Purpose: Following radical prostatectomy, prostate bed radiotherapy (PBRT) has been combined with either long-term androgen deprivation therapy (LT-ADT) or short-term ADT with pelvic lymph node radiotherapy (PLNRT) to provide an oncological benefit in randomized trials. McGill 0913 was designed to characterize the efficacy of combining PBRT, PLNRT, and LT-ADT. It is the first study to do so prospectively. Methods: In a single arm phase II trial conduced from 2010 to 2016, 46 post-prostatectomy prostate cancer patients at a high-risk for relapse (pathological Gleason 8+ or T3) were assessed for treatment with combined LT-ADT (24 months), PBRT, and PLNRT. Patients received PLNRT and PBRT (44 Gy in 22 fractions) followed by a PBRT boost (22 Gy in 11 fractions). The primary endpoint was progression-free survival (PFS). Toxicity and quality of life (QoL) were evaluated using CTCAE V3.0 and EQ-5D-3L questionnaires, respectively. Results: Among the 43 patients were treated as per protocol, median PSA was 0.30 µg/L. On surgical pathology, 51% had positive margins, 40% had Gleason 8+ disease, 42% had seminal vesicle involvement, and 19% had lymph node involvement. At a median follow-up of 5.2 years, there were no deaths or clinical progression. At 5 years, PFS was 78.0% (95% Confidence Interval 63.7-95.5%). Not including erectile dysfunction, patients experienced: 14% grade 2 endocrine toxicity while on ADT, one incident of long-term gynecomastia, 5% grade 2 acute urinary toxicity, 5% grade 2 late Urinary toxicity, and 24% long-term hypogonadism. No comparison between the average or minimum self-reported QoL at baseline, during ADT, nor after ADT demonstrated a statistically significant difference. Conclusions: Combining PBRT, PLNRT, and LT-ADT had an acceptable PFS in patients with significant post-operative risk factors for recurrence. While therapy was well-tolerated, long-term hypogonadism was a substantial risk. Further investigations are needed to determine if this combination is beneficial. Trial registration: NCT01255891.

The Biology of Oligometastatic Prostate Cancer: A Different Beast than Polymetastatic Prostate Cancer.

The natural history and molecular biology of oligometastatic prostate cancer differentiate it from polymetastatic disease. Clinically, oligometastatic disease is also predictive and prognostic for different outcomes. Studies specific to this population are required to establish the benefits of intervention.

Radiomics in Glioblastoma: Current Status and Challenges Facing Clinical Implementation.

Radiomics analysis has had remarkable progress along with advances in medical imaging, most notability in central nervous system malignancies. Radiomics refers to the extraction of a large number of quantitative features that describe the intensity, texture and geometrical characteristics attributed to the tumor radiographic data. These features have been used to build predictive models for diagnosis, prognosis, and therapeutic response. Such models are being combined with clinical, biological, genetics and proteomic features to enhance reproducibility. Broadly, the four steps necessary for radiomic analysis are: (1) image acquisition, (2) segmentation or labeling, (3) feature extraction, and (4) statistical analysis. Major methodological challenges remain prior to clinical implementation. Essential steps include: adoption of an optimized standard imaging process, establishing a common criterion for performing segmentation, fully automated extraction of radiomic features without redundancy, and robust statistical modeling validated in the prospective setting. This review walks through these steps in detail, as it pertains to high grade gliomas. The impact on precision medicine will be discussed, as well as the challenges facing clinical implementation of radiomic in the current management of glioblastoma.

Does Interfraction Cone Beam Computed Tomography Improve Target Localization in Prostate Bed Radiotherapy?

PURPOSE: In this prospective phase II study, we investigated whether cone beam computed tomography scan was a superior method of image-guided radiotherapy relative to 2D orthogonal kilovoltage images in the post-radical prostatectomy setting. METHODS: A total of 419 treatment fractions were included in this analysis. The shifts required to align the patient for each treatment were performed using 3D matching between cone beam computed tomography scans and the corresponding computed tomography images used for planning. This was compared with the shifts obtained from 2D orthogonal kilovoltage images, matching with the corresponding digitally reconstructed radiographs. Patients did not have fiducials inserted to assist with localization. Interfractional changes in the bladder and rectal volumes were subsequently measured on the cone beam computed tomography images for each fraction and compared to the shift differences between orthogonal kilovoltage and cone beam computed tomography scans. The proportion of treatment fractions with a shift difference exceeding the planning target volume of 7 mm, between orthogonal kilovoltage and cone beam computed tomography scans, was calculated. RESULTS: The mean vertical, lateral, and longitudinal shifts resulted from 2D match between orthogonal kilovoltage images and corresponding digitally reconstructed radiographs were 0.353 cm (interquartile range: 0.1-0.5), 0.346 cm (interquartile range: 0.1-0.5), and 0.289 cm (interquartile range: 0.1-0.4), compared to 0.388 cm (interquartile range: 0.1-0.5), 0.342 cm (interquartile range: 0.1-0.5), and 0.291 cm (interquartile range: 0.1-0.4) obtained from 3D match between cone beam computed tomography and planning computed tomography scan, respectively. Our results show a significant difference between the kilovoltage and cone beam computed tomography shifts in the anterior-posterior direction ( P = .01). The proportion of treatment fractions in which the differences in kilovoltage and cone beam computed tomography shifts between exceeded the 7 mm planning target volume margin was 6%, 2%, and 3% in the anterior-posterior, lateral, and superior-inferior directions, respectively. CONCLUSION: We prospectively demonstrated that the daily use of volumetric cone beam computed tomography for treatment localization in post-radical prostatectomy patients demonstrated an increased need for a shift in patient position. This suggests that in post-radical prostatectomy patients the daily cone beam computed tomography imaging improved localization of the prostate bed and may have prevented a limited number of geographic misses, compared to daily kilovoltage imaging that was not assisted with fiducials.

Evaluation of pseudoprogression in patients with glioblastoma.

BACKGROUND: Management of glioblastoma is complicated by pseudoprogression, a radiological phenomenon mimicking progression. This retrospective cohort study investigated the incidence, prognostic implications, and most clinically appropriate definition of pseudoprogression. METHODS: Consecutive glioblastoma patients treated at the Juravinski Hospital and Cancer Centre, Hamilton, Ontario between 2004 and 2012 with temozolomide chemoradiotherapy and with contrast-enhanced MRI at standard imaging intervals were included. At each imaging interval, patient responses as per the RECIST (Response Evaluation Criteria in Solid Tumors), MacDonald, and RANO (Response Assessment in Neuro-Oncology) criteria were reported. Based on each set of criteria, subjects were classified as having disease response, stable disease, pseudoprogression, or true progression. The primary outcome was overall survival. RESULTS: The incidence of pseudoprogression among 130 glioblastoma patients treated with chemoradiotherapy was 15%, 19%, and 23% as defined by RANO, MacDonald, and RECIST criteria, respectively. Using the RANO definition, median survival for patients with pseudoprogression was 13.0 months compared with 12.5 months for patients with stable disease (hazard ratio [HR]=0.70; 95% confidence interval [CI], 0.35-1.42). Similarly, using the MacDonald definition, median survival for the pseudoprogression group was 11.8 months compared with 12.0 months for the stable disease group (HR=0.86; 95% CI, 0.47-1.58). Furthermore, disease response compared with stable disease was also similar using the RANO (HR=0.52; 95% CI, 0.20-1.35) and MacDonald (HR=0.51: 95% CI, 0.20-1.31) definitions. CONCLUSIONS: Of all conventional glioblastoma response criteria, the RANO criteria gave the lowest incidence of pseudoprogression. Regardless of criteria, patients with pseudoprogression did not have statistically significant difference in survival compared with patients with stable disease.