Aims
Perineural invasion (PNI) by prostatic adenocarcinoma is debated as a prognostic parameter. This study investigates the prognostic predictive value of PNI in a series of patients with locally ...advanced prostate cancer treated with radiotherapy and androgen deprivation using 10 years outcome data from the TROG 03.04 RADAR trial.
Methods
Diagnostic prostate biopsies from 976 patients were reviewed and the presence of PNI noted. Patients were followed for 10 years according to the trial protocol or until death. The primary endpoint for the study was time to bone metastasis. Secondary endpoints included time to soft tissue metastasis, transition to castration resistance, prostate cancer‐specific mortality and all‐cause mortality.
Results
PNI was detected in 449 cases (46%), with 234 cases (24%) having PNI in more than one core. The presence of PNI was significantly associated with higher ISUP grade, clinical T staging category, National Comprehensive Cancer Network risk group, and percent positive biopsy cores. The cumulative probability of bone metastases according to PNI status was significant over the 10 years follow‐up interval of the study (log‐rank test P < 0.0001). PNI was associated with all endpoints on univariable analysis. After adjusting for baseline clinicopathological and treatment factors, bone metastasis was the only endpoint in which PNI retained its prognostic significance (hazard ratio 1.42, 95% confidence interval 1.05–1.92, P = 0.021).
Conclusions
The association between PNI and the development of bone metastases supports the inclusion of this parameter as a component of the routine histology report. Further this association suggests that evaluation of PNI may assist in selecting those patients who should be monitored more closely during follow‐up.
Radiotherapeutic normal tissue injury can be viewed as two simultaneously ongoing and interacting processes. The first has many features in common with the healing of traumatic wounds. The second is ...a set of transient or permanent alterations of cellular and extracellular components within the irradiated volume. In contrast to physical trauma, fractionated radiation therapy produces a series of repeated insults to tissues that undergo significant changes during the course of radiotherapy. Normal tissue responses are also influenced by rate of dose accumulation and other factors that relate to the radiation therapy schedule. This article reviews the principles of organised normal tissue responses during and after radiation therapy, the effect of radiation therapy on these responses, as well as some of the mechanisms underlying the development of recognisable injury. Important clinical implications relevant to these processes are also discussed.
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%).
In 2014 a consensus conference convened by the International Society of Urological Pathology (ISUP) adopted amendments to the criteria for Gleason grading and scoring (GS) for prostatic ...adenocarcinoma. The meeting defined a modified grading system based on 5 grading categories (grade 1, GS 3+3; grade 2, GS 3+4; grade 3, GS 4+3; grade 4, GS 8; grade 5, GS 9–10). In this study we have evaluated the prognostic significance of ISUP grading in 496 patients enrolled in the TROG 03.04 RADAR Trial. There were 19 grade 1, 118 grade 2, 193 grade 3, 88 grade 4 and 79 grade 5 tumours in the series, with follow-up for a minimum of 6.5 years. On follow-up 76 patients experienced distant progression of disease, 171 prostate specific antigen (PSA) progression and 39 prostate cancer deaths. In contrast to the 2005 modified Gleason system (MGS), the hazards of the distant and PSA progression endpoints, relative to grade 2, were significantly greater for grades 3, 4 and 5 of the 2014 ISUP grading scheme. Comparison of predictive ability utilising Harrell’s concordance index, showed 2014 ISUP grading to significantly out-perform 2005 MGS grading for each of the three clinical endpoints.
Fatigue is commonly reported in patients receiving radiotherapy for breast conservation, but the underlying mechanisms remain unclear.
Patients with early breast cancer participating in a prospective ...study of the impact of inflammatory processes on early and delayed breast morbidity were assessed for fatigue levels using the Functional Assessment of Cancer Therapy (FACT) fatigue subscale before and at intervals during and after radiotherapy. Blood for analysis of a variety of circulating cytokines, coagulation factors, peripheral blood indices and biochemical factors was collected at the same time points.
Fifty-two eligible patients were assessed. Twenty-one patients (43%) developed significant fatigue during radiotherapy, whereas 28 (54%) developed minimal or no fatigue. Fatigue appeared to plateau between week 4 of treatment and 2 weeks after treatment. The fatigue was beginning to settle by 6 weeks after treatment. Significant fatigue was predicted by a higher baseline fatigue score, red cell count, neutrophil count, and
D-dimer level. Baseline fatigue correlated with higher body mass index, C-reactive protein, soluble thrombomodulin, tissue plasminogen activator, von Willebrand factor antigen, interleukin-6, ICAM-1, hemoglobin and red cell, monocyte, and neutrophil counts. There were also significant correlations between body mass index and tissue plasminogen activator, C-reactive protein, interleukin-6, ICAM-1, and red cell count. After these factors were controlled for, baseline fatigue was seen to be associated with higher body mass index, soluble thrombomodulin, tissue plasminogen activator, von Willebrand factor antigen, monocyte count, and neutrophil count. Multiple logistic regression procedures indicated that the most predictive factors for fatigue during radiotherapy were higher baseline fatigue level and higher baseline neutrophil and red cell counts.
This study has shown that significant fatigue is common in patients receiving breast irradiation and is precipitated during radiotherapy in some patients but not others. The factors shown to be associated with fatigue in this study will be helpful in shaping future studies.
The optimal duration of androgen suppression for men with locally advanced prostate cancer receiving radiotherapy with curative intent is yet to be defined. Zoledronic acid is effective in preventing ...androgen suppression-induced bone loss, but its role in preventing castration-sensitive bone metastases in locally advanced prostate cancer is unclear. The RADAR trial assessed whether the addition of 12 months of adjuvant androgen suppression, 18 months of zoledronic acid, or both, can improve outcomes in men with locally advanced prostate cancer who receive 6 months of androgen suppression and prostatic radiotherapy. This report presents 10-year outcomes from this trial.
For this randomised, phase 3, 2 × 2 factorial trial, eligible men were 18 years or older with locally advanced prostate cancer (either T2b-4, N0 M0 tumours or T2a, N0 M0 tumours provided Gleason score was ≥7 and baseline prostate-specific antigen PSA concentration was ≥10 μg/L). We randomly allocated participants in a 2 × 2 factorial design by computer-generated randomisation (using the minimisation technique, and stratified by centre, baseline PSA concentration, clinical tumour stage, Gleason score, and use of a brachytherapy boost) in a 1:1:1:1 ratio to four treatment groups. Patients in the control group received 6 months of neoadjuvant androgen suppression with leuprorelin (22·5 mg every 3 months, intramuscularly) and radiotherapy alone (short-term androgen suppression STAS); this treatment was either followed by another 12 months of adjuvant androgen suppression with leuprorelin (22·5 mg every 3 months, intramuscularly; intermediate-term androgen suppression ITAS), or accompanied by 18 months of zoledronic acid (4 mg every 3 months, intravenously) starting at randomisation (STAS plus zoledronic acid), or both (ITAS plus zoledronic acid). All patients received radiotherapy to the prostate and seminal vesicles, starting from the end of the fifth month of androgen suppression; dosing options were 66, 70, and 74 Gy in 2-Gy fractions per day, or 46 Gy in 2-Gy fractions followed by a high-dose-rate brachytherapy boost dose of 19·5 Gy in 6·5-Gy fractions. Treatment allocation was open label. The primary endpoint was prostate cancer-specific mortality and was analysed according to intention-to-treat using competing-risks methods. The trial is closed to follow-up and this is the final report of the main endpoints. This trial is registered with ClinicalTrials.gov, number NCT00193856.
Between Oct 20, 2003, and Aug 15, 2007, 1071 men were enrolled and randomly assigned to STAS (n=268), ITAS (n=268), STAS plus zoledronic acid (n=268), and ITAS plus zoledronic acid (n=267). Median follow-up was 10·4 years (IQR 7·9–11·7). At this 10-year follow-up, no interactions were observed between androgen suppression and zoledronic acid so the treatment groups were collapsed to compare treatments according to duration of androgen suppression: 6 months of androgen suppression plus radiotherapy (6AS+RT) versus 18 months of androgen suppression plus radiotherapy (18AS+RT) and to compare treatments according to whether or not patients received zoledronic acid. The total number of deaths was 375 (200 men receiving 6AS+RT and 175 men receiving 18AS+RT), of which 143 (38%) were attributable to prostate cancer (81 men receiving 6AS+RT and 62 men receiving 18AS+RT). When analysed by duration of androgen suppression, the adjusted cumulative incidence of prostate cancer-specific mortality was 13·3% (95% CI 10·3–16·0) for 6AS+RT versus 9·7% (7·3–12·0) for 18AS+RT, representing an absolute difference of 3·7% (95% CI 0·3–7·1; sub-hazard ratio sHR 0·70 95% CI 0·50–0·98, adjusted p=0·035). The addition of zoledronic acid did not affect prostate cancer-specific mortality; the adjusted cumulative incidence of prostate cancer-specific mortality was 11·2% (95% CI 8·7–13·7) with zoledronic acid vs 11·7% (9·2–14·1) without, representing an absolute difference of −0·5% (95% CI −3·8 to 2·9; sHR 0·95 95% CI 0·69–1·32, adjusted p=0·78). Although safety analysis was not prespecified for this 10-year analysis, one new serious adverse event (osteonecrosis of the mandible, in a patient who received 18 months of androgen suppression plus zoledronic acid) occurred since our previous report, bringing the total number of cases of this serious adverse event to three (<1% out of 530 patients who received zoledronic acid evaluated for safety) and the total number of drug-related serious adverse events to 12 (1% out of all 1065 patients evaluable for safety). No treatment-related deaths occurred during the study.
18 months of androgen suppression plus radiotherapy is a more effective treatment option for locally advanced prostate cancer than 6 months of androgen suppression plus radiotherapy, but the addition of zoledronic acid to this treatment regimen is not beneficial. Evidence from the RADAR and French Canadian Prostate Cancer Study IV trials suggests that 18 months of androgen suppression with moderate radiation dose escalation is an effective but more tolerable option than longer durations of androgen suppression for men with locally advanced prostate cancer including intermediate and high risk elements.
National Health and Medical Research Council of Australia, Novartis Pharmaceuticals Australia, AbbVie Pharmaceuticals Australia, New Zealand Health Research Council, New Zealand Cancer Society, Cancer Standards Institute New Zealand, University of Newcastle (Australia), Hunter Medical Research Institute, Calvary Mater Newcastle Radiation Oncology Fund, and Maitland Cancer Appeal.
To describe the prevalence, severity and nature of depression in a sample of prostate cancer (PCa) survivors 10 years after diagnosis and treatment, 146 Australian patients from the RADAR trial who ...received their diagnosis 10 years previously completed the Zung Self‐rating Depression Scale and a background questionnaire. Prevalence rates for clinically significant depression and severe depression were higher than those reported for the non‐PCa men of the same age in Australia. The most common subtype of depression was Anhedonia, followed by Cognitive depression. Change in eating habits was the most powerful depression symptom predicting Anhedonia. By providing the first detailed documentation of major depression prevalence in PCa survivors, plus describing the nature of that depression, these data suggest that there is an ongoing need to provide treatments for these men and that those treatments should be focussed upon loss of previously available sources of enjoyment.
Despite clear guideline recommendations for initiating four drug classes in all patients with heart failure (HF) with reduced ejection fraction (HFrEF) and the availability of rapid titration ...schemes, information on real-world implementation lags behind. Closely following the 2021 ESC HF guidelines and 2023 focused update, the TITRATE-HF study started to prospectively investigate the use, sequencing, and titration of guideline-directed medical therapy (GDMT) in HF patients, including the identification of implementation barriers.
TITRATE-HF is an ongoing long-term HF registry conducted in the Netherlands. Overall, 4288 patients from 48 hospitals were included. Among these patients, 1732 presented with de novo, 2240 with chronic, and 316 with worsening HF. The median age was 71 years (interquartile range IQR 63-78), 29% were female, and median ejection fraction was 35% (IQR 25-40). In total, 44% of chronic and worsening HFrEF patients were prescribed quadruple therapy. However, only 1% of HFrEF patients achieved target dose for all drug classes. In addition, quadruple therapy was more often prescribed to patients treated in a dedicated HF outpatient clinic as compared to a general cardiology outpatient clinic. In each GDMT drug class, 19% to 36% of non-use in HFrEF patients was related to side-effects, intolerances, or contraindications. In the de novo HF cohort, 49% of patients already used one or more GDMT drug classes for other indications than HF.
This first analysis of the TITRATE-HF study reports relatively high use of GDMT in a contemporary HF cohort, while still showing room for improvement regarding quadruple therapy. Importantly, the use and dose of GDMT were suboptimal, with the reasons often remaining unclear. This underscores the urgency for further optimization of GDMT and implementation strategies within HF management.
Highlights • NTCP models were developed for stool frequency/rectal pain after 3DCRT. • A pooled population was investigated. • More than 1000 patients enrolled. • Significant association with large ...volume receiving medium doses was found. • Cardiovascular disease was a risk factor for stool frequency.
Traditionally rectal symptoms following pelvic/prostate radiotherapy are correlated to the dosimetry of the anorectum or a substructure of this. It has been suggested that the perirectal fat space ...(PRS) surrounding the rectum may also be relevant. This study considers the delineation and dosimetry of the PRS related to both rectal bleeding and control-related toxicity. Initially, a case–control cohort of 100 patients from the RADAR study were chosen based on presence/absence of rectal control-related toxicity. Automated contouring was developed to delineate the PRS. 79 of the 100 auto-segmentations were considered successful. Balanced case–control cohorts were defined from these cases. Atlas of Complication Incidence (ACI) were generated to relate the DVH of the PRS with specific rectal symptoms; rectal bleeding and control-related symptoms (LENT/SOM). ACI demonstrated that control-related symptoms were related to the dose distribution to the PRS which was confirmed with Wilcoxon rank sum test (p < 0.05). To the authors knowledge this is the first study implicating the dose distribution to the PRS to the incidence of control-related symptoms of rectal toxicity.
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