Redefining precision radiotherapy through liquid biopsy.

Precision radiotherapy refers to the ability to deliver radiation doses with sub-millimetre accuracy. It does not however consider individual variation in tumour or normal tissue response, failing to maximise tumour control and minimise toxicity. Combining precise delivery with personalised dosing, through analysis of cell-free DNA, would redefine precision in radiotherapy.

Acute Toxicity of Hypofractionated and Conventionally Fractionated (Chemo)Radiotherapy Regimens for Bladder Cancer: An Exploratory Analysis from the RAIDER Trial.

AIMS: Adding concurrent (chemo)therapy to radiotherapy improves outcomes for muscle-invasive bladder cancer patients. A recent meta-analysis showed superior invasive locoregional disease control for a hypofractionated 55 Gy in 20 fractions schedule compared with 64 Gy in 32 fractions. In the RAIDER clinical trial, patients undergoing 20 or 32 fractions of radical radiotherapy were randomised (1:1:2) to standard radiotherapy or to standard-dose or escalated-dose adaptive radiotherapy. Neoadjuvant chemotherapy and concomitant therapy were permitted. We report exploratory analyses of acute toxicity by concomitant therapy-fractionation schedule combination. MATERIALS AND METHODS: Participants had unifocal bladder urothelial carcinoma staged T2-T4a N0 M0. Acute toxicity was assessed (Common Terminology Criteria for Adverse Events) weekly during radiotherapy and at 10 weeks after the start of treatment. Within each fractionation cohort, non-randomised comparisons of the proportion of patients reporting treatment emergent grade 2 or worse genitourinary, gastrointestinal or other adverse events at any point in the acute period were carried out using Fisher's exact tests. RESULTS: Between September 2015 and April 2020, 345 (163 receiving 20 fractions; 182 receiving 32 fractions) patients were recruited from 46 centres. The median age was 73 years; 49% received neoadjuvant chemotherapy; 71% received concomitant therapy, with 5-fluorouracil/mitomycin C most commonly used: 44/114 (39%) receiving 20 fractions; 94/130 (72%) receiving 32 fractions. The acute grade 2+ gastrointestinal toxicity rate was higher in those receiving concomitant therapy compared with radiotherapy alone in the 20-fraction cohort [54/111 (49%) versus 7/49 (14%), P < 0.001] but not in the 32-fraction cohort (P = 0.355). Grade 2+ gastrointestinal toxicity was highest for gemcitabine, with evidence of significant differences across therapies in the 32-fraction cohort (P = 0.006), with a similar pattern but no significant differences in the 20-fraction cohort (P = 0.099). There was no evidence of differences in grade 2+ genitourinary toxicity between concomitant therapies in either the 20- or 32-fraction cohorts. CONCLUSION: Grade 2+ acute adverse events are common. The toxicity profile varied by type of concomitant therapy; the gastrointestinal toxicity rate seemed to be higher in patients receiving gemcitabine.

Clinically relevant fatigue in recurrence-free prostate cancer survivors.

BACKGROUND: Little is known about the prevalence and associations of clinically relevant fatigue (CRF) in recurrence-free prostate cancer survivors. PATIENTS AND METHODS: Four hundred and sixteen recurrence-free prostate cancer survivors who were >1 year post-radiotherapy or radical prostatectomy were surveyed. The prevalence of CRF (defined as Brief Fatigue Inventory >3) was determined and compared with a noncancer control group. Other measures included the Hospital Anxiety and Depression Scale, International Prostate Symptom Score, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire. Relationships between these factors and CRF were explored in univariate and multivariate analyses. RESULTS: Analyzable data were obtained from 91% (377/416) of patients. The prevalence of CRF was 29% (108/377) versus 16% (10/63) in the controls (P=0.031). CRF was more common in post-radiotherapy than in post-prostatectomy 33% (79/240) versus 22% (29/133), P=0.024. However, when other factors (current depression, anxiety, urinary symptoms, medical comorbidities, pain and insomnia) were controlled for, previous treatment did not predict CRF. Current depression [Hospital Anxiety and Depression Scale≥8 was by far the strongest association [odds ratio 9.9, 95% confidence interval 4.2-23.5)]. CONCLUSIONS: Almost one-third of recurrence-free prostate cancer survivors report CRF. Depression, anxiety, urinary symptoms, pain and insomnia measured at outcome are more strongly associated than type of cancer treatment previously received.

Clinically relevant fatigue in men with hormone-sensitive prostate cancer on long-term androgen deprivation therapy.

BACKGROUND: The purpose of the study was to determine the prevalence and associations of clinically relevant fatigue (CRF) in men with biochemically controlled prostate cancer on long-term androgen deprivation therapy (ADT). PATIENTS AND METHODS: One hundred and ninety-eight men were surveyed and the prevalence of CRF (Brief Fatigue Inventory score >3) determined. Associations with other measures (Hospital Anxiety and Depression Scale; International Prostate Symptom Score; European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire; Brief Pain Inventory worst pain; clinical and demographic information) were explored in univariate and multivariate analyses. RESULTS: Eight-one per cent (160 of 198) of questionnaires were analysable. CRF prevalence was 43% (68 of 160). CRF associations included moderate/severe urinary symptoms, anxiety and medical co-morbidities; the strongest associations were depression [odds ratio (OR) 9.8, 95% confidence interval (CI) 4.3-22.8] and pain (OR 9.2, 95% CI 4.0-21.5). After controlling for other factors, the independent associations were depression (OR 4.7, 95% CI 1.6-14.0) and pain (OR 3.1, 95% CI 1.0-8.9). There was no association with age, disease burden or treatment duration. CONCLUSIONS: Two-fifths of men with biochemically controlled prostate cancer on long-term ADT report CRF that interferes with function. Management aimed at improving CRF should address depression and pain.

Defining Biochemical Cure After Low Dose Rate Prostate Brachytherapy: External Validation of 4-year Prostate-specific Antigen Nadir as a Predictor of 10- and 15-year Disease-free Survival.

AIMS: To externally validate a proposed biochemical definition of cure following low dose rate (LDR) brachytherapy for prostate cancer - 4-year post-implant prostate-specific antigen (PSA) ≤0.2 ng/ml - in a UK population, and report the long-term (10- and 15-year) outcomes for patients stratified by National Comprehensive Cancer Network (NCCN) risk groups, through analysis of a large, prospectively collected, single-centre database. MATERIALS AND METHODS: All patients treated with LDR brachytherapy for prostate cancer at a single UK centre between 2001 and November 2020 (n = 1142) were eligible; 632 patients met the inclusion criteria for the analysis. The primary end point was disease-free survival (DFS), defined as freedom from clinical, radiological or PSA progression requiring androgen deprivation therapy. Four-year PSA was categorised as ≤0.2, >0.2 to ≤0.5, >0.5 to ≤1.0 and >1.0 ng/ml. Kaplan-Meier analysis to 15 years was undertaken for each group, and sensitivity and specificity of 4-year PSA as a surrogate for long-term cure were calculated. Kaplan-Meier analysis to 15 years was repeated, stratifying patients by NCCN risk groups. RESULTS: The median cohort age was 63 years; the median follow-up was 9.1 years (range 3.5-18.7). In total, 248 patients were available for analysis at year 10, 46 at year 15. Sixty-four patients (10.1%) relapsed during the study period. The 10-year DFS for 4-year PSA categories ≤0.2, >0.2 to ≤0.5, >0.5 to ≤1.0 and >1.0 ng/ml (95% confidence intervals) were 97.5% (95.4-99.6), 89.0% (82.4-96.1), 81.5% (70.5-94.2) and 41.8% (29.7-58.9), respectively. The 10-year DFS results for NCCN low, favourable-intermediate and unfavourable-intermediate risk disease were 93.1% (89.6-96.7), 92.1% (87.6-96.9) and 75.9% (67.8-84.9), respectively. CONCLUSIONS: Patients with 4-year PSA ≤0.2 ng/ml may be considered cured, and could be discharged to general practitioner follow-up. LDR brachytherapy is an excellent treatment option for patients with low and favourable-intermediate risk prostate cancer, but those with unfavourable-intermediate risk disease should be considered for treatment intensification strategies.

Neoadjuvant chemotherapy in transitional-cell carcinoma of the bladder.

Neoadjuvant chemotherapy in transitional-cell carcinoma of the bladder (TCC) improves survival. This is one of the most important developments in the management of muscle-invasive bladder cancer in recent times. There is an improved absolute 5-year survival of at least 5% for T2-T4 disease. To achieve this benefit, a cisplatin-containing combination is required. There is no difference in survival whether radical radiotherapy or radical cystectomy is given as subsequent definitive treatment.

Testicular sex cord-stromal tumours: the Edinburgh experience 1988-2002, and a review of the literature.

AIMS: Sex cord-stromal tumours of the testis are uncommon tumours, accounting for around 5% of testicular neoplasms. Treatment is primarily surgical, with no adjuvant therapy of proven benefit. We present a single-centre experience over a period of 15 years. MATERIALS AND METHODS: From 1988 to 2002, 18 patients with a diagnosis of sex cord-stromal tumour were referred to our centre. A retrospective analysis of their case notes was made and a pathological review undertaken. RESULTS: Sixteen were Leydig-cell tumours and two were Sertoli cell. For the Leydig-cell tumours, the median age at presentation was 42 years, 50% presented with a testicular mass and 31% with gynaecomastia. Two patients followed a malignant course: one revealing disease dissemination at initial staging, and a second 12 months after potentially curative orchidectomy. Salvage retroperitoneal lymphadenectomy in the latter patient proved unsuccessful. Clinical outcome correlated strongly with the presence of adverse pathological features described previously in the literature. After a median follow-up of 46 months, two patients have developed progressive disease, and two patients have died, one of metastatic Leydig-cell tumour. No patient defined as being of low malignant potential on pathological examination has relapsed outside our review period of 2 years. CONCLUSION: We confirm the overall excellent prognosis for most of the patients with sex cord-stromal tumours of the testis. Compared with most previous reports, pathological features seem to predict with reasonable accuracy the risk of malignant behaviour, and can adequately inform the subsequent review policy.

The management and outcome of patients with germ-cell tumours treated in the Edinburgh Cancer Centre between 1988 and 2002.

AIMS: The aim of this retrospective analysis was to review the outcome of patients with germ-cell tumours treated in the Edinburgh Cancer Centre over the past 15 years, and to see whether there had been any changes over three 5-year cohorts. MATERIALS AND METHODS: Patients referred with gonadal and extra-gonadal primary germ-cell tumours, between 1988 and 2002, were identified from the departmental database, and survival by stage and prognostic group was analysed. RESULTS AND CONCLUSIONS: The proportion of patients with stage I seminoma has significantly increased. The good prognosis of patients with early stage disease is confirmed, with the outcome for some groups of patients being better than expected. There is a non-significant trend to improved results over the three 5-year cohorts. The outcome for patients with stage IV seminoma is worse than would be expected, but numbers are small. The poor prognosis of patients with non-seminomatous germ-cell tumours who fall into the International Germ Cell Consensus Classification (IGCCC) poor-prognostic group is confirmed. Failure of patients with metastatic non-seminomatous germ-cell tumours to achieve a complete response to initial therapy is shown to be a poor prognostic indicator.

The Importance of Prostate-specific Antigen (PSA) Nadir and Early Identification of PSA Relapse after 10 Years of Prostate Iodine 125 Seed Brachytherapy in Edinburgh.

AIMS: To analyse our 5 and 10 year prostate brachytherapy outcome data and to assess the impact of PSA nadir on relapse free survival and whether an alternative definition of PSA relapse could detect men destined to fail by the Phoenix definition at an earlier time point. MATERIALS AND METHODS: 474 men were treated over a 10 year period between 20012 and 2011 and divided into 2 five year cohorts for the purpose of the analysis. RESULTS: The risk of relapse is strongly predicted by post treat prostate-specific antigen (PSA) nadir. After 3 years post-treatment, PSA nadir plus 0.4 ng/ml identified men at risk of relapse 17 months earlier than the Phoenix definition. CONCLUSION: The Phoenix definition of nadir plus 2.0 ng/ml does not allow the early identification of men destined to relapse. The initiation of salavage therapy at the earliest opportunity could potentially affect subsequent survival and an outline randomised controlled trial proposal is presented.

Hypofractionated radiotherapy for muscle invasive bladder cancer in the elderly.

BACKGROUND AND PURPOSE: We have retrospectively investigated a hypofractionated regimen in a cohort of 65 elderly patients (median age 78 years), designed to minimise acute radiation affects and maximise patient tolerance and convenience in this frail group. MATERIALS AND METHODS: All patients were CT planned to a small volume. Once weekly fractions (6 Gy) prescribed to the 100% isodose as a target minimum to 30 Gy (n = 53) and 36 Gy (n = 12) were administered. Palliation of symptoms before, during, and 1 month from completion of radiotherapy were graded using the urinary and bowel symptom and toxicity index. RESULTS: Fifty-five patients had persisting urinary symptoms following trans urethral resection of bladder. Twenty-eight (51%) were completely palliated of symptoms and 7 (13%) noticed an improvement at a 1 month review. Ninety-two percent of patients with haematuria were completely palliated compared to only 24% of those with dysuria and frequency. The median symptom free interval was 7 months (range 2-40months). Median overall survival was 9 months (range 2-41months). Twelve percent of patients required inpatient admission and only three failed to complete the prescribed course due to bowel toxicity. Grade 3 acute urinary and bowel treatment related toxicity, were recorded in 18% and 9% of patients, respectively. In total, 43% of patients noticed a transient worsening of their presenting symptoms on treatment. To date no significant late toxicity (>grade 2) has been recorded. CONCLUSIONS: This regimen is generally well tolerated and offers reasonable palliation of symptoms on an outpatient basis for this frail poor prognosis group. Haematuria is particularly well palliated although only a quarter of patients presenting with dysuria and frequency were rendered symptom free.

Impact of nicotinamide on human tumour hypoxic fraction measured using the comet assay.

BACKGROUND AND PURPOSE: Nicotinamide has been shown to reduce hypoxia in experimental tumours, but there are no data that measure the hypoxic fraction at the time of irradiation in humans. This study investigates whether nicotinamide with radiation can reduce human tumour hypoxia. MATERIALS AND METHODS: Twenty-two patients undergoing palliative radiotherapy for treatment of accessible metastatic tumours were exposed to two doses of radiation (3.5-8 Gy, median 6 Gy) separated by 1-6 days. Directly on completion of the first dose, two fine needle aspirate biopsies (FNAB) were taken and analyzed for hypoxic fraction using the alkaline comet assay. On the second day of radiation, 13 patients were given 80 mg/kg nicotinamide post-operatively on an empty stomach 2 h before treatment; the remaining nine patients acted as controls. A second comparative pair of aspirates were obtained immediately on completion of the second fraction. RESULTS: Sixteen tumours were suitable for analysis (nine nicotinamide and seven controls). Marked inter-tumour variations in hypoxic fraction were noted (0-67%). Both nicotinamide treated tumours and controls demonstrated a significant increase in the percentage of cells containing heavily damaged DNA following the second dose of radiation (P = 0.01). A significant reduction in mean hypoxic fraction after the second radiation treatment was noted (22 to 13%, P = 0.04). This reduction was predominantly due to the nicotinamide treated group, where mean hypoxic fraction fell from 25 to 11% (P = 0.08) compared to the much smaller change in the radiation only control group, 18 to 15% (P = 0.3). CONCLUSIONS: The decrease in hypoxic fraction suggests that nicotinamide can improve tumour hypoxia measured at the time of irradiation. Exposure to the first dose of radiation, or an effect of the first FNAB on microregional tumour blood flow may also contribute.

Radical radiotherapy and salvage cystectomy as the primary management of transitional cell carcinoma of the bladder. Results following the introduction of a CT planning technique.

The objective of this study was to review the results of our policy of primary radiotherapy (RT) and salvage cystectomy for transitional carcinoma (TCC) of the bladder in the light of changes in our radiotherapy planning procedure, in particular the introduction of CT planning. The case notes of 163 patients treated with radical radiotherapy using a CT planning technique were examined. The main endpoint for assessment was response at the time of the check cystoscopy 6 months after the completion of treatment. In addition survival was estimated by stage of disease and by response at the time of first cystoscopy. Patterns of relapse and time to relapse were analysed. All percentages quoted in the text use the initial 163 patients as the denominator. One hundred patients (61%) achieved a complete response. The complete response rate was significantly related to T stage at presentation being 90% for T1, 75% for T2, and 53% for T3 disease respectively. Of these patients 78 remain disease free in the bladder (47%). Twenty-two have relapsed in the bladder, of whom 5 have also relapsed at metastatic sites. Fifteen patients have relapsed outside the bladder whilst remaining disease free within the bladder. At the time of last follow up or death from other causes 63 of the 100 patients who had a complete response remained disease free with an intact bladder. There were 18 (11%) partial responders. Seven of these patients went on to have a cystectomy. Ten remain alive, 7 disease free, 4 with intact bladders. In 24 patients (15%) there was no response and these patients have all died, the median survival being 10 months. In 21 patients (13%) a postradiotherapy cystoscopy was not performed. In all but one patient, who was lost to follow up, this was because of progressive disease. The median survival of these 20 patients was 6 months. Of the 163 patients 35% are alive and well with an intact bladder. If patients dying from other causes are included then 42% were rendered disease free. Cause specific survival was significantly related to stage of disease at presentation with 5 year actuarial survival being 87%, 48% and 26%, for T1, T2 and T3 disease respectively. Survival was also related to response to treatment at 6 months with 5 year survival being 64%, and 52% for complete and partial responders respectively. Survival was extremely poor for non-responders with only 37.5% surviving 1 year and none 5 years. There was a highly significant relationship between response and the development of, and the time to developing metastatic disease. Of those who exhibited a response 21% developed metastatic disease compared to 78% of non-responders. Salvage cystectomy offers the possibility of cure in those who achieve a complete or partial response with 42% of such patients being rendered disease free. Results however are poor in those who did not respond with all patients dying of their disease. Response rates for all stages, and survival for stages T1 and T2 are much improved from those previously reported from this centre and compare favourably with other published series. These results confirm the place of radiotherapy and salvage cystectomy in the management of TCC of the bladder in selected patients. In about one-third of patients the desired outcome of curing the patient of their cancer with organ preservation is achieved. The prognostic significance of cystoscopic response at 6 months and stage at presentation is confirmed. The outcome for patients with early stage disease is excellent. The relationship between response and the development of metastatic disease would suggest that even if these patients had had a primary cystectomy they may have fared badly, a conclusion supported by the fact that these results are comparable with surgical series. This series supports the role of radiotherapy in the management of this disease and suggests that modern RT techniques including CT planning have had a beneficial effect on the results of radical radiotherapy.

Non-surgical treatment for early prostate cancer.

Prostate cancer incidence is rising due to the ageing population and increased public and doctor awareness. The role of screening is still not clear due to the large number of asymptomatic men who would need to be screened and treated to prevent one death. Discussion of all treatment options should be undertaken, with the patient having the opportunity to meet a clinical oncologist and urological surgeon. Treatment options include active surveillance, external beam radiotherapy, brachytherapy and surgery. Low-dose rate brachytherapy involves the permanent insertion of radioactive seeds (half-life 60 days) under ultrasound guidance. It is a good option for many men as impotence and incontinence rates are lower than for surgery and it has reduced hospital costs and time off work and high rates of relapse-free survival (90-95% in low-risk disease). External beam radiotherapy offers a good treatment for men with more locally advanced disease and men who do not want to undergo an anaesthetic. New developments allow higher doses of radiotherapy to be given with reduced relapse rates and reduced toxicity to neighbouring structures such as bowel and bladder. High-dose rate brachytherapy involves the temporary insertion of applicators into the prostate so that a high energy source can temporarily be fed into different positions in the prostate, ensuring a high dose to the prostate gland but minimising dose to the bladder and bowel. It can be used as monotherapy or in combination with external beam radiotherapy.

The prevalence and significance of cyst-like changes at the cruciate ligament attachments in the knee.

Approximately 1% of the total population referred for magnetic resonance imaging (MRI) of the knee at our facility have cystic changes at or near the attachment of the anterior or posterior cruciate ligaments (ACL, PCL). Cases were collected prospectively from a group of 1710 consecutive knee MR examinations, and a retrospective study analyzed the typical appearance of these cysts and any associated findings. Although most of the cysts were an incidental finding, two were associated with significant adjacent marrow edema.

Watchful waiting or watchful progression?: Prostate specific antigen doubling times and clinical behavior in patients with early untreated prostate carcinoma.

BACKGROUND: Prostate specific antigen doubling time (PSAdt) is a dynamic model of prostate tumor biology. It predicts aggressive disease and subsequent clinical recurrence after radical treatment. However, as yet there is only limited evidence for its validity in the watchful waiting population. METHODS: One hundred and thirteen previously untreated patients with adenocarcinoma of the prostate who were referred to the British Columbia Cancer Agency for a management opinion subsequently were placed into a prospective watchful waiting program. The reasons for watchful waiting, previous medical history, serial PSA, and histopathologic data were recorded. RESULTS: The median age of patients was 75 years (range, 49-85 years). The median follow-up from the time of the first appointment was 14 months (range, 0-58 months). The reasons for watchful waiting were correlated highly with T classification (P = 0.003) and past medical history (P = 0.002). Approximately 40% of T1 patients and 51% of T2 patients had clinical progression by 2 years, increasing to 60% at 3 years. On multivariate analysis PSAdt strongly correlated with clinical progression (P < 0.0001), stage progression (P = 0.01), and time to treatment (P = 0.0001); tumor grade and initial stage were not found to be predictive for any of the endpoints studied. Initial PSA only was significant in predicting for time to treatment (P = 0.03). Approximately 50% of patients with a PSAdt of <18 months progressed within 6 months. At last follow-up, no deaths from prostate carcinoma had been recorded. Overall survival at 2 and 5 years was 92% and 68%, respectively. CONCLUSIONS: Using digital rectal examination, the findings of this study demonstrated high rates of clinical tumor progression within the watchful waiting population. PSAdt rather than standard histopathologic criteria was found to be the most powerful indicator of disease activity.

The comet assay in clinical practice.

The comet assay is a single-cell gel electrophoresis technique that measures DNA damage in individual cells. Since radiation produces 3-4 times more DNA damage in well-oxygenated cells compared with hypoxic cells, this assay can quantify the fraction of radiation-resistant hypoxic cells found in many solid tumours. This paper summarizes our results with 73 accessible metastatic tumours irradiated with palliative intent. Hypoxic fractions ranged from 0.0 to 0.67 with a mean of 0.15; 62% of these advanced tumours showed a hypoxic fraction > 0.05. Comparisons between two sequential aspirates in 33 tumours gave a slope of 0.92 (r2 = 0.88), suggesting that a single aspirate is generally representative of the tumour. A limitation, however, is that the hypoxic fraction could not be measured in clinical samples given a conventional dose of 2 Gy.