Timing of radiotherapy (RT) after radical prostatectomy (RP): long-term outcomes in the RADICALS-RT trial (NCT00541047).

BACKGROUND: The optimal timing of radiotherapy (RT) after radical prostatectomy for prostate cancer has been uncertain. RADICALS-RT compared efficacy and safety of adjuvant RT versus an observation policy with salvage RT for prostate-specific antigen (PSA) failure. PATIENTS AND METHODS: RADICALS-RT was a randomised controlled trial enrolling patients with ≥1 risk factor (pT3/4, Gleason 7-10, positive margins, preoperative PSA≥10 ng/ml) for recurrence after radical prostatectomy. Patients were randomised 1:1 to adjuvant RT ('Adjuvant-RT') or an observation policy with salvage RT for PSA failure ('Salvage-RT') defined as PSA≥0.1 ng/ml or three consecutive rises. Stratification factors were Gleason score, margin status, planned RT schedule (52.5 Gy/20 fractions or 66 Gy/33 fractions) and treatment centre. The primary outcome measure was freedom-from-distant-metastasis (FFDM), designed with 80% power to detect an improvement from 90% with Salvage-RT (control) to 95% at 10 years with Adjuvant-RT. Secondary outcome measures were biochemical progression-free survival, freedom from non-protocol hormone therapy, safety and patient-reported outcomes. Standard survival analysis methods were used; hazard ratio (HR)<1 favours Adjuvant-RT. RESULTS: Between October 2007 and December 2016, 1396 participants from UK, Denmark, Canada and Ireland were randomised: 699 Salvage-RT, 697 Adjuvant-RT. Allocated groups were balanced with a median age of 65 years. Ninety-three percent (649/697) Adjuvant-RT reported RT within 6 months after randomisation; 39% (270/699) Salvage-RT reported RT during follow-up. Median follow-up was 7.8 years. With 80 distant metastasis events, 10-year FFDM was 93% for Adjuvant-RT and 90% for Salvage-RT: HR=0.68 [95% confidence interval (CI) 0.43-1.07, P=0.095]. Of 109 deaths, 17 were due to prostate cancer. Overall survival was not improved (HR=0.980, 95% CI 0.667-1.440, P=0.917). Adjuvant-RT reported worse urinary and faecal incontinence 1 year after randomisation (P=0.001); faecal incontinence remained significant after 10 years (P=0.017). CONCLUSION: Long-term results from RADICALS-RT confirm adjuvant RT after radical prostatectomy increases the risk of urinary and bowel morbidity, but does not meaningfully improve disease control. An observation policy with salvage RT for PSA failure should be the current standard after radical prostatectomy. TRIAL IDENTIFICATION: RADICALS, RADICALS-RT, ISRCTN40814031, NCT00541047.

The gut microbiota in adults with cystic fibrosis compared to colorectal cancer.

BACKGROUND: Gut dysbiosis is implicated in colorectal cancer (CRC) pathogenesis. Cystic fibrosis (CF) is associated with both gut dysbiosis and increased CRC risk. We therefore compared the faecal microbiota from individuals with CF to CRC and screening samples. We also assessed changes in CRC-associated taxa before and after triple CF transmembrane conductance regulator (CFTR) modulator therapy. METHODS: Bacterial DNA amplification comprising V4 16S rRNA analysis was conducted on 84 baseline and 53 matched follow-up stool samples from adults with CF. These data were compared to an existing cohort of 430 CRC and 491 control gFOBT samples from the NHS Bowel Cancer Screening Programme. Data were also compared to 26 previously identified CRC-associated taxa from a published meta-analysis. RESULTS: Faecal CF samples had a lower alpha diversity and clustered distinctly from both CRC and control samples, with no clear clinical variables explaining the variation. Compared to controls, CF samples had an increased relative abundance in 6 of the 20 enriched CRC-associated taxa and depletion of 2 of the 6 taxa which have been reported as reduced in CRC. Commencing triple modulator therapy had subtle influence on the relative abundance of CRC-associated microbiota (n = 23 paired CF samples). CONCLUSIONS: CF stool samples were clearly dysbiotic, clustering distinctly from both CRC and control samples. Several bacterial shifts in CF samples resembled those observed in CRC. Studies assessing the impact of dietary or other interventions and the longer-term use of CFTR modulators on reducing this potentially pro-oncogenic milieu are needed.

Artificial intelligence in healthcare: Proposals for policy development in South Africa.

Despite the tremendous promise offered by artificial intelligence (AI) for healthcare in South Africa, existing policy frameworks are inadequate for encouraging innovation in this field. Practical, concrete and solution-driven policy recommendations are needed to encourage the creation and use of AI systems. This article considers five distinct problematic issues which call for policy development: (i) outdated legislation; (ii) data and algorithmic bias; (iii) the impact on the healthcare workforce; (iv) the imposition of liability dilemma; and (v) a lack of innovation and development of AI systems for healthcare in South Africa. The adoption of a national policy framework that addresses these issues directly is imperative to ensure the uptake of AI development and deployment for healthcare in a safe, responsible and regulated manner.

Real-world Outcomes and Factors Predicting Survival and Completion of Radium 223 in Metastatic Castrate-resistant Prostate Cancer.

AIMS: To analyse outcomes in metastatic castrate-resistant prostate cancer (mCRPC) patients treated with radium 223 (Ra-223) across the Yorkshire and Humber Cancer Network. MATERIALS AND METHODS: A regional, multicentre, retrospective cohort study of 189 men undergoing Ra-223 for mCRPC between March 2014 and April 2017 was undertaken. Factors predicting overall survival and completion of planned treatment were assessed. RESULTS: The median overall survival for the entire cohort was 10.5 months. Those completing five to six cycles of Ra-223 had a higher overall survival of 18.6 months. On multivariable analysis, four factors remained independent significant predictors of overall survival: age (P = 0.005, hazard ratio 1.07 [1.02-1.12]); number of cycles of Ra-223: 5-6 versus 1-4 (P ≤ 0.001, hazard ratio 0.10 [0.005-0.20]); baseline alkaline phosphatase (P = 0.044, hazard ratio 1.06 [1.002-1.12]); neutrophil-to-lymphocyte ratio (P = 0.033, hazard ratio 1.19 [1.01-1.40]). Baseline performance status 0 versus 2 (P = 0.026, odds ratio 0.080 [0.001-0.74]) and higher baseline haemoglobin (P = 0.028, odds ratio 1.04 [1.004-1.074]) were independent predictors of the completion of five to six cycles of Ra-223. CONCLUSIONS: Younger age, completion of five to six cycles of Ra-223, lower alkaline phosphatase and neutrophil-to-lymphocyte ratio are predictors of overall survival. This is the first study to report neutrophil-to-lymphocyte ratio as an independent predictor of overall survival in a Ra-223 cohort. Good performance status and higher baseline haemoglobin predict the completion of five to six cycles of Ra-223.

Diagnostic performance of a streamlined 18F-choline PET-CT protocol for the detection of prostate carcinoma recurrence in combination with appropriate-use criteria.

AIM: To evaluate the efficacy of single time-point half-body (skull base to thighs) fluorine-18 choline positron emission tomography-computed tomography (PET-CT) compared to a triple-phase acquisition protocol in the detection of prostate carcinoma recurrence. MATERIALS AND METHODS: Consecutive choline PET-CT studies performed at a single tertiary referral centre in patients with biochemical recurrence of prostate carcinoma between September 2012 and March 2017 were reviewed retrospectively. The indication for the study, imaging protocol used, imaging findings, whether management was influenced by the PET-CT, and subsequent patient outcome were recorded. RESULTS: Ninety-one examinations were performed during the study period; 42 were carried out using a triple-phase protocol (dynamic pelvic imaging for 20 minutes after tracer injection, half-body acquisition at 60 minutes and delayed pelvic scan at 90 minutes) between 2012 and August 2015. Subsequently following interim review of diagnostic performance, a streamlined protocol and appropriate-use criteria were introduced. Forty-nine examinations were carried out using the single-phase protocol between 2015 and 2017. Twenty-nine (69%) of the triple-phase studies were positive for recurrence compared to 38 (78%) of the single-phase studies. Only one patient who had a single-phase study would have benefited from a dynamic acquisition, they have required no further treatment or imaging and are currently under prostate-specific antigen (PSA) surveillance. CONCLUSION: Choline PET-CT remains a useful tool for the detection of prostate recurrence when used in combination with appropriate-use criteria. Removal of dynamic and delayed acquisition phases reduces study time without adversely affecting accuracy. Benefits include shorter imaging time which improves patient comfort, reduced cost, and improved scanner efficiency.

The Effect of Dose and Quality Assurance in Early Prostate Cancer Treated with Low Dose Rate Brachytherapy as Monotherapy.

AIMS: To examine the relationship between post-implant computed tomography dosimetry and long-term prostate-specific antigen relapse-free survival in patients treated with iodine 125 (I-125) low dose rate prostate brachytherapy as monotherapy and, second, to audit recent practice against Royal College of Radiologists' (RCR) guidelines after the re-introduction of post-implant dosimetry for all patients in our centre. MATERIALS AND METHODS: Between March 1995 and September 2007, 2157 consecutive patients with localised prostate cancer underwent I-125 permanent prostate brachytherapy as monotherapy in a single UK centre. All patients were transrectal ultrasound planned delivering a 145 Gy (TG 43) minimum peripheral dose. None received supplemental external beam radiotherapy. Post-implant computed tomography-based dosimetry was undertaken between 4 and 6 weeks after treatment and was available for 711 (33%). Outcomes were analysed in terms of the relationship of D90 to prostate-specific antigen relapse-free survival (nadir 2+ definition) and all patients had a minimum follow-up of 5 years. For contemporary patients from 2011, quality metrics from post-implant computed tomography as defined by RCR guidelines are presented. RESULTS: A mean D90 of 138.7 Gy (standard deviation 24.7) was achieved for the historic cohort. Biochemical control at 10 years was 76% in patients with D90 > 140 Gy and 68% in those with D90 < 140 Gy (P < 0.01). In current practice, over the last 3 years the mean (standard deviation) D90 has increased from 154 (15.3) Gy in 2011 to 164 (13.5) Gy in 2013. Similarly, an increase in the mean (standard deviation) V100 from 92 (4.4) to 95 (3.2) % is noted over time. No difference between clinicians was noted. CONCLUSION: D90 values of less than 140 Gy continue to be predictive of increased risk of recurrence of prostate cancer across risk groups with longer follow-up. Quality assurance can be used to ensure improved and consistent implant quality in a team with multiple clinicians.

Second primary cancers occurring after I-125 brachytherapy as monotherapy for early prostate cancer.

AIMS: Prostate brachytherapy may be associated with a lower risk of radiation-induced second primary cancer (SPC) as a significantly smaller volume of normal tissue is irradiated when compared with external beam techniques. Limited data are available as it has been a routine treatment option for less than 20 years. This study identified cases of SPC in patients who underwent I-125 prostate brachytherapy as monotherapy in a single institution. MATERIALS AND METHODS: SPC incidence was retrieved by conducting a UK cancer registry search (Northern and Yorkshire Cancer Registry and Information Service) for 1805 consecutive patients with localised prostate cancer who received monotherapy with I-125 brachytherapy from 1995 to 2006 at a single public hospital. Of 1730 UK residents, the completeness of the registry match was 91% (1574 patients). The mean age at treatment (interquartile range) of the cohort was 63 (58-68) years with 1100 patients (70%) over the age of 60 years at treatment. The median (range) follow-up was 8 (6-10) years with 487 patients (31%) having 10 years or more. RESULTS: In total, 170 patients (10.8%) were diagnosed with second primaries (1 year or more after implant); 20 of these were bladder and 10 rectal cancers. The 10 year cumulative incidences were 14.6, 1 and 0.84% for any second malignancy, bladder and rectal cancer, respectively. Only the standardised incidence rate (SIR) for bladder cancer was higher at 1.54 (95% confidence interval 0.96-2.46) compared with the general population. The SIR for bladder cancer was higher in the first few years after treatment, suggesting that the increased incidence of bladder cancer is due to increased urological surveillance. CONCLUSIONS: Overall, the incidence of SPC after I-125 is comparable with other published data with no significant excess more than 5 years from treatment. Mortality secondary to SPC of the bladder or rectum is unusual.

Alpha emitter radium-223 and survival in metastatic prostate cancer.

BACKGROUND: Radium-223 dichloride (radium-223), an alpha emitter, selectively targets bone metastases with alpha particles. We assessed the efficacy and safety of radium-223 as compared with placebo, in addition to the best standard of care, in men with castration-resistant prostate cancer and bone metastases. METHODS: In our phase 3, randomized, double-blind, placebo-controlled study, we randomly assigned 921 patients who had received, were not eligible to receive, or declined docetaxel, in a 2:1 ratio, to receive six injections of radium-223 (at a dose of 50 kBq per kilogram of body weight intravenously) or matching placebo; one injection was administered every 4 weeks. In addition, all patients received the best standard of care. The primary end point was overall survival. The main secondary efficacy end points included time to the first symptomatic skeletal event and various biochemical end points. A prespecified interim analysis, conducted when 314 deaths had occurred, assessed the effect of radium-223 versus placebo on survival. An updated analysis, when 528 deaths had occurred, was performed before crossover from placebo to radium-223. RESULTS: At the interim analysis, which involved 809 patients, radium-223, as compared with placebo, significantly improved overall survival (median, 14.0 months vs. 11.2 months; hazard ratio, 0.70; 95% confidence interval [CI], 0.55 to 0.88; two-sided P=0.002). The updated analysis involving 921 patients confirmed the radium-223 survival benefit (median, 14.9 months vs. 11.3 months; hazard ratio, 0.70; 95% CI, 0.58 to 0.83; P<0.001). Assessments of all main secondary efficacy end points also showed a benefit of radium-233 as compared with placebo. Radium-223 was associated with low myelosuppression rates and fewer adverse events. CONCLUSIONS: In this study, which was terminated for efficacy at the prespecified interim analysis, radium-223 improved overall survival. (Funded by Algeta and Bayer HealthCare Pharmaceuticals; ALSYMPCA ClinicalTrials.gov number, NCT00699751.).

KRAS and BRAF mutations are rare and related to DNA mismatch repair deficiency in gastric cancer from the East and the West: results from a large international multicentre study.

BACKGROUND: Inhibitors of the epidermal growth factor (EGFR) signaling pathway have a major role in the treatment of KRAS wild-type colorectal cancer patients. The EGFR pathway has been shown to be activated in gastric cancer (GC). However, published data on KRAS and BRAF mutation status is limited in GC and has not been compared between GC from different geographic regions. METHODS: The prevalence of KRAS and BRAF mutations was established in 712 GC: 278 GC from the United Kingdom, 230 GC from Japan and 204 GC from Singapore. The relationship between KRAS/BRAF mutation status, DNA mismatch repair (MMR) status, clinicopathological variables and overall survival was analysed. RESULTS: Overall, 30 (4.2%) GC carried a KRAS mutation. In total, 5.8% of the UK GC, 4% of Japan GC and 1.5% of Singapore GC were KRAS mutant. KRAS mutant GC had fewer lymph node metastases in the UK cohort (P=0.005) and were more frequent in elderly patients in the Japan cohort (P=0.034). KRAS mutations were more frequent in MMR-deficient GC in the UK and the Japanese cohort (P<0.05). A BRAF mutation was only detected in a single Japanese GC. CONCLUSIONS: This large multicentre study demonstrated that KRAS mutations and DNA MMR deficiency have a role in a small subgroup of GC irrespective of country of origin, suggesting that this subgroup of GC may have developed along a common pathway. Further studies need to establish whether concomitant mutations or amplifications of other EGFR signalling pathway genes may contribute to the activation of this pathway in GC.

Report on the early efficacy and tolerability of I(125) permanent prostate brachytherapy from a UK multi-institutional database.

AIMS: To report the results of I(125) prostate brachytherapy from a central, prospectively collected database of three UK institutions. MATERIALS AND METHODS: All patients treated with I(125) permanent prostate brachytherapy at the Christie Hospital, Manchester (CHM), Cookridge Hospital, Leeds (CKL) and Mount Vernon Hospital, Northwood, London (MVL) since 2003 have been prospectively registered on a detailed central database. Patient, tumour, pre- and post-implant dosimetry data have been recorded. Urinary toxicity as assessed by the International Prostate Symptom Score, catheterisation and urinary stricture rates after implant have been documented and biochemical failure determined, using both the American Society for Therapeutic Radiology and Oncology (ASTRO) consensus and the Phoenix (nadir + 2 ng/ml) definition. RESULTS: In total, 1535 patients were registered on the database between January 2003 and October 2006, including 432 from CHM, 926 from CKL and 177 from MVL, with a median follow-up of 21 months (range 1-56). Patient and tumour characteristics were similar at all centres. Pre-implant dose indices were comparable between centres, except for the V150, with median values of 51.9, 64.3 and 69.8% at CHM, CKL and MVL, respectively. Median post-implant dose parameters were lower than pre-planned constraints by up to 33.0% at each centre for all values, except at CKL where the V200 was 23.9% higher. The International Prostate Symptom Score increased from a median of 5 at baseline to 18, 6 weeks after implant, but was not significantly different to baseline values by 12 months. Nine per cent of men required catheterisation after implant for a median duration of 53 days, but urinary stricture rates remained low at 1%. Neoadjuvant hormonal manipulation was used in 228 men (15%) for downsizing and 159 (10%) for intermediate/high-risk disease. Collated biochemical failure rates were low at this point of follow-up, with actuarial 2-year ASTRO and Phoenix biochemical failure-free survival rates of 94.4 and 94.5%, respectively, consistent with other large single centre reports. When post-implant dosimetric factors were assessed for a relationship to biochemical failure, no indices consistently predicted for improved ASTRO and Phoenix biochemical failure-free survival rates. CONCLUSIONS: This ongoing collaboration shows that with limited infrastructure (a single industry-sponsored data manager), a large multi-institutional database estimated to represent one-third of implants carried out in the UK during this time can be developed. Patient selection was similar across all centres and adhered to published guidelines. Early biochemical and toxicity outcomes confirm the efficacy and tolerability of I(125) prostate brachytherapy in a large cohort of patients. A further analysis is planned.

Recto-urethral fistula following brachytherapy for localized prostate cancer.

OBJECTIVE: The use of prostate brachytherapy (BT) in the management of prostate cancer is increasing. BT is often chosen because of its perceived lower toxicity when compared with other radical therapy options. Rarely however serious complications can occur. One such complication is recto-urethral fistula (RUF). We report the incidence of RUF following BT at our centre and review the potential factors in fistula development. METHOD: A prospectively collected database was used to identify cases of RUF among 1455 patients treated with prostate BT at a single UK centre with at least 2 years of follow up. This included patients treated with BT monotherapy, as well as those treated with BT combined with external beam radiotherapy and BT used as salvage as all these groups have a higher incidence of RUF. Implant dose and volume characteristics for those patients, their co-morbidities and history of endoscopic procedures were recorded. RESULTS: Recto-urethral fistula was identified in three (0.2%) patients, occurring at 19-27 months following BT. All these patients had BT monotherapy. All three patients had rectal symptoms after their BT and had been investigated with endoscopy and low rectal biopsy. Subsequent surgical management with faecal and/or urinary diversion was required. On review of patients' BT details, radiation dose and volume parameters were higher on the postprocedure CT calculations than had been suggested by the preimplant plan. No other predisposing risk factors for RUF were identified. CONCLUSION: The incidence of RUF in our population is low. RUF following BT has been associated with rectal biopsy in previous series and this is confirmed in our report. Gastrointestinal specialists should not perform biopsy of the anterior rectum in patients who have had BT unless there is a very high clinical suspicion of malignancy.

The use of CT-MR image registration to define target volumes in pelvic radiotherapy in the presence of bilateral hip replacements.

Increasing numbers of patients with hip replacements are presenting for pelvic radiotherapy, which is usually planned using CT images. Image artefacts caused by the presence of metallic implants tend not to be severe for single hip replacements and allow for adequate definition of target volumes. When bilateral hip replacements are present, the image artefacts can render CT images useless for target definition, particularly for tumours of the prostate and bladder. MR images are not susceptible to such severe artefacts. This note describes a small series of patients with bilateral hip replacements on whom CT-MR image registration has been used to successfully define adequate target volumes.

Lithium isotope geochemistry and origin of Canadian shield brines.

Hypersaline calcium/chloride shield brines are ubiquitous in Canada and areas of northern Europe. The major questions relating to these fluids are the origin of the solutes and the concentration mechanism that led to their extreme salinity. Many chemical and isotopic tracers are used to solve these questions. For example, lithium isotope systematics have been used recently to support a marine origin for the Yellowknife shield brine (Northwest Territories). While having important chemical similarities to the Yellowknife brine, shield brines from the Sudbury/Elliot Lake (Ontario) and Thompson/Snow Lake (Manitoba) regions, which are the focus of this study, exhibit contrasting lithium behavior. Brine from the Sudbury Victor mine has lithium concentrations that closely follow the sea water lithium-bromine concentration trajectory, as well as delta6Li values of approximately -28/1000. This indicates that the lithium in this brine is predominantly marine in origin with a relatively minor component of crustal lithium leached from the host rocks. In contrast, the Thompson/Snow Lake brine has anomalously low lithium concentrations, indicating that it has largely been removed from solution by alteration minerals. Furthermore, brine and nonbrine mine waters at the Thompson mine have large delta6Li variations of approximately 30/1000, which primarily reflects mixing between deep brine with delta6Li of -35 +/- 2/1000 and near surface mine water that has derived higher delta6Li values through interactions with their host rocks. The contrary behavior of lithium in these two brines shows that, in systems where it has behaved conservatively, lithium isotopes can distinguish brines derived from marine sources.

Short-term morbidity and acceptability of 125iodine implantation for localized carcinoma of the prostate.

OBJECTIVE: To report the short-term morbidity and acceptability of the first 50 patients treated with the percutaneous implantation of radioactive iodine seeds for localized carcinoma of the prostate at the Cookridge Hospital. PATIENTS AND METHODS: Fifty patients were treated with transrectal ultrasonography-guided percutaneous implants with radioactive (125I) iodine seeds for localized carcinoma of the prostate. The mean hospital stay was 36 h and most patients were able to return to work or normal activity within one week of implantation. RESULTS: All patients developed urethritis which was most marked within the first 3 months of treatment; 8% of patients developed acute retention which resolved after temporary catheterization. At 3 months, 36% of patients still had moderate frequency and 18% moderate dysuria, but by 12 months these had resolved and only 5% of patients still complained of moderate nocturia. There were no cases of incontinence. The incidence of proctitis was very low, with only 2% still complaining of moderate symptoms at one year. Of those potent before implantation, 72% retained potency at one year. CONCLUSIONS: Although it is too early to comment either on late morbidity or on outcome, the results of this study show a side-effect profile similar to that reported by other centres using the same technique.

Prostate brachytherapy.

In recent years there has been an increase in the number of centres, especially in the USA, using prostate brachytherapy as a means of treating localised prostate cancer. Several centres now have medium term follow up data of large numbers of patients treated with this technique suggesting that outcome in terms of tumour control may be comparable to patients treated surgically. This review summarises results from different brachytherapy series and outlines some of the possible advantages of this technique compared with current conventional treatments for localised prostate cancer.