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.

Changes in Magnetic Resonance Imaging Radiomic Features in Response to Androgen Deprivation Therapy in Patients with Intermediate- and High-risk Prostate Cancer.

AIMS: The benefits of neoadjuvant androgen deprivation therapy (nADT) in the management of intermediate- and high-risk prostate cancer patients have been well-established. The aim of this study was to identify radiomic prognostic features derived from routine anatomic magnetic resonance imaging (MRI) sequences that can predict the response of the prostate cancer to nADT. MATERIALS AND METHODS: Patients with intermediate- and high-risk prostate cancer (with one of clinical stage ≥ T2c, Gleason score ≥7 or presenting prostate-specific antigen ≥10) who received 3 months of ADT prior to radical external beam radiotherapy were enrolled into this study. The relative blood volume and the relative blood flow were used as dynamic MRI kinetic parameters to quantify vascular changes as responses to nADT. For all pre- and post-nADT data sets, a combination of T2-weighted and contrast-enhanced T1-weighted anatomic images were used to define regions of interest (ROI) as the dominant malignant nodules (DMNs) and the benign prostate (the entire prostate with the summed DMNs being subtracted). MRI textural radiomic features associated with prostate cancer response in the literature of energy and homogeneity were selected. Pyradiomics was used to extract textural features of the ROIs. A Wilcoxon signed-rank test was carried out to investigate if there were statistically significant differences in values of radiomic features between: (i) benign prostate ROI and DMN pre-nADT; (ii) pre- and post-nADT of benign prostate ROI; (iii) pre- and post-nADT of DMN. Changes in radiomic features and dynamic MRI kinetic parameters were correlated using the Spearman correlation test. RESULTS: Twenty prostate cancer patients were recruited into the study. The median time between the first baseline scan and the first on-treatment scan was 91.5 days (range 82-105). One patient had no discernible tumour visible, leaving 19 patients with evaluable data for the analysis. Baseline homogeneity and energy values differed significantly between benign and malignant tissue (P < 0.01). In response to nADT, homogeneity and energy showed reciprocal changes, significantly increased in benign prostate while decreasing in the DMN. The reduction in tumour homogeneity and energy feature values showed a positive association with the decline in tumour blood flow and tumour blood volume induced by androgen deprivation as derived from dynamic MRI parameters. CONCLUSION: Energy and homogeneity radiomic features derived from MRI of benign and malignant prostate showed significant reciprocal changes in response to nADT. This study confirms the potential of these radiomic features to act as surrogate markers of tumour androgen sensitivity due to their strong association with ADT-induced physiological effects in prostate tumours.

Single-Dose Focal Salvage High Dose Rate Brachytherapy for Locally Recurrent Prostate Cancer.

AIMS: To evaluate focal high dose rate (HDR) brachytherapy in locally recurrent prostate cancer. MATERIALS AND METHODS: Patients with biochemical relapse after non-surgical primary treatment for localised prostate cancer were selected after a negative screen for metastatic disease. Template mapping biopsies combined with multiparametric magnetic resonance imaging were used to identify the location of the tumour and the focal clinical target volume. The planning aim dose prescription was 19 Gy. Outcome measures were biochemical relapse-free survival and toxicity using International Prostate Symptom Score and Common Terminology Criteria for Adverse Events (version 4.0) scores. RESULTS: Between March 2013 and December 2018, 50 patients underwent salvage HDR brachytherapy. The median follow-up was 21 months (range 1-53). Biochemical progression-free survival at 2 and 3 years was 63% and 46%, respectively. On multivariate analysis, only prostate-specific antigen nadir ≤0.5 ng/ml post-salvage (P = 0.03, hazard ratio 0.04) was associated with biochemical progression-free survival. Relapse was associated with distant metastases in 11/13 patients in whom this was investigated. Late grade 3 genitourinary toxicities were gross haematuria (three patients), severe lower urinary tract symptoms (two patients), erectile dysfunction (one patient) and urethral stricture requiring surgery (four patients). No acute and late grade 4 or 5 genitourinary and no grade 3 or higher gastrointestinal toxicities were recorded. CONCLUSIONS: Focal salvage HDR monotherapy achieves biochemical control in 46% of patients at 3 years with acceptable toxicity rates in selected patients. Biochemical relapse was related to a post-salvage prostate-specific antigen nadir of ≥0.5 ng/ml. Long-term outcomes are needed to assess the impact on the natural history of prostate cancer in these patients.

The Role of Magnetic Resonance Imaging in Brachytherapy.

The application of magnetic resonance imaging (MRI) in image-guided brachytherapy has expanded rapidly over the past two decades. In cervix cancer, significant improvements in overall survival, local control and long-term morbidity have been shown in patients treated with MRI-guided brachytherapy, changing clinical practice and directing an international approach to standardise the technique; unifying adaptive target volume definition and dose reporting. MRI-guided prostate brachytherapy has significantly improved the accuracy of tumour and organ-at-risk delineation, facilitating targeted implantation and dose optimisation. It also has potential to improve clinical outcomes through enhancement of the therapeutic ratio and the identification of dominant lesions that can be the targets of sub-volume boosting and salvage therapy. However, MRI-guided brachytherapy presents a number of logistical and financial challenges in modern healthcare systems, requiring technologically advanced imaging and planning techniques, as well as robust safety and quality assurance procedures. A collaborative, multidisciplinary approach involving clinical oncologists, radiologists, medical physicists, therapy radiographers, nurses and technical staff is therefore critical to its successful incorporation into any clinical brachytherapy workflow. In this overview we evaluate the current role of MRI in image-guided brachytherapy, primarily in cervix and prostate cancer, but also in other tumour sites, and review its potential future developments in the context of both clinical and research spheres.

Functional Radiotherapy Targeting using Focused Dose Escalation.

Various quantitative and semi-quantitative imaging biomarkers have been identified that may serve as valid surrogates for the risk of recurrence after radiotherapy. Tumour characteristics, such as hypoxia, vascularity, cellular proliferation and clonogen density, can be geographically mapped using biological imaging techniques. The potential gains in therapeutic ratio from the precision targeting of areas of intrinsic resistance makes focused dose escalation an exciting field of study. This overview will explore the issues surrounding biologically optimised radiotherapy, including its requirements, feasibility, technical considerations and potential applicability.

Using routinely collected data to stratify prostate cancer patients into phases of care in the United Kingdom: implications for resource allocation and the cancer survivorship programme.

BACKGROUND: Prostate cancer is the most commonly diagnosed malignancy in British men. The increasing use of PSA screening test has resulted in many more patients being diagnosed with this condition. Advances in its treatment have improved the survival rate among these patients. By 2040, the prevalence of prostate cancer survivors is expected to reach 830 000. Many of them will require medical support for the management of their progressive disease or long-term toxicities from previous treatments. Successful implementation of the cancer survivorship programme among these patients depends on a good understanding of their demand on the health care system. The aim of this study is to segment the population of prostate cancer survivors into different needs groups and to quantify them with respect to their phase of care. METHODS: Incidence, survival, prevalence and mortality data collected and reported by cancer registries across the United Kingdom have been used for the current study to provide indicative estimates as to the number of prostate cancer patients in each phase of the care pathway in a year. RESULTS: The majority of prostate cancer patients are in the post-treatment monitoring phase. Around a fifth of the patients are either receiving treatment or in the recovery and readjustment phase having completed their treatment in the preceding year. Thirteen percent have not received any anticancer treatment, a further 12% (32 000) have developed metastatic disease and 4% are in the final stage of their lives. CONCLUSION: On the basis of our estimates, patients undergoing post-treatment monitoring phase will constitute the biggest group among prostate cancer survivors. The pressure to provide adequate follow-up care to these patients will be a challenge. There is limited data available to definitively quantify the number of prostate cancer patients who follow different pathways of care, and we hope this study has highlighted the importance of collecting and reporting of such data to help future health care planning for these patients.

Hypofractionated radiotherapy for localized prostate cancer using three-dimensional conformal radiotherapy technique: 3 years toxicity analysis.

BACKGROUND: Hypofractionated radiotherapy in the radical treatment of localized prostate cancer has potential biological advantages relative to conventional fractionation. We report prospectively collected toxicity data from a cohort of patients treated with a 3D conformal technique (3DCRT). MATERIALS AND METHODS: 90 patients receiving curative intent hypofractionated radiotherapy with 57Gy in 19 daily fractions over 3.8 weeks were evaluated prospectively for the development of radiation related toxicity over a 3 year period. RESULTS: All patients completed treatment. Maximal acute toxicity experienced was 58.6, 10 and 1.1% for grade 1, 2 and 3 genitourinary (GU) toxicity respectively and 75.6, 9 and 0% for gastrointestinal (GI) toxicity. For late toxicity the three year actuarial rates of grade 1, 2 and 3 GU and GI toxicity respectively were 47.3, 2.4 and 0%; and 40, 9.3 and 4.7%. There were no grade 4 or worse acute or late toxicities. 97.6% of evaluable patients remained free of biochemical failure 36 months post radiotherapy. CONCLUSIONS: A 57Gy in 19 daily fraction radiotherapy schedule using 3D conformal radiotherapy for the definitive treatment of localized prostate cancer has acceptable early and late toxicity.

Imaging vascular function for early stage clinical trials using dynamic contrast-enhanced magnetic resonance imaging.

Many therapeutic approaches to cancer affect the tumour vasculature, either indirectly or as a direct target. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has become an important means of investigating this action, both pre-clinically and in early stage clinical trials. For such trials, it is essential that the measurement process (i.e. image acquisition and analysis) can be performed effectively and with consistency among contributing centres. As the technique continues to develop in order to provide potential improvements in sensitivity and physiological relevance, there is considerable scope for between-centre variation in techniques. A workshop was convened by the Imaging Committee of the Experimental Cancer Medicine Centres (ECMC) to review the current status of DCE-MRI and to provide recommendations on how the technique can best be used for early stage trials. This review and the consequent recommendations are summarised here. Key Points • Tumour vascular function is key to tumour development and treatment • Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can assess tumour vascular function • Thus DCE-MRI with pharmacokinetic models can assess novel treatments • Many recent developments are advancing the accuracy of and information from DCE-MRI • Establishing common methodology across multiple centres is challenging and requires accepted guidelines.

Current status and guidelines for the assessment of tumour vascular support with dynamic contrast-enhanced computed tomography.

Dynamic contrast-enhanced computed tomography (DCE-CT) assesses the vascular support of tumours through analysis of temporal changes in attenuation in blood vessels and tissues during a rapid series of images acquired with intravenous administration of iodinated contrast material. Commercial software for DCE-CT analysis allows pixel-by-pixel calculation of a range of validated physiological parameters and depiction as parametric maps. Clinical studies support the use of DCE-CT parameters as surrogates for physiological and molecular processes underlying tumour angiogenesis. DCE-CT has been used to provide biomarkers of drug action in early phase trials for the treatment of a range of cancers. DCE-CT can be appended to current imaging assessments of tumour response with the benefits of wide availability and low cost. This paper sets out guidelines for the use of DCE-CT in assessing tumour vascular support that were developed using a Delphi process. Recommendations encompass CT system requirements and quality assurance, radiation dosimetry, patient preparation, administration of contrast material, CT acquisition parameters, terminology and units, data processing and reporting. DCE-CT has reached technical maturity for use in therapeutic trials in oncology. The development of these consensus guidelines may promote broader application of DCE-CT for the evaluation of tumour vascularity. Key Points • DCE-CT can robustly assess tumour vascular support • DCE-CT has reached technical maturity for use in therapeutic trials in oncology • This paper presents consensus guidelines for using DCE-CT in assessing tumour vascularity.

Phase Ib trial of radiotherapy in combination with combretastatin-A4-phosphate in patients with non-small-cell lung cancer, prostate adenocarcinoma, and squamous cell carcinoma of the head and neck.

BACKGROUND: The vascular disrupting agent combretastatin-A4-phosphate (CA4P) demonstrated antitumour activity in preclinical studies when combined with radiation. METHODS: Patients with non-small-cell lung cancer (NSCLC), prostate adenocarcinoma, and squamous cell carcinoma of the head and neck (SCCHN) received 27 Gy in 6 fractions treating twice weekly over 3 weeks, 55 Gy in 20 fractions over 4 weeks, and 66 Gy in 33 fractions over 6 weeks respectively. CA4P was escalated from 50 mg/m2 to 63 mg/m2. CA4P exposure was further increased from one to three to six doses. Patients with SCCHN received cetuximab in addition. RESULTS: Thirty-nine patients received 121 doses of CA4P. Dose-limiting toxic effects (DLTs) of reversible ataxia and oculomotor nerve palsy occurred in two patients with prostate cancer receiving weekly CA4P at 63 mg/m2. DLT of cardiac ischaemia occurred in two patients with SCCHN at a weekly dose of 50 mg/m2 in combination with cetuximab. Three patients developed grade 3 hypertension. Responses were seen in 7 of 18 patients with NSCLC. At 3 years, 3 of 18 patients with prostate cancer had prostate-specific antigen relapse. CONCLUSIONS: Radiotherapy with CA4P appears well tolerated in most patients. The combination of CA4P, cetuximab, and radiotherapy needs further scrutiny before it can be recommended for clinical studies.

Carbogen breathing increases prostate cancer oxygenation: a translational MRI study in murine xenografts and humans.

Hypoxia has been associated with poor local tumour control and relapse in many cancer sites, including carcinoma of the prostate. This translational study tests whether breathing carbogen gas improves the oxygenation of human prostate carcinoma xenografts in mice and in human patients with prostate cancer. A total of 23 DU145 tumour-bearing mice, 17 PC3 tumour-bearing mice and 17 human patients with prostate cancer were investigated. Intrinsic susceptibility-weighted MRI was performed before and during a period of carbogen gas breathing. Quantitative R(2)* pixel maps were produced for each tumour and at each time point and changes in R(2)* induced by carbogen were determined. There was a mean reduction in R(2)* of 6.4% (P=0.003) for DU145 xenografts and 5.8% (P=0.007) for PC3 xenografts. In all, 14 human subjects were evaluable; 64% had reductions in tumour R(2)* during carbogen inhalation with a mean reduction of 21.6% (P=0.0005). Decreases in prostate tumour R(2)* in both animal models and human patients as a result of carbogen inhalation suggests the presence of significant hypoxia. The finding that carbogen gas breathing improves prostate tumour oxygenation provides a rationale for testing the radiosensitising effects of combining carbogen gas breathing with radiotherapy in prostate cancer patients.

Functional imaging in clinical oncology: magnetic resonance imaging- and computerised tomography-based techniques.

Over recent years, advances in cellular biology, molecular biology and genetics have led to a leap forward in our understanding of the biological basis of cancer. Some of these developments have revealed processes and targets that can be visualised and measured by new functional imaging techniques. The resulting images have the potential to improve cancer staging, prognosis and risk assessment, guide radiotherapy planning, direct treatment schedules, improve response assessment and provide new end points for clinical trials. In this review, we have outlined the magnetic resonance imaging- and computerised tomography-based functional techniques and provide evidence for their use.

Novel therapies in bladder cancer.

The most effective non-surgical treatment for bladder cancer remains radiotherapy. The dramatic technical developments in radiotherapy have enabled greater accuracy and reliability based on three-dimensional imaging for both planning and verification. Particle therapy, in particular using protons, provides further opportunities for optimising radiation delivery and dose escalation. Novel fractionation schedules with both hyperfractionation and hypofractionation may have added benefits. Chemoradiation has been shown in one randomised-controlled trial to improve the results of radiotherapy alone, and requires further investigation. Hypoxia modification using carbogen and nicotinamide has also shown promising results in a phase II trial, and is now in phase III evaluation. Novel drug agents for bladder cancer are few, but the anti-EGFR agents and anti-angiogenic agents may have promise; the development of anti-apoptotic agents and antisense gene therapy may also become a component of the future multimodality management of this tumour.