Patterns of Failure After Stereotactic Body Radiotherapy to Sacral Metastases.

AIMS: Stereotactic body radiotherapy (SBRT) is increasingly used to treat sacral metastases. We analysed our centre's local relapse rates and patterns of failure after sacral SBRT and assessed whether using the consensus contouring recommendation (CCR) may have prevented local relapse. MATERIALS AND METHODS: We conducted a single-centre retrospective review of patients treated with sacral SBRT between February 2012 and December 2021. The cumulative incidence of local relapse, patterns of failure and overall survival were determined. Two investigators reviewed planning computed tomography scans and imaging at relapse to determine if local relapse was potentially preventable with a larger CCR-derived radiotherapy field. RESULTS: In total, 34 patients received sacral SBRT, with doses ranging from 24 to 40 Gy over three to five fractions. The most frequently used schedule was 30 Gy in three fractions. Common primaries treated included prostate (n = 16), breast (n = 6), lung (n = 3) and renal (n = 3) cancers. The median follow-up was 20 months (interquartile range 13-55 months). The cumulative incidence of local relapse (4/34) was 2.9% (95% confidence interval 0.2-13.2), 6.3% (95% confidence interval 1.1-18.5) and 16.8% (95% confidence interval 4.7-35.4) at 6 months, 1 year and 2 years, respectively. The patterns of failure were local-only (1/34), local and distant (3/34) and distant relapse (10/34). The overall survival was 96.7% (95% confidence interval 90.5-100) and 90.6% (95% confidence interval 78.6-100) at 1 and 2 years, respectively. For prostate/breast primaries, the cumulative incidence of local relapse was 4.5% (95% confidence interval 0.3-19.4), 4.5% (95% confidence interval 0.3-19.4) and 12.5% (95% confidence interval 1.7-34.8) at 6 months, 1 and 2 years, respectively. Twenty-nine cases (85.3%) deviated from the CCR. Sacral relapse was potentially preventable if the CCR was used in one patient (2.9% of the whole cohort and 25% of the relapsed cohort). DISCUSSION: We have shown excellent local control rates with sacral SBRT, which was largely planned with a margin expansion approach.

Assessing Bladder Radiotherapy Response With Quantitative Diffusion-Weighted Magnetic Resonance Imaging Analysis.

AIMS: Radiotherapy with radiosensitisation offers opportunity for cure with organ preservation in muscle-invasive bladder cancer (MIBC). Treatment response assessment and follow-up are reliant on regular endoscopic evaluation of the retained bladder. In this study we aim to determine the role of diffusion-weighted magnetic resonance imaging (DWI) and apparent diffusion coefficient (ADC) analysis to assess bladder radiotherapy response. MATERIALS AND METHODS: Patients with T2-T4aN0-3M0 MIBC suitable for radical radiotherapy were recruited prospectively to an ethics approved protocol. Following transurethral resection of the bladder tumour and prior to any treatment, magnetic resonance imaging including DWI was performed on a 1.5T system using b values of 0, 100, 150, 250, 500, 750 s/mm2. DWI was repeated 3 months after completing radiotherapy. Cystoscopy and tumour site biopsy were undertaken following this. The response was dichotomised into response (0.9, P < 0.01). ΔADCall mean of 0.16 × 10-3 mm2/s and ΔADCb100 mean 0.12 × 10-3 mm2/s predicted radiotherapy response with sensitivity/specificity/positive predictive value/negative predictive value of 92.9%/100.0%/100.0%/75.0% and 89.3%/100.0%/100.0%/66.7%, respectively. CONCLUSIONS: Quantitative DWI analysis can successfully provide non-invasive assessment of bladder radiotherapy response. Multicentre validation is required before prospective testing to inform MIBC radiotherapy follow-up schedules and decision making.

Metastasis-directed Therapy in Prostate Cancer: Prognostic Significance of the ESTRO/EORTC Classification in Oligometastatic Bone Disease.

AIMS: Oligometastatic disease (OMD) represents a spectrum of clinical scenarios and various classification systems have been proposed. Bone-only OMD can occur in patients with advanced prostate cancer and validated decision-making tools are needed to assist patient selection for metastasis-directed therapy. The aim of the present study was to determine the prognostic utility of a classification system for OMD. MATERIALS AND METHODS: A retrospective review was conducted of all patients with bone-only oligometastatic prostate cancer treated with stereotactic body radiotherapy (SBRT) since November 2011. SBRT was delivered using CyberKnife® and gantry-based linear accelerator platforms. All patients were classified into oligometastatic states based on the European Society for Radiotherapy and Oncology/European Organisation for Research and Treatment of Cancer (ESTRO/EORTC) classification system. Kaplan-Meier and Cox regression analyses were carried out to determine the prognostic utility of this classification system. RESULTS: In total, 105 patients with 145 osseous metastases were treated over 119 sessions. The median follow-up after SBRT was 23 months (interquartile range 10-39.8). Twelve patients had died after a median time of 31 months. The 3-year metastatic progression-free survival was 23% (95% confidence interval 13-32) and the 3-year overall survival was 88% (95% confidence interval 80-96). Patients in a metachronous oligometastatic state were 4.50 (95% confidence interval 1.19-17.10, P = 0.03) times more likely to experience metastatic progression compared with those with synchronous oligometastases, and 6.69 (95% confidence interval 1.05-42.50, P = 0.04) times more likely to experience any failure. Hazard ratio magnitudes increased for patients in a repeat oligometastatic state. The multivariate model for both metastatic progression-free survival and failure-free survival found prostate-specific antigen doubling time <4 months (P = 0.002; P = 0.05) to independently predict for progression. CONCLUSION: The ESTRO/EORTC classification of OMD predicts for progression in patients treated with SBRT for bone-only oligometastatic prostate cancer at our institution. Further validation in prospective series over multiple tumour sites is needed. These characterisation factors should be assessed in patients considered for metastasis-directed therapy together with established prognostic features.

Spine and Non-spine Bone Metastases - Current Controversies and Future Direction.

Bone is a common site of metastases in advanced cancers. The main symptom is pain, which increases morbidity and reduces quality of life. The treatment of bone metastases needs a multidisciplinary approach, with the main aim of relieving pain and improving quality of life. Apart from systemic anticancer therapy (hormonal therapy, chemotherapy or immunotherapy), there are several therapeutic options available to achieve palliation, including analgesics, surgery, local radiotherapy, bone-seeking radioisotopes and bone-modifying agents. Long-term use of non-steroidal analgesics and opiates is associated with significant side-effects, and tachyphylaxis. Radiotherapy is effective mainly in localised disease sites. Bone-targeting radionuclides are useful in patients with multiple metastatic lesions. Bone-modifying agents are beneficial in reducing skeletal-related events. This overview focuses on the role of surgery, including minimally invasive treatments, conventional radiotherapy in spinal and non-spinal bone metastases, bone-targeting radionuclides and bone-modifying agents in achieving palliation. We present the clinical data and their associated toxicity. Recent advances are also discussed.

Clinical Outcomes of Stereotactic Body Radiotherapy With Immediate Versus Delayed Hormone Therapy in Men With Oligometastatic Recurrence of Prostate Cancer.

AIMS: Stereotactic body radiotherapy (SBRT) with the delayed option of androgen deprivation therapy (ADT) is the current treatment paradigm in men relapsed with oligometastatic prostate cancer based on the outcome of a phase II randomised controlled study. The immediate (concomitant) use of ADT in this clinical setting potentially augments the efficacy of SBRT by improving systemic disease control. The aim of this study was to compare the clinical outcomes of these two treatment strategies. MATERIALS AND METHODS: Eighty-eight patients with up to three oligometastases and controlled primary disease who had been treated using SBRT with immediate or delayed ADT were included in this retrospective analysis. Progression-free survival (PFS), widespread failure-free survival (WFFS) and freedom from further interventions (FFFI) were assessed using Kaplan-Meier and Cox proportional hazard regression methods. Toxicity was evaluated using Common Terminology Criteria for Adverse Events (CTCAE) v4.0. RESULTS: Thirty-nine patients (44.3%) were treated with SBRT and immediate ADT (continuous ADT, n = 7; intermittent ADT, n = 32) and 49 (55.7%) with SBRT and delayed ADT. The median follow-up was 24 months (interquartile range 13.5-37.0 months). PFS in the immediate and delayed ADT groups were 26 months and 16 months, respectively (P < 0.007). The median WFFS in the immediate ADT group was not reached compared with 21 months in the delayed ADT group (P = 0.025). The 1- and 2-year FFFI in the immediate ADT group were 88% and 64.1%, respectively, significantly higher than those in the delayed ADT group (63.8% and 30.2%, respectively, P < 0.002). Acute toxicities of grade 1-2 occurred in 17.9% of the immediate ADT group and 18.4% of the delayed ADT group (P = 0.96). Only one case of grade 3 late toxicity (pelvic insufficiency) was identified in this study. CONCLUSIONS: SBRT with concomitant ADT improves PFS, WFFS and FFFI as compared with SBRT with delayed ADT; this finding needs validation in a prospective, randomised study.

Forward- and Inverse-Planned Intensity-Modulated Radiotherapy in the CHHiP Trial: A Comparison of Dosimetry and Normal Tissue Toxicity.

AIMS: The CHHiP (Conventional or Hypofractionated High-dose Intensity Modulated Radiotherapy In Prostate Cancer; CRUK/06/016) trial investigated hypofractionated radiotherapy for localised prostate cancer. Forward- (FP) or inverse-planned (IP) intensity-modulated techniques were permitted. Dose-volume histogram and toxicity data were compared to explore the effects of planning method. MATERIALS AND METHODS: In total, 337 participants with intermediate-risk disease and prospectively collected toxicity data were included. Patients were matched on prostate and rectum/bladder volumes and on radiotherapy dose for toxicity comparisons. The primary outcome was grade 2 or higher Radiation Therapy Oncology Group (RTOG) bowel or bladder toxicity at 2 years. RESULTS: IP patients had smaller volumes of rectum irradiated to 50-70 Gy (P < 0.001); FP patients had smaller volumes of bladder irradiated to 74 Gy (P = 0.001). Acute grade 2 + bowel toxicity was worse with FP (27/53 [52%]; 11/53 [21%] IP; P = 0.0002); with no significant differences in acute urinary toxicity. At 2 years, RTOG grade 2 + bowel toxicity rates were FP 0/53 and IP 2/53 and RTOG grade 2 + bladder rates were FP 0/54 and IP 1/57. CONCLUSIONS: Significant differences were found between dose-volume histograms from FP and IP methods. IP may result in small reductions in acute bowel toxicity but both techniques were associated with low rates of late radiotherapy side-effects.

Radiotherapy Quality Assurance for the CHHiP Trial: Conventional Versus Hypofractionated High-Dose Intensity-Modulated Radiotherapy in Prostate Cancer.

AIMS: The CHHiP trial investigated the use of moderate hypofractionation for the treatment of localised prostate cancer using intensity-modulated radiotherapy (IMRT). A radiotherapy quality assurance programme was developed to assess compliance with treatment protocol and to audit treatment planning and dosimetry of IMRT. This paper considers the outcome and effectiveness of the programme. MATERIALS AND METHODS: Quality assurance exercises included a pre-trial process document and planning benchmark cases, prospective case reviews and a dosimetry site visit on-trial and a post-trial feedback questionnaire. RESULTS: In total, 41 centres completed the quality assurance programme (37 UK, four international) between 2005 and 2010. Centres used either forward-planned (field-in-field single phase) or inverse-planned IMRT (25 versus 17). For pre-trial quality assurance exercises, 7/41 (17%) centres had minor deviations in their radiotherapy processes; 45/82 (55%) benchmark plans had minor variations and 17/82 (21%) had major variations. One hundred prospective case reviews were completed for 38 centres. Seventy-one per cent required changes to clinical outlining pre-treatment (primarily prostate apex and base, seminal vesicles and penile bulb). Errors in treatment planning were reduced relative to pre-trial quality assurance results (49% minor and 6% major variations). Dosimetry audits were conducted for 32 centres. Ion chamber dose point measurements were within ±2.5% in the planning target volume and ±8% in the rectum. 28/36 films for combined fields passed gamma criterion 3%/3 mm and 11/15 of IMRT fluence film sets passed gamma criterion 4%/4 mm using a 98% tolerance. Post-trial feedback showed that trial participation was beneficial in evolving clinical practice and that the quality assurance programme helped some centres to implement and audit prostate IMRT. CONCLUSION: Overall, quality assurance results were satisfactory and the CHHiP quality assurance programme contributed to the success of the trial by auditing radiotherapy treatment planning and protocol compliance. Quality assurance supported the introduction of IMRT in UK centres, giving additional confidence and external review of IMRT where it was a newly adopted technique.

New concepts in prostate cancer management: the conundrum of managing oligometastatic disease in prostate cancer-through the looking glass darkly.

The management of oligometastatic prostate cancer continues to stimulate as well as vex cancer professionals since the concept was raised more than two decades ago. The use of regular prostate-specific antigen (PSA) monitoring together with advances in imaging technology such as combined positron-emission tomography (PET)/computed tomography (CT) has enable earlier identification of potential initial spread of disease and recurrence. Recent systematic reviews and trials have supported the feasible and safe delivery of local ablative therapies for oligometastatic lesions with high local control rates and low morbidity. This is very appealing not only to the clinician but hugely to the patient; however, many questions remain as to whether this patient cohort is prognostically and clinically relevant as well as ultimately if local aggressive therapies can alter the natural history of disease progression and benefit these men. This overview examines the issues for identification, treatment, and management of men with oligometastatic prostate cancer.

UK Consensus on Normal Tissue Dose Constraints for Stereotactic Radiotherapy.

Six UK studies investigating stereotactic ablative radiotherapy (SABR) are currently open. Many of these involve the treatment of oligometastatic disease at different locations in the body. Members of all the trial management groups collaborated to generate a consensus document on appropriate organ at risk dose constraints. Values from existing but older reviews were updated using data from current studies. It is hoped that this unified approach will facilitate standardised implementation of SABR across the UK and will allow meaningful toxicity comparisons between SABR studies and internationally.

Oncolytic vaccinia virus as a vector for therapeutic sodium iodide symporter gene therapy in prostate cancer.

Oncolytic strains of vaccinia virus are currently in clinical development with clear evidence of safety and promising signs of efficacy. Addition of therapeutic genes to the viral genome may increase the therapeutic efficacy of vaccinia. We evaluated the therapeutic potential of vaccinia virus expressing the sodium iodide symporter (NIS) in prostate cancer models, combining oncolysis, external beam radiotherapy and NIS-mediated radioiodide therapy. The NIS-expressing vaccinia virus (VV-NIS), GLV-1h153, was tested in in vitro analyzes of viral cell killing, combination with radiotherapy, NIS expression, cellular radioiodide uptake and apoptotic cell death in PC3, DU145, LNCaP and WPMY-1 human prostate cell lines. In vivo experiments were carried out in PC3 xenografts in CD1 nude mice to assess NIS expression and tumor radioiodide uptake. In addition, the therapeutic benefit of radioiodide treatment in combination with viral oncolysis and external beam radiotherapy was measured. In vitro viral cell killing of prostate cancers was dose- and time-dependent and was through apoptotic mechanisms. Importantly, combined virus therapy and iodizing radiation did not adversely affect oncolysis. NIS gene expression in infected cells was functional and mediated uptake of radioiodide both in vitro and in vivo. Therapy experiments with both xenograft and immunocompetent Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mouse models showed that the addition of radioiodide to VV-NIS-infected tumors was more effective than each single-agent therapy, restricting tumor growth and increasing survival. In conclusion, VV-NIS is effective in prostate cancer models. This treatment modality would be an attractive complement to existing clinical radiotherapy practice.

Selective organ preservation with neo-adjuvant chemotherapy for the treatment of muscle invasive transitional cell carcinoma of the bladder.

BACKGROUND: Radiotherapy for muscle invasive bladder cancer (MIBC) aims to offer organ preservation without oncological compromise. Neo-adjuvant chemotherapy provides survival advantage; response may guide patient selection for bladder preservation and identify those most likely to have favourable result with radiotherapy. METHODS: Ninety-four successive patients with T2-T4aN0M0 bladder cancer treated between January 2000 and June 2011 were analysed at the Royal Marsden Hospital. Patients received platinum-based chemotherapy following transurethral resection of bladder tumour; repeat cystoscopy (± biopsy) was performed to guide subsequent management. Responders were treated with radiotherapy. Poor responders were recommended radical cystectomy. Progression-free survival (PFS), disease-specific survival (DSS) and overall survival (OS) were estimated using Kaplan-Meier method; univariate and multivariate analyses were performed using the Cox proportional hazard regression model. RESULTS: Response assessment was performed in 89 patients. Seventy-eight (88%) demonstrated response; 53 (60%) achieved complete response (CR); 74 responders had radiotherapy; 4 opted for cystectomy. Eleven (12%) demonstrated poor response, 10 received cystectomy. Median survival for CR was 90 months (95% CI 64.7, 115.9) compared with 16 months (95% CI 5.4, 27.4; P < 0.001) poor responders. On multivariate analysis, only response was associated with significantly improved PFS, OS and DSS. After a median follow-up of 39 months (range 4-127 months), 14 patients (16%) required salvage cystectomy (8 for non-muscle invasive disease, 5 for invasive recurrence, 1 for radiotherapy related toxicity). In all, 82% had an intact bladder at last follow-up after radiotherapy; 67% had an intact bladder at last follow-up or death. Our study is limited by its retrospective nature. CONCLUSIONS: Response to neo-adjuvant chemotherapy is a favourable prognostic indicator and can be used to select patients for radiotherapy allowing bladder preservation in >80% of the selected patients.

Initial UK Experience of Stereotactic Body Radiotherapy for Extracranial Oligometastases: Can We Change the Therapeutic Paradigm?

AIMS: To retrospectively review the toxicity and early outcome data from patients who have received stereotactic body radiotherapy (SBRT) for extracranial oligometastases at a single UK institution. MATERIALS AND METHODS: Eligible patients had ≤3 extracranial metastases and performance status ≤2. Prior systemic therapy and radical treatment of oligometastastic relapse with any standard treatment modality was permitted. Patients with synchronous metastatic disease were excluded unless they had evidence of controlled primary disease after radical therapy. Follow-up consisted of clinical examination, biochemical and radiological assessments in accordance with standard clinical care. Progression events were defined using RECIST. Toxicity was evaluated using CTCAE v4.0. Local control, progression-free survival (PFS), freedom from widespread distant metastasis (defined as disease not amenable to further radical salvage therapy) and overall survival were calculated. RESULTS: Between July 2011 and April 2014, 73 patients with 87 metastases received SBRT (range 1-3 per patient). The median follow-up was 14.5 months (range 0-26.4). The median PFS was 14.5 months (1 year PFS 57%, 2 year 28%); 1 year overall survival 96%, 2 year 79.8%; 2 year local control 88%. At 2 years, 46% of patients were free from widespread distant metastases. No ≥ grade 3 acute or late toxicity was observed. CONCLUSION: At this time point, observed toxicity is minimal with excellent local control rates. This promising treatment paradigm requires further investigation in the context of a randomised controlled trial to establish if the addition of SBRT to standard care improves survival outcomes.