A. Tree

Stereotactic body radiotherapy for oligometastases

The management of metastatic solid tumours has historically focused on systemic treatment given with palliative intent. However, radical surgical treatment of oligometastases is now common practice in some settings. The development of stereotactic body radiotherapy (SBRT), building on improvements in delivery achieved by intensity-modulated and image-guided radiotherapy, now allows delivery of ablative doses of radiation to extracranial sites. Many non-randomised studies have shown that SBRT for oligometastases is safe and effective, with local control rates of about 80%. Importantly, these studies also suggest that the natural history of the disease is changing, with 2-5 year progression-free survival of about 20%. Although complete cure might be possible in a few patients with oligometastases, the aim of SBRT in this setting is to achieve local control and delay progression, and thereby also postpone the need for further treatment. We review published work showing that SBRT offers durable local control and the potential for progression-free survival in non-liver, non-lung oligometastatic disease at a range of sites. However, to test whether SBRT really does improve progression-free survival, randomised trials will be essential.

Progression-free Survival Following Stereotactic Body Radiotherapy for Oligometastatic Prostate Cancer Treatment-naive Recurrence: A Multi-institutional Analysis

UNLABELLED The literature on metastasis-directed therapy for oligometastatic prostate cancer (PCa) recurrence consists of small heterogeneous studies. This study aimed to reduce the heterogeneity by pooling individual patient data from different institutions treating oligometastatic PCa recurrence with stereotactic body radiotherapy (SBRT). We focussed on patients who were treatment naive, with the aim of determining if SBRT could delay disease progression. We included patients with three or fewer metastases. The Kaplan-Meier method was used to estimate distant progression-free survival (DPFS) and local progression-free survival (LPFS). Toxicity was scored using the Common Terminology Criteria for Adverse Events. In total, 163 metastases were treated in 119 patients. The median DPFS was 21 mo (95% confidence interval, 15-26 mo). A lower radiotherapy dose predicted a higher local recurrence rate with a 3-yr LPFS of 79% for patients treated with a biologically effective dose ≤100Gy versus 99% for patients treated with >100Gy (p=0.01). Seventeen patients (14%) developed toxicity classified as grade 1, and three patients (3%) developed grade 2 toxicity. No grade ≥3 toxicity occurred. These results should serve as a benchmark for future prospective trials. PATIENT SUMMARY This multi-institutional study pools all of the available data on the use of stereotactic body radiotherapy for limited prostate cancer metastases. We concluded that this approach is safe and associated with a prolonged treatment progression-free survival.

Improvement in tumour control probability with active breathing control and dose escalation: A modelling study

INTRODUCTION The prognosis from non-small cell lung cancer remains poor, even in those patients suitable for radical radiotherapy. The ability of radiotherapy to achieve local control is hampered by the sensitivity of normal structures to irradiation at the high tumour doses needed. This study aimed to look at the potential gain in tumour control probability from dose escalation facilitated by moderate deep inspiration breath-hold. METHOD The data from 28 patients, recruited into two separate studies were used. These patients underwent planning with and without the use of moderate deep inspiration breath-hold with an active breathing control (ABC) device. Whilst maintaining the mean lung dose (MLD) at the level of the conventional plan, the ABC plan dose was theoretically escalated to a maximum of 84 Gy, constrained by usual normal tissue tolerances. Calculations were performed using data for both lungs and for the ipsilateral lung only. Resulting local progression-free survival at 30 months was calculated using a standard logistic model. RESULTS The prescription dose could be escalated from 64 Gy to a mean of 73.7+/-6.5 Gy without margin reduction, which represents a statistically significant increase in tumour control probability from 0.15+/-0.01 to 0.29+/-0.11 (p<0.0001). The results were not statistically different whether both lungs or just the ipsilateral lung was used for calculations. CONCLUSION A near-doubling of tumour control probability is possible with modest dose escalation, which can be achieved with no extra increase in lung dose if deep inspiration breath-hold techniques are used.

MRI-guided prostate adaptive radiotherapy - A systematic review.

Dose escalated radiotherapy improves outcomes for men with prostate cancer. A plateau for benefit from dose escalation using EBRT may not have been reached for some patients with higher risk disease. The use of increasingly conformal techniques, such as step and shoot IMRT or more recently VMAT, has allowed treatment intensification to be achieved whilst minimising associated increases in toxicity to surrounding normal structures. To support further safe dose escalation, the uncertainties in the treatment target position will need be minimised using optimal planning and image-guided radiotherapy (IGRT). In particular the increasing usage of profoundly hypo-fractionated stereotactic therapy is predicated on the ability to confidently direct treatment precisely to the intended target for the duration of each treatment. This article reviews published studies on the influences of varies types of motion on daily prostate position and how these may be mitigated to improve IGRT in future. In particular the role that MRI has played in the generation of data is discussed and the potential role of the MR-Linac in next-generation IGRT is discussed.

Stereotactic body radiotherapy for prostate cancer.

The use of stereotactic body radiotherapy (SBRT) for localised prostate cancer is now supported by a substantial body of non-randomised data, with medium-term outcomes consistent with current standard radiotherapy. The ability to deliver profoundly hypofractionated treatment, combined with the relatively low α/β ratio of prostate cancer, may result in a more favourable therapeutic ratio, presenting an opportunity for isotoxic dose escalation. Furthermore, as treatment can be given in five attendances, SBRT has the potential both to reduce costs and improve patient quality of life. However, in a treatment landscape with many competing options of broadly similar efficacy, randomised trials are essential to define the relative benefits of this approach. SBRT also has an emerging application in oligometastatic prostate cancer, with promising early outcomes for delaying disease progression and deferring the need for androgen deprivation therapy.

Biological Dose Escalation and Hypofractionation: What is There to be Gained and How Will it Best be Done?

The evidence supporting dose escalation for localised prostate cancer is widely accepted, but in tandem with improvements in biochemical control, dose escalation increases side-effects. In a scenario where most patients achieve control of their cancer, quality of life concerns predominate. Here we examine the biological ways in which an effective dose can be escalated without an unacceptable increase in toxicity. Possible avenues include exploiting the unusual radiobiology of prostate cancer by hypofractionation, the use of image guidance, adaptive planning and prostate motion management. We await with anticipation the results of large randomised trials of hypofractionation, moderate and profound, to establish whether we can further improve the balance between cure and quality of life.

Prostate Stereotactic Body Radiotherapy - First UK Experience

AIMS Stereotactic body radiotherapy (SBRT) combines image-guided radiotherapy with hypofractionation, both of which will probably result in improvements in patient outcomes in prostate cancer. Most clinical experience with this technique resides in North America. Here we present the first UK cohort to receive SBRT for prostate cancer. MATERIALS AND METHODS Fifty-one prostate cancer patients (10 low risk, 35 intermediate risk and 6 high risk) were treated with 36.25 Gy in five fractions over 1-2 weeks and gold seed image guidance. All patients had toxicity International Prostate Symptom score (IPSS) and Radiation Therapy Oncology Group recorded prospectively and prostate-specific antigen was measured 3-6 monthly during follow-up. RESULTS The median IPSS was 6, 11, 8 and 5 at baseline, 1-3 weeks, 4-6 weeks and 7-12 weeks after treatment. Radiation Therapy Oncology Group genitourinary and gastrointestinal toxicity of grade 2 was seen in 22% and 14%, respectively, at 1-3 weeks after treatment; no patient had grade 3+ toxicity at this time point, although two patients had grade 3 urinary frequency recorded during treatment. The median follow-up for the 42 patients who did not receive androgen deprivation was 14.5 months. Prostate-specific antigen at 13-18 months after treatment was 1.3 ng/ml. CONCLUSION Prostate SBRT is a promising treatment for organ-confined prostate cancer and is currently being investigated in a UK-led phase III trial.

Is Biochemical Relapse-free Survival After Profoundly Hypofractionated Radiotherapy Consistent with Current Radiobiological Models?

AIMS The α/β ratio for prostate cancer is thought to be low and less than for the rectum, which is usually the dose-limiting organ. Hypofractionated radiotherapy should therefore improve the therapeutic ratio, increasing cure rates with less toxicity. A number of models for predicting biochemical relapse-free survival have been developed from large series of patients treated with conventional and moderately hypofractionated radiotherapy. The purpose of this study was to test these models when significant numbers of patients treated with profoundly hypofractionated radiotherapy were included. MATERIALS AND METHODS A systematic review of the literature with regard to hypofractionated radiotherapy for prostate cancer was conducted, focussing on data recently presented on prostate stereotactic body radiotherapy. For the work described here, we have taken published biochemical control rates for a range of moderately and profoundly fractionated schedules and plotted these together with a range of radiobiological models, which are described. RESULTS The data reviewed show consistency between the various radiobiological model predictions and the currently observed data. CONCLUSION Current radiobiological models provide accurate predictions of biochemical relapse-free survival, even when profoundly hypofractionated patients are included in the analysis.

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.

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.