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There are two articles in this month's issue of the BJUI that are a little unusual, of great interest and may indeed point the way to the future [1, 2]. So far, in our attempt to come up with less invasive and better tolerated treatments for men with early prostate cancer, clinicians have tended to adopt and adapt existing technologies. The two best known examples are cryotherapy and high-intensity focused ultrasonography (HIFU), energy-delivery systems that were originally used to treat the whole prostate, which have, over time, become the energy platforms that have permitted us to treat the prostate in a selective manner. Put another way, these energy sources have allowed us to substitute our previous target (the organ) with an alternative one (the tumour); something that puts us more in line with the way we treat most other solid-organ cancers. The early signs are that this effort is certainly worth pursuing given that the approach reduces urinary incontinence to a rare event, preserves erectile function in the majority and is associated with promising levels of cancer control in the short to medium term [3, 4]. However, cryotherapy and HIFU have not proved easy to master. They are dynamic therapies in the sense that they need to be ‘driven’ by the operator. The real-time feedback that is available to inform the conduct of the therapies comes largely in the form of subtle changes in grey-scale. Recognizing these changes and responding to them in a timely and measured manner are skills that are hard to teach and difficult to acquire. Their expert delivery is therefore more of an art form than a science. This is one reason why the outcomes have been variable in less experienced hands.

There exists, therefore, a pressing need for interventions that are easier to perform and easier to quality control. The two technologies that have been introduced to us in this issue may indeed have these attributes. The first of these uses sound energy administered via a catheter placed in the urethra to a dose that is pre-set by the operator and controlled by estimates of tissue temperatures that are derived from MRI thermography [1]. This could become a completely automated system with built-in safety controls predicated on maximum and minimum temperature/time exposures. The only practical skill that would be retained would be that of placing the catheter. The rest would be limited to MRI contouring or the prostate, the tumour and the margin (currently a radiological skill set) and the setting of temperature limits; something that is likely to be protocol-driven.

The second uses low-energy direct current as its method of tissue destruction [2]. This technique is novel in the sense that it uses a non-thermal energy source. This means that the mode of action is not that of coagulative necrosis, with which we are very familiar. Instead, the thinking is that the cell kill comes about by tripping the cells into an apoptotic state by compromising the integrity of the cell membrane; hence, the common descriptor of ‘irreversible electroporation’. In terms of ease-of-use, the skill set that is required is the reasonably accurate placement (within 5 mm) of three to four needles to surround the tumour (which will still need to be contoured on MRI and, for this particular technology, will need to be co-registered to the ultrasound image) and the pressing of a button to begin and subsequently complete the energy delivery. The initiation of each needle, the needle sequencing, energy delivery and safety alarms are all automatically controlled by the system, largely by means of monitoring tissue impedance.

One other thing that should be noted is that both procedures are likely to be quick. Current estimates place both technologies at well under 1 h for a completed procedure based on a target volume of ∼4–6 cc (tumour volume of ∼1–2 cc, plus a margin). At present MRI and theatre time are costed at equivalent rates per h (£1000.00; EUR 1115.00; $1504.00), although this of course may change.

So, where next? Electroporation in the form of Nanoknife™ has been used in the USA (US Food and Drug Administration [FDA] 510[k] approval for tissue ablation) and in Europe to treat men with prostate cancer in a tissue-selective manner (Figs 1, 2), albeit in single-centre case-series. A registered, prospective development study of this technology is about to start in the UK (clinicaltrials.gov NCT01726894). The clinical regulatory pathway for the MRI-guided TRUS therapy is yet to be determined and may indeed be dependent on how the evaluation of medical devices is handled by the different regulatory agencies. It is no secret that the FDA is struggling to come up with phase III designs that do not incorporate some form of survival endpoint. Such endpoints will not only require thousands of patients to be recruited but will also take between 10 and 20 years to mature and many millions of dollars to deliver. This is clearly not going to happen, given the number of technologies that require evaluation, the current pressure on funding agencies and the absence of large pharmaceutical companies in this space. There are signs, however, that the FDA recognizes that an impasse exists and, in its desire to resolve this, has initiated a dialogue with patients and interested clinicians to see if a way forward can be agreed and delivered (Dr Peter Scardino, pers. comm.). The signs in the UK are much more optimistic. Multicentre prospective development studies are under way and recruiting well (Clinicaltrials.gov NCT01194648) [5]. Comparative effectiveness designs that incorporate surrogate endpoints that can be derived within a 5-year time frame are, at the time of writing, being considered by UK funding agencies (Professor Freddie Hamdy, pers. comm.). These new studies will be designed in such a way as to incorporate new technologies once their safety profile is secured. This emphasis on the ‘adaptive’ and ‘pragmatic’ will ensure that evaluation can stay at the forefront of technological development and not lag behind innovation or changes in practice [6].

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Figure 1. T1 Gadolinium MRI taken preoperatively, showing tumour (Gleason 3 + 4) arising from the anterior fibromuscular septum to the left of the midline.

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Figure 2. T1 Gadolinium MRI taken 1-week after NanoknifeTM irreversible electroporation demonstrating absence of perfusion to the treated area.

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Conflict of Interest

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Mark Emberton is a principal investigator in a number of trials evaluating focal therapies. These are supported by the Wellcome Trust, STEBA Biotech, Prostate Cancer UK, Angiodynamics INC and by Sonacare INC. He has acted as consultant to both Sonacare INC and STEBA Biotech in this capacity. Mark Emberton's research activity is supported by the National Institute of Health Research through the UCLH/UCL Biomedical Research Centre, London UK.

References

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  2. Conflict of Interest
  3. References