There are two patient cohorts that could benefit from primary focal therapy; firstly, men with low-risk disease who wish to opt for treatment over active surveillance, and secondly, men with intermediate risk disease for whom radical therapy has been offered, but who seek an alternative strategy with the aim of preserving functional status (erectile function and continence) (Fig. 19.1). These patient groups reflect the two opposing schools of thought regarding patient selection. One believes that focal therapy, as a novel treatment strategy, should only be offered to men with low-risk disease and who therefore have minimal risk of disease progression. The opposing stance is that those patients with intermediate disease are most likely to benefit from treatment if cancer control is achievable together with a lower side-effect profile.

Focal therapy trials provide us with the opportunity of addressing two alternative strategies. Firstly, cancer cure, and secondly, cancer control. The first strategy implies treatment of all identifiable disease within a focal defined area. The second addresses the notion of treating the “index lesion,” i.e. that disease most likely to confer harm if left untreated, with ongoing surveillance of untreated clinically low-risk disease.

Up to approximately 40% of patients have been found to have either unifocal or unilateral disease [38–40]. These patients could undergo a hemi-ablation, or a more targeted focal treatment. However, for the majority, multi-focality exists throughout the gland. There is usually a dominant or index lesion of maximum volume with co-existing multiple smaller lesions. The smaller lesions usually measure less than 0.5 cm³ in volume, in contrast to a much larger average volume of the index lesion (4.3 cm³ in Stamey’s series of radical prostatectomy specimens) [41]. In addition, the index lesion also tends to confer the maximum Gleason grade [42]. There is evidence from molecular genetic studies that metastases originate from a single clone of clinically significant disease, with the suggestion (although with no definitive molecular evidence at present) that the original disease is from the index lesion [43]. This would support the notion of offering disease control by focally treating the index lesion, as long as cancer burden had been accurately assessed and localised from pre-treatment diagnostic investigations [44].

Focal therapy trials therefore have the potential for evaluating a treatment strategy that has not been formally explored before. A protocol that treats all identifiable disease, e.g. with a hemi-ablation of unilateral disease, aims to offer cancer cure, whereas a protocol that offers index lesion treatment and surveillance of remaining clinically insignificant disease offers cancer control. Some current trial protocols allow both treatment options to co-exist, with an upper threshold for untreated clinically insignificant disease of ≤3 mm Gleason 3+3 disease. It could be argued that definitive knowledge of whether index lesions drive disease progression could only be answered within a clinical trial such as this, whereby untreated clinically insignificant disease is monitored and any disease progression detected and treated early.

An international consensus expert panel recently defined focal therapy as ”a type of treatment that aims to eradicate known cancer within the prostate and at the same time preserve uninvolved prostatic tissue with the aim of preserving genitourinary function” [45]. This definition covers a range of protocols that could be incorporated into a focal therapy programme, with different thresholds for treatment volume. For example, the term “focal” may range from treatment of the lesion itself with a minimal margin, through to a subtotal ablation of the prostate allowing a more generous margin. Both have the potential to reduce side effect burden, as long as at least one neurovascular bundle is spared. The tighter the margin, the lower the volume of healthy tissue that would be unnecessarily treated. However, this strategy also carries a greater risk of under-treatment unless tumour locality, size and total peripheral extent can be highly accurately assessed. Image-directed treatment has the potential to permit this strategy. However, the majority of treatment modalities in use, such as cryotherapy and HIFU, currently rely on a cognitive correlation of tumour position from biopsies and pre-operative imaging for treatment planning. Registration techniques that can merge contoured MR visible lesions onto ultrasound platforms are currently under development. If successful, this technique is likely to permit greater precision of truly focal treatments.

Another consideration in setting a treatment protocol is standardisation of outputs. Hemi-ablation can be easily adopted for all focal modalities. The urethra acts as a convenient anatomical marker at the mid-point of the gland on a transverse view. Left or right hemi-gland treatments can thus be planned either side of this, or even the anterior or posterior hemi-glands. However, treatment volumes and protocols usually require tailoring to the treatment modality that is being used. Some treatments, such as cryotherapy and HIFU, are amenable to ablation of relatively large tissue volumes such as a hemi-gland. However, other treatments such as laser may be better suited to treatment of smaller tissue volumes, particularly when they demand time-consuming use of the MR scanner, and where treatment can be more accurately focused according to visual feedback from imaging. Standardisation of treatment protocols across modalities may therefore be difficult to achieve.

Another potential adaptation within a treatment plan is that of targeting the majority of the “dose” to the cancer, with a lower dose to surrounding normal prostatic tissue. Thus, a patient could undergo a hemi-ablation of the ipsilateral lesion at a therapeutic dose, with a lower dose given contra-laterally. This strategy may be preferable to those clinicians concerned with the notion of leaving clinically insignificant disease fully untreated. It may also potentially minimise the risk of leaving previously undetected very low volume disease behind. This idea is already being addressed by new techniques such as CyberKnife that, although not a true form of focal therapy, tailors the dose to be maximal at cancer lesions. Normal tissue receives a lower dose, with therefore presumed lower toxicity overall. Figure 19.2 illustrates this.