Patients diagnosed with localized prostate cancer are now faced with a multitude of treatment options ranging from active surveillance, focal partial gland therapy, and whole-gland radiation or definitive removal via prostatectomy. Despite advances in treatment techniques, posttreatment morbidity remains significantly high after radical options.^1-4 Patients undergoing tissue preserving approaches—such as active surveillance or focal therapy—are subject to regular monitoring with serum PSA testing, interval MRIs, and prostate biopsies which lead to morbidity and patient anxiety.^5,6 Given the low therapeutic ratio shown in the latest ProtecT update, a randomized controlled trial evaluating radical prostatectomy, radical radiotherapy, and active monitoring (an early version of active surveillance), it is vital that clinicians are able to accurately determine and discuss the risks of disease progression and impact on quality of life associated with each form of treatment.^7,8

Although prostate cancer is multifocal in the majority of cases, it is commonly acknowledged at present that the natural history of the disease is driven by the presence of aggressive clones. In other words, not all foci of disease have the ability to progress and metastasize. From a biological perspective, there is an open debate concerning whether low-volume, low-grade prostate cancer foci deserve the label of “cancer” since the inherent hallmarks are not fully represented, namely the ability to:

1. Evade apoptosis
2. Be insensitive to antigrowth signals
3. Be self-sufficient in growth signals
4. Have unlimited replication potential
5. Demonstrate ongoing angiogenesis
6. Invade local tissues and metastasize.⁹

These inherent characteristics are associated with either downregulation or insensitivity of tumor suppressor genes or signals such as cyclin D2, and/or upregulation or overexpression of oncogenes such as DAD 1, EGF, HER2, VEGF, and CXCR4. It is understood that International Society of Urological Pathology (ISUP) 1 disease does not bear the hallmarks of these characteristics, thus is often considered “clinically insignificant disease.”¹⁰ The key is not just to identify any prostatic disease, but to specifically identify disease that has the potential to further mutate and metastasize.

As a result, it is of utmost importance to define whether: (1) only clinically insignificant lesion/s are present; (2) multiple clinically significant lesions are present; (3) 1 clinically significant lesion with satellite-insignificant lesions is present. In the latter case, the index lesion theory arises. The index lesion is typically considered to be the largest, and with it the highest histological grade. The benefit of identifying the index lesion allows treatment to be focused on the lesion of concern, with the aim of maintaining excellent oncological outcomes whilst minimizing treatment-associated morbidity and subsequent posttreatment functional outcomes.¹¹

Over time, diagnostic pathways to identify and localize the index lesion have improved. Previous use of transrectal ultrasound–guided prostate biopsies have developed into nuanced MRI-directed transperineal prostate biopsies. As such, the limitations of transrectal ultrasound biopsies, including under sampling and under staging disease, is minimized.^12-14 MRI has been a helpful tool in identifying clinically significant prostate cancer, where MRI “invisible” disease is often of small volume and/or minimally aggressive.^15,16 Further, typically disease “visible” on MRI is associated with upregulation of genes associated with tumor aggressivity; consequently, such disease is considered likely to represent a more aggressive phenotype with greater potential to progress and metastasize compared to MRI “invisible” disease.^17,18 Finally, despite initial suitability for active surveillance, patients with MRI “visible” disease are noted to have higher rates of upgrading of disease and proceeding to treatment. It has been observed that MRI “invisibility” ISUP 2 disease may act similarly to ISUP 1 and may also be considered clinically insignificant disease.¹⁹ Thus, MRI imaging is an important tool in identifying the index lesion. However, MRIs are not foolproof, thus double reporting and use of other parameters such as PSA density and other imaging modalities are advocated for.²⁰

The implications of a better biological understanding and an enhanced risk stratification at a lesion level should be clearly reflected in treatment allocation. If men with no index lesion should undergo active surveillance, men with multiple clinically significant lesions should undergo radical and maybe multimodal treatment, men with an index lesion should be offered a personalized approach deriving from the abovementioned modalities. Focal therapy plus a margin, or nerve-sparing prostatectomy with preservation of surrounding structures as much as possible, or radiation therapy with a boost to the index lesion are all ways to implement the index lesion context to the treatment planning.²¹ In the case of focal therapy, it would be possible to treat just the index lesion and avoid treatment of clinically insignificant disease. The use of MRI and transperineal biopsies are not the only advancements in the diagnosis of prostate cancer. Interestingly, the SPCG-4 update demonstrated that patients with higher Gleason Score pathology or extracapsular extension on prostatectomy analysis had a higher risk of death from prostate cancer than those with lower-grade pathology or no evidence of extracapsular extension. This may represent a cohort in which micrometastases are present at time of radical treatment. In current practice, patients with high-risk disease are advised to undergo prostate-specific membrane antigen positron emission tomography–CT to detect nodal disease otherwise not visible on MRI and/or extra-pelvic metastases.^22,23). Further in some circumstances the use of prostate-specific membrane antigen positron emission tomography–CT with MRI can improve the negative predictive value compared to MRI alone.²⁴ Innovations are not limited to the high-risk setting. The use of novel biomarkers, separate to the use of serum PSA testing, has the ability to identify patients at risk of having prostate cancer as well as risk-stratify patients once diagnosed with prostate cancer.²⁵

Clinicians can now be more confident in the accurate diagnosis and use this to interpret the randomized controlled trials determining likelihood of disease progression.²⁶ In doing so, the traditional morbidity associated with treatment is minimized in the development of image-modulated radiation treatment and the introduction of robotic assisted nerve sparing techniques along with the uptake of focal therapy for suitable patients. These treatments are vital to optimize treatment morbidity and to allow nuanced conversations regarding disease risk, treatment risk, and outcomes associated with patient preferences and priorities.²⁷