Platinum Priority – Editorial and Reply from Authors

Referring to the article published on pp. 30–36 of this issue

Active Surveillance, Quality of Life, and Cancer-related Anxiety

Living with an untreated cancer may alter quality of life (QoL) in the long term.

To prospectively study long-term changes in general, mental, and physical QoL in a contemporary active surveillance (AS) patient cohort with low-risk prostate cancer (PCa).

The study population consisted of patients enrolled in the PRIAS trial in Helsinki University Hospital (n = 348). The RAND-36 questionnaire was used to assess general QoL at the start of AS and at 1, 3, 5, 7, 9, and 11 years during follow-up. Patients who had undergone robot-assisted laparoscopic prostatectomy (RALP; n = 88) also received the questionnaire after treatment.

Changes over time were analysed using multilevel mixed-effects regression models, and reported as the mean and95% confidence interval. A rule of 0.5 × standard deviation was used to estimate changes of clinical importance.

Median follow-up until the end of AS or last follow-up was 7.2 (range 0.3−12.7) yr. A decrease was observed in six of eight QoL subdomains at 7 yr. However, all scores were above age-stratified reference values. There was no difference between the group who continued AS throughout the study period and the group who discontinued AS and underwent RALP. More than half of the study cohort discontinued AS (n = 198; 57%), 135 men (68%) because of events specified in the protocol and only seven (3.5%) because of anxiety. Metastatic disease developed in six patients (1.7%), and two cases (0.6%) of PCa-related death were recorded among 348 patients in more than 12 yr of overall follow-up. The lack of a randomised control population is a limitation of the study.

Contemporary protocolised AS does not impair general QoL. Men undergoing a treatment change (RALP) did not experience a decrease in QoL before or after their treatment change.

Active surveillance is a safe treatment option for men with low-risk prostate cancer. We show that this follow-up strategy does not cause a decline in patients’ general quality of life.

Hedyotis diffusa Willd. (H) and Scutellaria barbata D.Don (S) are ancient anti-cancer Chinese herb medicines. When combined, known as HS, it is one of the most commonly prescribed Chinese Medicines for cancer patients today in China.

The prevention of disease progression is a dominant concern for the growing number of men with prostate cancer. The purpose of this work is to evaluate the action and mode of action of Chinese Medicine recipe HS in inhibiting prostate cancer progression in preclinical models.

Effects of HS were analyzed in prostate cancer cell lines by evaluating proliferation, cell cycle profile, DNA damage and key regulators responsible for G₂ to M phase transition. The transcriptional activities of these regulators were determined by RT-PCR and ChIP. The efficacy of HS in vitro was validated in an animal model.

HS treatment was observed to reduce DNA content and accumulated prostate cancer cells at the G₂/M phase. Immunolabeling for phospho-Histone H3 in association with nocodazole to capture mitotic cells confirmed that HS impeded G₂ to M transition. After excluding DNA damage-induced G₂ arrest, it was revealed that HS reduced expression of Cyclin B1, CDK1, PLK1 and Aurora A at both protein and mRNA levels, with concomitant reduction of H3K4 tri-methylation at their promoter-regions. Animals that received oral administration of HS with a dosage relevant to clinical application showed reduced tumor volume and weight with a reduction of Cyclin B1, CDK1, PLK1 and Aurora A protein levels.

HS acts by impeding the G₂ to M transition of prostate cancer cells. It is likely that the mode of action is transcriptionally suppressing proteins governing mitotic entry, without eliciting significant DNA damage.

Active surveillance is the preferred management of low risk prostate cancer. Cancer specific anxiety during active surveillance remains under studied. We evaluated long-term anxiety in men on active surveillance to determine whether interventions must be tailored to improve adherence.

A total of 413 men enrolled in active surveillance at a single tertiary care center completed quality of life surveys as part of routine care. A modified version of the MAX-PC (Memorial Anxiety Scale for Prostate Cancer) was used to determine cancer specific anxiety. Generalized estimating equations were applied to evaluate the association between anxiety and the duration on surveillance. Additionally, we examined associations between anxiety and patient age, marital status, Gleason score, the number of positive cores, family history and overall health.

Median patient age was 61 years, median prostate specific antigen at diagnosis was 4.4 ng/ml and 95% of the patients had Gleason 6 disease. Median time from the initiation of active surveillance to the last survey was 3.7 years. There was a 29% risk of reporting cancer specific anxiety within year 1. Anxiety significantly decreased with time (OR 0.87, 95% CI 0.79–0.95, p = 0.003). Pathological and demographic characteristics were not associated with anxiety after adjusting for time on surveillance.

In men undergoing active surveillance we observed a moderate risk of cancer specific anxiety which significantly decreases with time. Those considering conservative management can be informed that, although it is common to experience some anxiety initially, most patients rapidly adjust and report low anxiety levels within 2 years.

Active surveillance is an important alternative to definitive therapy for men with low risk prostate cancer. However, the impact of active surveillance on health related quality of life compared to that in men without cancer remains unknown. In this study we evaluated health related quality of life outcomes in men on active surveillance compared to men followed after negative prostate needle biopsy.

A prospective study was conducted on men who were enrolled into the Center for Prostate Disease Research Multicenter National Database and underwent prostate needle biopsy for suspicion of prostate cancer between 2007 and 2014. Health related quality of life was assessed at biopsy (baseline) and annually for up to 3 years using SF-36 and EPIC questionnaires. Health related quality of life scores were modeled using generalized estimating equations, adjusting for baseline health related quality of life, and demographic and clinical characteristics.

Of the 1,204 men who met the initial eligibility criteria 420 had a negative prostate needle biopsy (noncancer comparison group). Among the 411 men diagnosed with low risk prostate cancer 89 were on active surveillance. Longitudinal analysis revealed that for most health related quality of life subscales there were no significant differences between the groups in adjusted health related quality of life score trends over time.

In this study most health related quality of life outcomes in patients with low risk prostate cancer on active surveillance did not differ significantly from those of men without prostate cancer. A comparison group of men with a similar risk of prostate cancer detection is critical to clarify the psychological and physical impact of active surveillance.

The diagnosis and treatment of prostate cancer have changed dramatically in the prostate specific antigen era. We are now faced with the clinical dilemma of over diagnosis and overtreatment. Targeted focal therapy offers a potential middle ground between the binary choices of active surveillance and the whole gland treatments of radical prostatectomy or radiotherapy.

A PubMed® search was performed using the terms “targeted focal therapy,” “focal therapy,” “hemiablation” and “transperineal mapping biopsy” to locate studies and reviews published after 2000 pertaining to targeted focal therapy of the prostate. Key articles were selected and included in this review, which covers the practical aspects of targeted focal therapy for prostate cancer.

Three international, multidisciplinary consensus statements were located which provide best practice for patient selection in ongoing and future trials of targeted focal therapy. Other studies located for the review elaborate on the best techniques to properly stage a case of histologically confirmed prostate cancer under consideration for focal therapy and summarize outcomes reported to date in the literature.

Phase I and II studies of targeted focal therapy for prostate cancer have demonstrated safety and efficacy. With improved imaging and standardized patient selection criteria, phase III study is under way, perhaps setting the stage for a new era of prostate cancer therapy for many individuals.