Unravelling the natural history of localised prostate cancer in the post-prostate specific antigen era: implications for clinical management

Introduction

Worldwide, prostate cancer (PCa) now represents the second most common cancer affecting men (1). One in eight men will be diagnosed with PCa in their lifetime (2,3). The incidence of PCa has continued to rise over the last few decades, partly driven by men living older and also the advent of prostate-specific antigen (PSA) screening for early detection (4,5). Despite the increasing prevalence, the management of localized PCa remains controversial (6).

Two large randomized controlled trials (RCTs) have evaluated the role of active treatment for PCa, but similarly yield negative results. The PIVOT study compared radical prostatectomy with observation, and found no survival benefit in favor of the former (7). However, the study recruited participants with presumably poorer health status with nearly half of the cohort dying from other causes rather than PCa by the 10-year mark (8). The PROTECT study similarly did not find survival benefit with curative treatments of either prostatectomy or radiotherapy compared to active monitoring, although the study was criticized for having a predominant low risk disease profile (~77%) (9). Nevertheless, patients assigned to active monitoring were more likely to experience disease progression and metastasis.

With the results from these studies, it remains uncertain as to which group of patients will truly benefit from active treatment for localized PCa. Treatment decisions are complex, as there is a need to balance prostate cancer mortality (PCM) against treatment morbidity and competing mortality risks (10). While it is generally accepted that men with significant medical comorbidities do have a higher probability of non-prostate cancer mortality (NPCM), and should therefore consider conservative management, it remains unclear if the converse is true (11). To address these controversies, this study revisits the natural history of untreated PCa to determine the long-term survival implications on various subgroups of patients. This may allow us to determine which patients are suitable for expectant or active management. We present this article in accordance with the STROBE reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-24-322/rc).

Methods

We reviewed our institution’s prospectively maintained cancer registry and selected patients diagnosed with PCa between 2002–2010. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study was approved by the SingHealth Institutional Review Board (SingHealth IRB: 2009/1053/D). Informed consent was obtained from all individual participants included in the study.

Patients with metastatic disease (based on conventional staging computed tomography and bone scintigraphy) were excluded, and so were patients who received any form of PCa treatment (prostatectomy, radiotherapy or hormonal therapy) (Figure 1).

Figure 1 Flowchart of participants’ disposition throughout the study. EBRT, external beam radiotherapy; LDR, low-dose-rate; T, tumour; PSA, prostate-specific antigen.

Clinicopathological parameters and comorbidities status were collected. All specimens were reported by our institution’s dedicated uropathology service according to the College of American Pathologists protocol. Risk stratification was performed using European Association of Urology (EAU) risk groups (12). Charlson Comorbidity Index (CCI) score calculation was based on the age-adjusted Charlson Comorbidity index (13). All patients were followed up until the date of death or the end of study (December 2022). Follow-up strategies employed were patient-specific with the goal to monitor and minimize symptoms from their PCa, often with biannual to annual clinic visits with PSA monitoring and digital rectal examinations (if there is significant PSA rise). The primary outcomes of interest were PCM and death from other causes (NPCM).

Statistical analysis

Patient characteristics were compared using descriptive analysis. Univariate analysis was performed using chi-square test, and a logistic binary regression was performed for the multivariate analysis. In determining the primary outcome, we employed the Fine-Gray model to conduct a competing risk analysis. This model accounts for competing risks by modelling the cumulative incidence function (CIF) of the event of interest (PCM), while considering the occurrence of competing events as a possible cause of failure (NPCM) (14). This effect of the predictor variable on CIF of PCM after taking into account the occurrence of NPCM is computed as the subdistribution hazard ratio (sdHR) (15). The sdHR reports the relative change in the instantaneous rate of the occurrence of the event (PCM vs. NPCM) in subjects who are event-free (i.e., still alive) or who have experienced a competing event (NPCM vs. PCM, respectively). Variables that were statistically significant in the logistic binary regression were used to create the model for the sdHR analysis. All statistical analyses were performed using R 3.5.3. A P value <0.05 was considered to indicate statistically significant difference.

Results

A total of 1,679 consecutive men were identified. After the exclusion process as outlined above, a total of 204 patients were identified to have been conservatively managed upon diagnosis and were analysed.

The median age of PCa diagnosis was 73 years [interquartile range (IQR), 66–78 years]. A total of 113 (55.4%), 83 (40.7%), and 8 (3.9%) patients had a CCI of 0–3, 4–6, and >6 respectively. In terms of the cancer profile, the median PSA at diagnosis was 8.85 ng/mL (IQR, 4.2–16.5 ng/mL), and in particularly, 37 patients (18.1%) had PSA >20 ng/mL. There was a relatively even distribution across the EAU risk groups, with 96 patients (47.0%) having low risk, 64 (31.4%) intermediate and 44 (21.6%) with high-risk disease. Patient demographics are detailed in Table 1.

The median follow-up was 12.5 years (IQR, 8.8–16.5 years). The 15-year cumulative overall mortality, PCM, and NPCM were 50.5%, 9.3%, and 41.2% (Figure 2). The univariate 15-year NPCM and PCM are detailed in Table 1. Older patients (P<0.001) and those with poorer comorbidities (P<0.001) were more likely to experience NPCM, while a more aggressive tumour biology, characterized by higher PSA (P<0.001) and prostate cancer grade groups (PCGG) (P<0.001), is associated with higher PCM. A competing risk model was subsequently developed to account for the interaction between different causes of death and again, yielded similar results (Table 2). Older patients >75 years old [sdHR 7.77, 95% confidence interval (CI): 2.85–21.2; P<0.001] and those with poorer comorbidities (CCI >6) (sdHR 8.51, 95% CI: 3.08–23.51; P<0.001) were associated with NPCM, while the PCGG (sdHR 30.38, 95% CI: 7.48–123.3; P<0.001), PSA (sdHR 8.08, 95% CI: 1.59–41.00; P=0.01) and risk stratification (sdHR 17.36, 95% CI: 4.06–74.3; P<0.001) affected PCM.

Figure 2 Cumulative incidence of overall mortality, PCM, and NPCM. PCM, prostate cancer mortality; NPCM, non-prostate cancer mortality.

To better evaluate the potential role of active treatment in the management of localized advanced PCa, a subgroup analysis evaluating the effect of CCI scores in patients with high-risk PCa (n=44) was performed. The 15-year cumulative incidence of PCM for patients with CCI 0–3 and ≥4 was 63.6% and 15.6% (P=0.004), whereas the 15-year cumulative incidence of NPCM for patients with CCI 0–3 and ≥4 was 18.2% and 68.6% (P=0.008). Figure 3 depicts the PCM and NPCM of high-risk PCa patients when subdivided according to their CCI score. Patients with high-risk PCa and a concurrent CCI score of 3 or less had a greater risk of PCM than NPCM with the following sdHR of 4.31 (95% CI 1.49–12.5; P=0.007) and 0.22 (95% CI: 0.078–0.65; P=0.005) respectively. This means that patients with high-risk PCa and CCI score of 3 or less was associated with a 331% increase in rate of PCM in subjects who were still alive or experienced NPCM. They were also associated with a 78% decrease in rate of NPCM in subjects who were still alive or experienced PCM.

Figure 3 These figures show cumulative incidence of prostate cancer mortality and non-prostate cancer mortality in subjects with CCI scores of 3 or less (A) and 4 or more (B). PCM, prostate cancer mortality; NPCM, non-prostate cancer mortality; CCI, Charlson Comorbidity Index.

The converse held true as well, high-risk PCa patients with higher CCI scores had an increased risk of NPCM (sdHR 5.52, 95% CI: 3.012–8.78; P=0.003) than PCM (sdHR 0.88, 95% CI: 0.032–0.97; P=0.005).

Discussion

For most invasive cancers, effective curative treatment makes all the difference between life and death. While PCa can follow an aggressive and ultimately fatal course, a significant proportion of cases will behave in an indolent fashion, with no impact on neither health nor longevity, even in the absence of treatment (16). Partly for these reasons, it is crucial for us to gain a better understanding of the natural history of localized PCa, so as to aid decision making on who should receive conservative or radical treatment.

In this present study, the results showed that death from PCa in patients with localized disease at 12.5 years of follow-up hovered at 9.3%, while death from other causes in the same period was 41.2%. Older patients and those with greater morbidities are more likely to die from competing non-PCa causes, while patients with a more aggressive cancer biology remains more likely to die from PCa. Notably, these trends were discerned within a study cohort representative of a diverse patient population commonly encountered in clinical practice, encompassing older men with multiple comorbidities and a relatively balanced distribution of PCa lesions across the EAU risk groups. This broader patient inclusivity enhances the external validity of our results, thereby augmenting their clinical relevance and applicability to real-world clinical practice.

The last few decades have seen limited advancements in our understanding of the natural history of PCa, with only a handful of publications investigating this topic in recent years, and with study populations in the pre-PSA era (16-19). Most notable of which was Kessler & Albertsen (2003), where they surmised an estimated 15-year survival rate based on patient age and Gleason score without considering competing medical hazards (16). Popiolek et al. (2013) similarly studied the natural history of PCa in the Swedish population and reported a PCM of 17% over three decades (17). Much has changed since then, with lead time differences from an accelerated date of diagnosis for many patients following the advent of PSA testing, as well as the changes in the incidence and mortality rates (19). It is thus timely for us to revisit the natural history of PCa in the context of contemporary practice to better evaluate overall disease mortality and guide our selection of patients who may benefit from radical treatment.

The two landmark studies have both shown that undergoing radical treatment do not significantly reduce all-cause or PCM in men with clinically localized PCa in the era of PSA testing, especially in those with low PSA value or low-risk disease (7,9). However, it remains to be seen if the converse is true for patients with high-risk disease (17,20,21). Subgroup analysis of the PIVOT study suggested a potential role of radical treatment in the intermediate-risk group, but these results were not replicated in the PROTECT study, even at the latest 15 years of follow up (22,23). This present study included a substantial proportion of high-risk PCa (21.6%) to examine the natural history of the more aggressive and advanced phenotype. We identify that healthy patients with a low CCI score (≤3) were more likely to die from PCa (sdHR 4.31, 95% CI: 1.49–12.5; P=0.007) than other causes (sdHR 0.22, 95% CI: 0.078–0.65; P=0.005) and therefore, may be more amenable for active treatment. On the other hand, even in the high-risk group, patients with significant comorbidities remained more likely to die from other causes, and therefore, PCa treatments in these patients are potentially unnecessary and inconsequential to survival outcomes. Thus, this supports the notion that CCI can potentially be used to discern who should receive conservative or radical therapies. We postulate that CCI may be able to serve as an effective tool for physicians to provide individualized estimates of NPCM and PCM to patients and empower them to make a more informed treatment decision (11,24). Specifically, patients with high-risk disease and few competing comorbidities are most likely to benefit from radical treatment (11,24).

Our study is not without its limitations. Firstly, the retrospective nature of our data collection may have introduced some inherent information errors from selection biases that may potentially limit the accuracy of the evaluations. The relatively small population of patients in the high-risk PCa group (n=44) also poses challenges to the analysis. However, it is still noteworthy that a clear relationship could be elucidated despite the small population size, that in high-risk PCa patients, healthy patients with a CCI score less than 3 had a greater risk of PCM, while those with higher CCI scores had an increased risk of NPCM. Future research is warranted to see if this relationship still holds true in larger population group. Secondly, in this study, we were unable to identify the underlying rationales for opting for conservative management in the studied patient cohort. It is pertinent to highlight that expectant management of PCa, especially intermediate and high-risk PCa, does not align with the standard of care practiced in our institution. Thus, we believe that the decision-making process regarding conservative management likely reflects a complex interplay of patient-specific and surgeon-related factors, including but not limited to, patient’s understanding and expectations of disease, financial considerations, comorbidities, and goals of care. Thirdly, most of these patients may not have undergone multiparametric magnetic resonance imaging which is crucial in providing anatomical staging and may have upstaged those with biopsy-determined intermediate risk patients. Fourthly, the study could not explore the quality of life as a complementary index to survival to evaluate the psychological trade-off of monitoring versus active treatment in patients with localized PCa.

Conclusions

In our cohort of elderly men with PCa being treated conservatively, we reported an overall low PCM of 9.3% at 15 years of follow up. Older patients with poorer comorbidities were more likely to die from other causes, while PSA, PCGG and higher risk groups accounted for PCM. Even within the high-risk PCa subgroup, patients with significant comorbidities exhibited a heightened likelihood of succumbing to non-PCa-related causes, indicating the potential insignificance of PCa treatments in this subset of patients concerning survival outcomes. Consequently, this suggests that CCI may be important in decision making. While active treatment may be pursued in fit patients with low CCI, those with high CCI regardless of cancer risk profile may be amenable for a conservative management approach. Further prospective investigations are warranted to further ascertain the feasibility and efficacy of employing CCI as a guiding parameter in clinical decision-making processes.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tau.amegroups.com/article/view/10.21037/tau-24-322/rc

Data Sharing Statement: Available at https://tau.amegroups.com/article/view/10.21037/tau-24-322/dss

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-24-322/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-24-322/coif). Y.G.T. serves as an unpaid editorial board member of Translational Andrology and Urology from July 2024 to June 2026. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study was approved by the SingHealth Institutional Review Board (SingHealth IRB: 2009/1053/D). Informed consent was obtained from all individual participants included in the study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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