Introduction
In Europe, prostate cancer ranks first among the most frequently diagnosed cancers in men (1). It is more common in men aged >65 years (2), however studies have documented an age-migratory pattern towards an increase in prostate cancer cases in younger age groups (50–59 years) (3). As in other developed countries, prostate cancer incidence has been rising in Portugal since 1998 (4). This cancer was the most common among Portuguese men with 7,529 new diagnoses in 2022 (19.9% of all new cases of malignancy in men) and an age-standardized incidence rate of 62.6 cases/100,000 men (vs. 59.9/100,000 men in Europe) (1). Prostate cancer mortality has declined in most high-income countries since the mid-1990s, including in Portugal (4), likely reflecting advances in treatment and earlier detection with the increased use of prostate-specific antigen (PSA) testing (5–7). In Portugal, there were 2,083 prostate cancer-related deaths in 2022 and the age-standardised mortality rate was 11.1 deaths/100,000 men (vs. 11.2 deaths/100,000 men in Europe (1). Localised disease accounts for >80% of prostate cancer diagnoses and of these 15% are at high risk of cancer recurrence (8,9).
Although the aetiology of prostate cancer is not well understood, risk factors such as age, family history, certain genetic mutations, such as BRCA gene mutation (10), and ethnicity may contribute to the development of prostate cancer (11,12). These may influence both genetic and epigenetic factors (13). Of all the men who receive a diagnosis of prostate cancer, 30–50% may not have a life-threatening condition (14). Therefore, choice of treatment may be complex since it must consider tumour staging, risk stratification, comorbidities, life expectancy, potential side effects of the different treatments and the preference of the patient (14).
Localized prostate cancer has often an indolent course but disease progression and metastases can develop in the long-term (15), thus reinforcing the importance of early diagnosis and adequate clinical management. Nevertheless, the clinical approach to patients with early-stage prostate cancer remains controversial (16). Active surveillance is considered appropriate for selected patients, namely for those with a clinically low-risk and for some with an (favourable) intermediate-risk. Remaining patients (intermediate- and high-risk) may undergo radical prostatectomy, radiotherapy including external beam radiotherapy (EBRT) or brachytherapy, or even experimental focal therapies, including high-intensity focused ultrasound, cryotherapy or laser ablation therapy (17).
The natural course of prostate cancer, the time of diagnosis and the available treatment options make the characterisation of patients at the time of diagnosis extremely relevant. Portuguese Oncology Institute of Porto (IPO Porto; Porto, Portugal) is a Portuguese comprehensive cancer centre with integrated oncology and palliative care that serves a large population region. It includes multidisciplinary clinical units, termed the Pathology Clinics, which ensure, in the same physical space, that all the needs of healthcare patients are met according to their diagnosis. Each case is evaluated by different medical specialists, and decision-making occurs through knowledge and expertise, whilst taking into account the preferences, values and priorities of the patients (18).
It is of utmost importance to understand current multidisciplinary clinical practice in the management of these patients and the clinical outcomes resulting from this practice in a real-world setting outside of clinical trials. In this context, the Prostate Early Cancer (PEarlC) study was conducted primarily to investigate real-world characteristics and treatment patterns of a retrospective cohort of patients with early-stage prostate cancer followed up at IPO Porto and to evaluate the response to treatment by clinical outcomes commonly used in real-world practice. As a secondary objective, the present study compared clinical outcomes between different disease risk subgroups.
Discussion
It is known that the number of patients in treatment for LPC has been increasing in Portugal (26) likely due to the widespread use of PSA (contributing to an increase in incidence and early cancer detection), improved access to healthcare (mainly hospital specialist consultations) and population aging (26). However, there is still a lack of knowledge on the characteristics and clinical outcomes of these patients with early prostate cancer, namely those with high-risk LPC and LAPC. Real-world data is important to characterise patients treated in clinical practice and measure outcomes outside of the clinical trial setting where highly selected patients are frequently enrolled (27). It can also be of importance to provide insights about health care patterns, including treatments (27). Real-world data is increasingly being used to propose and support decision-making in the clinical management of patients (27).
To the best of our knowledge, the present retrospective study provided the first characterisation of a large cohort of patients with early-stage prostate cancer treated in real-world conditions at a tertiary cancer institute in Portugal, together with an exhaustive set of clinical outcomes. The present study covered the clinical practice at IPO Porto over 6 years (2015–2020). Clinical practice at IPO Porto for early-stage prostate cancer has not suffered major changes since then. Therefore, it is expected that the results presented here are still valid for the present setting. Although this is a single-centre study, IPO Porto is one of the most relevant Portuguese centres treating oncologic diseases, including prostate cancer, and is responsible for the management of ~850 new patients with prostate cancer per year, equating to ~11.3% of all new cases in Portugal (1). The present study conducted at this centre allowed the inclusion of a large sample and the calculation of precise estimates for the overall sample with a low margin of error.
In the present study, the exclusion criteria were mainly defined to exclude patients with incomplete follow-up data, as they would not be suitable to estimate 5-year clinical outcomes. A total of 259 patients were excluded from the study due to continuation of treatment outside IPO Porto, which is common in reference oncology centres; namely, when patients looked for a second opinion on the treatment protocol suggested by another hospital, or wished to have access to treatment techniques, such as robotic or laparoscopic surgery, that were not available at IPO at the time of the study. However, these excluded patients are not expected to have more severe disease than the included patients, and therefore their exclusion likely did not limit the internal validity of the results for all patients treated at IPO Porto. Furthermore, a characterisation of the subjects lost to follow-up was not performed, but their exclusion did not introduce any bias in the results considering their low number (n=23), as compared with the total sample size (n=790). Thus, the present sample appears to have been highly representative of all early-stage prostate cancer cases attended at IPO Porto.
It was not expected that the characteristics of the patients treated at IPO Porto differed significantly from those of patients treated at other reference Portuguese oncology centres. Given the small number of patients in palliative care, non-treated or only in HT, the sample of the present study mainly reflected patients being followed up using a multidisciplinary approach and treated with curative intentions including brachytherapy, radical prostatectomy or radiotherapy combined with HT. Missing data was minimal (only missing for ECOG status) due to exclusion criteria and data quality control. The quality of the data retrospectively collected in the present study was ensured by the standard operating procedures for data management and statistical analysis implemented at IPO Porto.
In the present study, 14.3% of all PC diagnoses were high-risk, which is aligned with what has been described in the literature (15%) (8,9). Within the LPC subgroup, there was a higher percentage of patients submitted to prostatectomy in the non-high-risk patients (38.8%) compared with high-risk patients (16.3%). There is likely a judicious use of surgery as a single recommendation for high-risk patients, mainly because most of the time there is a need for multimodal treatments, and this is of the utmost importance to the multidisciplinary board of IPO Porto. There is still a discussion about the use of radical prostatectomy as a first-line treatment for LAPC (28). At IPO Porto, only 4.5% (n=5) of patients with LAPC were submitted to this type of surgery. At IPO Porto, the clinical protocol is to treat patients with LAPC with radiotherapy combined with hormonotherapy, a practice aligned with the European Association of Urology recommendations (22).
Only four studies with Portuguese patients with LPC/LAPC published in indexed journals were identified for the purpose of the present study. A previous study (29), including 300 Portuguese patients with LPC and a first prostate biopsy at another Portuguese oncology reference centre (Portuguese Oncology Institute of Coimbra, Coimbra, Portugal) between January 2014 and December 2018, reported 17.3% (vs. 30.1% at IPO Porto) patients who underwent radical prostatectomy, 39.3% (vs. 43.2%) who underwent external radiotherapy, 29.3% (vs. 21.7%) who underwent brachytherapy and 14.1% (vs. 5.0%) who were treated with other options (active surveillance, cryotherapy and hormonal therapy). Since there is no information on the risk of these patients, the differences in treatment practices between IPO Coimbra and IPO Porto could not be justified.
A registry-based study (30) carried out in 43 Portuguese centres and published in 2010 included 1,767 patients with early-stage prostate cancer, of whom 69.8% had LPC (vs. 85.7% at IPO Porto) and 30.2% had LAPC. In patients with LPC, the most common treatments were radical prostatectomy (43.9%), radical radiotherapy (25.3%) and pelvic adjuvant radiotherapy (9.3%). In LAPC, 67.8% were first treated with HT. However, the study was published >10 years ago, and the authors recognized limitations on the sampling methods and external validity.
In addition, a Portuguese single-centre retrospective study (31) was identified that reported 6-year real-world outcomes in non-high-risk LPC [defined according to European Organisation for Research and Treatment of Cancer (32)] between 2003 and 2013; however, in this previous study, the patients were only treated with brachytherapy, and therefore it cannot be used for comparing outcomes or treatment patterns with the present study.
Botelho et al (26) performed a nationwide study which described treatment patterns over time in localized prostate cancer in the Portuguese National Health System hospitals between 2000 and 2020. Still, the results were mainly presented at treatment-level rather than patient-level, focused mostly on hospital case volume (cumulative number of treatments per year) and data for radiotherapy were not available after 2012. Therefore, the lack of recent real-world Portuguese studies in patients with LPC and/or LAPC limited our understanding and the comparison of the current clinical practice and outcomes in other hospitals vs. IPO Porto.
Furthermore, the comparison with published studies from other countries is not straightforward due to differences in the included patient population (namely the stage of the disease), treatments, outcome definitions and study period. Goy et al (33) compared clinical outcomes of radical prostatectomy vs. EBRT vs. brachytherapy for patients with intermediate-risk prostate cancer only (a subgroup included in the non-high-risk LPC of PEarlC study) treated between 2004 and 2007 and followed-up for 10 years. The 5-year survival rate seen in the PEarlC study for the non-high-risk group (96.8%) is within the range estimates by treatment in the former study (90.6–98.1%) as well as the PSA progression-free survival rate (87.4% in PEarlC study vs. 73–90.7% in Goy et al).
In the PEarlC study, the majority of patients with early-stage prostate cancer appear to have a favourable 5-year prognosis, with positive real-world outcomes, namely metastasis-free survival, disease-free survival, progression-free survival and OS. No statistical difference was observed between the results of patients with LPC vs. LAPC patients. Notably, patients with high-risk LPC exhibited worse outcomes compared with non-high-risk but only the difference in OS was statistically significant. Indeed, the short follow-up to measure clinical outcomes of patients at an early stage of the disease may have been a study limitation, due to the availability and quality of electronic data and urgency to accelerate evidence generation, which is at present scarce. In addition, when analysing some outcomes (progression-free survival, PSA response rate, no evidence of residual tumour), the number of available patients was small, particularly in the LAPC subgroup. This may have also contributed to the lack of statistical significance. In fact, the study was not powered to compare results between subgroups of patients. The comparison of clinical outcomes between different treatments were not aimed in the present study, since the choice of the treatment depends on patient and disease characteristics, including severity which is itself a prognostic variable. Finally, the healthcare resource use and corresponding costs estimated for these patients were previously presented (34) and beyond the scope of the current analysis.
To conclude, the clinical management of patients with early-stage prostate cancer is multifactorial, considering patient-related factors, such as age, comorbidities, previous treatments or conditions, and cancer-related factors, such as tumour grading, staging or risk group, with some patients showing an indolent course of the disease and being more suited to surveillance, and others with indications to start active local treatment with curative intent, such as surgery or radiotherapy. The best approach should be decided in a multidisciplinary team setting. At IPO Porto and following recommendations from several medical societies (especially from the European Urology Oncology), the treatment modality is always decided in a multidisciplinary meeting, and patients included in this study were treated with a wide range of therapies. In LPC or LAPC, systemic therapies have a potentiating role in curative treatment in selected patient subgroups, or as subsequent treatment lines following the failure of local treatment. The range of prognostic factors and therapeutic options, often with overlapping efficacy rates but different toxicity profiles, highlights the importance of taking the therapeutic decision in a truly multidisciplinary setting, of which IPO Porto was a pioneer. The PEarlC study highlighted that the current strategy has high success rates in disease control and survival, and there is a need for long follow-ups, due to the often indolent course of this disease. Overall, the prognosis for most patients is rather positive, as there is a possibility to adjust the type of therapy to the clinical characteristics of the patient. There is a confined subgroup of patients (high-risk), who in most cases are not eligible for curative therapy, and for whom future pharmacological innovation may bring improvements, namely in OS or metastasis-free survival.
In the future, treatments closely tailored to disease risk, the advancement of the technical development of local therapies, such as surgery and radiotherapy, with improved results in clinical outcomes and less side effects, together with the development of new medicines and an improved disease control with a first-line treatment or following treatment failure are expected. Furthermore, it will be relevant to periodically update the results of the present study for a close monitoring of the ongoing practice, its clinical benefits and expand evidence on respective outcomes. The present large real-world study is an important contribution to reducing the evidence gap for early stages of prostate cancer, ultimately improving public health impact of this disease in the future.