The impact of the time interval from diagnosis to radical prostatectomy on oncological outcomes in high-risk prostate cancer

INTRODUCTION

The time interval (TI) to surgical treatment in patients with oncological diseases remains an acute dispute. A recently changed concept regarding localized forms of prostate cancer (PCa) allowed the researchers to revise the approaches not only to aggressive variants of cancer but also to high-risk PCa (HR-PCa).

Although domestic standards recommend providing medical care to oncological patients as soon as possible, sometimes it can be quite complicated (social-geographic reasons, necessity in the correction of comorbid diseases, patient unwillingness to start therapy when PCa is revealed, long-term treatment of complications, or inflammatory process after prostate biopsy, etc.). In 2020, the epidemiological situation highlighted the importance of the influence of TI on the initiation of therapy, which was postponed for many patients. Furthermore, such organizations as the European Association of Urology (EAU), the National Comprehensive Cancer Network (NCCN), and others proposed their own recommendations on the management tactics for patients with verified PCa (including HR-PCa) under the pandemic conditions [1][2]. Still, the issue of the influence of the pre-treatment TI on oncological outcomes is especially relevant.

The study aimed to evaluate the effect of the timespan from diagnosis to radical treatment of PCa patients on tumor morphology and long-term oncological outcomes.

MATERIALS AND METHODS

A retrospective analysis of treatment results was performed in patients with HR-PCa. The patients underwent radical prostatectomy (RPE) with extended lymphadenectomy (LAE) from 2001 to 2019 at three medical institutions in Saint Petersburg (Oncological Urology Division, the Petrov National Medical Research Centre for Oncology; Oncological Urology Division, the Pavlov First St. Petersburg State Medical University; Urology Division, the Nikiforov All-Russian Center for Emergency and Radiation Medicine).

Study inclusion criteria. All patients had a high risk of disease progression (minimum one of the following criteria): PSA > 20 ng/ml, ISUP group 4–5 (Gleason score > 8), the local advanced degree cT3a and higher. The staging was performed according to the relevant EUA standard when the disease was verified. The study entry criteria included morphologically verified prostate adenocarcinoma, localized and locally advanced forms, classified as high risk by the NCCN criteria [3], absence of regional and remote metastases, absence of therapy for PCa in medical history, age ≤ 75 years old, Karnofsky index > 70%, absence of active associated pathology (including second oncologic disease), complete information on clinical staging, treatment stage, results of the pathomorphological study of the biopsy specimens and post-operative material, and the post-operative follow-up period for at least a year. Patients with the metastatic (remote metastases and/or regional lymph node lesion) process and patients who received radiotherapy or systemic therapy (hormonal or chemohormonal) before RPE were excluded from the study.

Pre-surgical examination and staging. At the stage of consulting after the examination, all patients were informed that the diagnostics of the process advancing, and correction of the pathology might require a longer time and increase the TI to the surgery. All patients signed a form of informed consent. The treatment tactics and confidentiality of the data complied with the principles of the Declaration of Helsinki. The staging and stratification into a high-risk group were performed based on the objective examination (including digital rectal examination (DRE), laboratory tests (PSA), biopsy data (conducted under transrectal US control, 12–16 tissue samples from both prostate lobes and seminal vesicles) according to the system of classification proposed by the International Society of Urological Pathology, ISUP (revision of 2005 and 2014), radio diagnostics data (pelvic MRI, chest and abdominal organs CT, bone scintigraphy).

The TI was calculated as the number of days between the prostate biopsy and RPE. Depending on TI, patients were divided into the following groups: patients who received surgical treatment within 30 days, within 30 to 90 days and after 90 days.

Surgical treatment and pathomorphological evaluation of the specimens. All patients underwent laparoscopic non-sparing RPE (excision of the prostate and seminal vesicles) with bilateral extended LAE in the volume described above [4]. All surgeries were performed by a surgeon on the surgical team who had experience in laparoscopic interventions (A.N., S.P., S.R.). According to recommendations [5], the pathomorphological material was studied before treatment and after RPE.

Unfavorable pathomorphological changes were defined as an intensification of tumor aggressiveness (in comparison with the biopsy specimens), a locally advanced process (pT3a) or invasion to seminal vesicles, positive surgical margin, or metastases in the regional lymph nodes (pN1).

Follow-up and treatment efficiency evaluation. PSA dynamics were evaluated by comparing the values before the treatment, every month before the treatment, a month after the surgery, every 3 months for 2 years, and every 6 months. Biochemical relapse (BCR) was observed after PRE when PSA reached < 0.2 ng/ml and increased twice over 0.2 ng/ml.

The impact of TI from biopsy to RPE was defined by the difference between the groups of unfavorable postoperative pathomorphological characteristics (PSB, local advancement, Gleason score 8, metastases in regional lymph nodes, CSS and OS).

Statistical analysis. Statistical analysis was performed using the software GraphPad Prism ver.8.0.1 («GraphPad Software Inc.», Lajolla, CA, USA). The parameters were analyzed for the normality of distribution with the Shapiro-Wilk and Kolmogorov-Smirnov tests. Overall, cancer-specific, and relapse-free survival (OS, CSS, and RFS) was evaluated by the Kaplan-Mayer log-rank test. The values were statistically significant at p < 0.05. The evaluation of the significance of differences in the parameters studied was made with Pearson’s chi-square test, Mann-Whitney’s U test, Student’s t-test, and Wilcoxon’s test with Bonferroni correction for multiple comparisons.

RESULTS

During the specified period, 305 patients were included in the study and received treatment. The preoperative characteristics of the patients in all groups were comparable by age, level of total PSA, and degree of differentiation (Gleason score) (Table 1). The follow-up medians in groups of patients who underwent surgery within < 30 days, 30–90 days, and >90 days were 83.6 (67.9 – 110.2), 81.6 (63.5 – 107.3), and 77.5 (60.5 – 105.3) months, respectively.

The main reasons for delayed therapy included social-geographic complications (remote residence and time for paperwork, the impossibility of hospitalization because of coronavirus infection), need for correction of comorbid diseases, neo-adjuvant therapy, and patients’ unwillingness to start therapy during PCa detection.

Early oncological outcomes in patients with HR-PCa are presented in Table 2. The main morphological characteristics did not differ between patients in the period from biopsy to surgery <30 days and 30–90 days (p > 0.05). An increase in the TI to surgery over 3 months did not affect the pathomorphological characteristics of the tumor. Adjuvant therapy was indicated for 63 patients (20.7%); the therapy rate did not differ between the groups.

The Kaplan-Meyer test showed that 5-year RFS was observed in 79.7%, 67.8%, and 52.5% among patients with TI from biopsy to surgical treatment < 30 days, 30–90 days, and >90 days (Fig. 1). A comparison of CSS and OS between the patients who underwent surgery in different TIs from biopsy did not show any differences in the survival dependence from TI (Fig. 2)

DISCUSSION

The results of the first studies on the issue of TI to RPE were controversial. One of the first studies on the evaluation of TI on OS among PCa patients showed that among 645 patients (retropubic RPE, 1987 – 1997), 10-year BCR-free survival was significantly higher in those patients who underwent surgery within the first 3 months after prostate biopsy (74.6%) compared to patients with longer IT (61.3%, p < 0.05) [6]. Along with this, Khan et al. (2004) analyzed the results of the long-term treatment outcomes in 926 patients after retropubic RPE (radical surgery, 1989 – 1994). At the same time, only 162 patients underwent surgery within 60 days after biopsy. In the group of patients who received treatment within the first 5 months after the diagnosis, 5 and 10-year BCR-free survival was 89.0% and 87.0%, respectively (p < 0.04 in the analysis of the group of treatment within 5 months after biopsy). There were no differences in BCR-free survival in patients with various TI to surgery. However, the authors of that study used different methods of clinical stage evaluation, stratification by risk group, and pathomorphological criteria. Therefore, among the patients included in the analysis who received treatment within > 4 months after biopsy, there were only 2 (2.0%) patients with a locally advanced process (verified based only on DRE results), while T3a and higher was pathomorphologically verified in 40.6% of patients [7].

The evaluation of the TI impact on the results of RPE by Patt et al. (2020) showed that in the second quarter of 2020, the number of RPE decreased by 50.0% in comparison with the analog period in 2019 [8]. This analysis did not include the definition of “time interval” and “delayed treatment”, which are defined differently in various studies. Most authors (including modern) believe that delayed treatment TI can be 3 months [9][10], while some other authors suggested 6 months [11]. Other authors did not provide threshold values and included various intervals: fixed – ≤ 3. 4 – 6, 7–12, 12–26, and over 26 weeks [12], or continuous-variable [13].

The authors who consider the criteria of high risk of progression evaluate early outcomes such as unfavorable pathomorphology compared to clinical data (an increase in the degree of local advancing, tumor aggressiveness, rate of PSM, local advancing, invasion into seminal vesicles, and pN+), the rate of indication of adjuvant treatment, and remote oncological parameters (BCR-free survival, CSS, and OS).

Changes in the pathomorphological parameters associated with the TI before surgery are the most frequent endpoint in numerous studies. The analysis of treatment outcomes in 332 patients (RPE, 2014–2018) revealed an impact of the TI over 3 months on the higher rate of extraprostatic advancing (pT3) (p = 0.04) [10], while Patel et al. (2019) did not reveal any differences in unfavorable pathomorphological results (PSM, pT3 and higher, N+) when RPE was conducted with a delay to 6 months [14]. In the present study, RPE in TI > 3 months after biopsy resulted in an increase in the rate of PSM compared to those who underwent surgery within the first 30 days after diagnosis. However, there were no differences revealed by this parameter among patients who underwent surgery within the first 30 days and 1–3 months.

The impact of the TI on the possibility of BCR seems controversial. Several studies on the HR-PCa showed the impact of the TI between the biopsy and RPE on the relapse rate. However, there is no consistent opinion on the TI duration. Zanaty et al. (2018) showed the impact of the shortest TI on BCR. Their work included the analysis of 619 patients who were in the group of high progression risk according to the D'Amico criteria and had a higher risk of BCR when RPE was performed in TI > 3 months after biopsy compared to a shorter TI (p < 0.001) [13]. A significantly higher TI was described in the study by Fossati et al. (2017). The first 12 months from the time of biopsy did not increase the risk of BCR; and after this period, in a group of patients with HR-PCa, the risk of relapse was significantly higher (HR = 1.02; p = 0.0005) [15]. At the same time, some authors did not reveal any TI associations between biopsy and treatment with the risk of BCR and CSS [16]. In that study, similar results were obtained on the influence of TI on the beginning of treatment on another oncological parameter (metastasis-free survival). It also did not differ in those who underwent surgery within 3 months (and over) and after diagnosis, even in patients with more aggressive tumors (Gleason score 9 – 10). The development of metastases within 5 years in this subgroup was not observed in 81.0% and 71.0% of patients, respectively (p = 0.9). The data obtained in this study showed that RPE in the TI > 90 days led to a decrease in RFS. At the same time, there were no differences revealed in the oncological results between patients who were operated within 30 days after biopsy and treated within 1–3 months.

The results of the present study showed that there were no differences between CSS and OS in all groups of patients who underwent surgery within a month, 1–3 months, and over 3 months after diagnosis. At the same time, a recent systemic review by Laukhtina et al. (2021), which included the analysis of 19 studies on the impact of TI to the beginning of therapy on the oncological outcome, revealed significant differences in the study results on the impact of TI between biopsy and RPE on oncological outcomes. The authors concluded that there was no consistent opinion on acceptable TI in patients with HR-PCa, which appears to be safe within 2 – 3 months [17].

Thus, most modern data indicate that the risk of unresolved problems that lead to the treatment delay (risk of coronavirus infection or unstable comorbid pathology) has a more significant impact on survival than oncological characteristics [18]. Furthermore, there are no studies that confirm the impact of TI on oncological parameters such as CSS and OS.

The novel study methods (PET/CT) used in the primary diagnosis of nonmetastatic PCa can affect TI. Nesbitt et al. (2020) analyzed 332 cases of examination and treatment of patients with HR-PCa and revealed that primary staging by PSMA and PET/CT, in comparison with patients who had the disease advancing evaluated by a standard method (CT and bone scintigraphy), led to an increase in the TI between biopsy and final diagnosis (47.1 ± 40.4 versus 32.3 ± 22.9 days; p < 0.01). However, in general, it reduced the TI between biopsy and surgical treatment (109.5 ± 64.7 versus 132.5 ± 70.8 days, p < 0.01) [10]. In the present study, three patients underwent PET/CT with 68Ga-PSMA or 11C-choline in 2017. When it was not possible to analyze TI separately at the diagnostic stage, the mean time to RPE in patients with HR-PCa was 73.7 (from 18 to 179) days after PET/CT. Considering the potential benefits in the therapeutic tactics of PET/CT in patients with HR-PCa [19], this approach in diagnostics of the process advancing in these patients seems feasible.

CONCLUSION

The time interval from disease diagnostics to surgical treatment is not the determining factor in PCa patients. However, TI from the biopsy to the histological study results and surgical intervention should be no longer than 3 months. If this period is longer, an increase in the rate of PSM is observed compared to those who underwent surgery within the first 30 days after diagnosis verification. In addition, RPE performed later than 90 days after biopsy leads to a decrease in RFS. There are no differences in oncological outcomes between those who underwent surgery within the first 30 days after biopsy and those who underwent surgery within 1 – 3 months.

Thus, in patients with HR-PCa, TI up to 3 months can be considered safe regarding the detection of less favorable pathomorphological characteristics and BCR-free survival.