Abstract
Background/Aim: A much-debated topic relating to patients at risk of local prostate cancer recurrence, but with post-operative leveIs of prostate-specific antigen (PSA) lower than 0.2 ng/ml, concerns the best timing of postoperative radiotherapy (RT), adjuvant or salvage? The present monocentric, retrospective study aimed to investigate the best PSA value at which to plan salvage RT for patients with recurrent prostate cancer. Patients and Methods: From January 2011 to December 2019, 158 patients were treated with adjuvant RT at Pisa University Hospital, whilst 91 patients underwent salvage RT. We grouped the patients treated with salvage RT using their PSA values at the time of salvage RT: PSA >0.5 ng/ml, PSA between 0 and 0.5 ng/ml, and PSA ≤0.2 ng/ml. The median follow-up was 63 months. Biochemical recurrence-free survival (BFS) measured from surgery was the primary endpoint. Results: Salvage RT led to shorter BFS compared to adjuvant RT considering the whole cohort of patients, with a hazard ratio of 3.195 (95% confidence interval=1.534-6.655, p=0.002). However, analysing only the group of patients with PSA ≤0.2 ng/ml at the time of salvage RT, salvage RT led to BFS similar to that achieved with adjuvant RT (p=0.35). Conclusion: Our results suggest that when scheduled for patients with a PSA ≤0.2 ng/ml, salvage RT results in equivalent biochemical control to that with adjuvant RT.
- Prostate cancer
- biochemical recurrent prostate cancer
- radiotherapy timing
- adjuvant radiotherapy
- salvage radiotherapy
Surgery represents the milestone of an upfront strategy for clinically localised prostate cancer, which is the most common cancer in men (1, 2). However, after prostatectomy, many patients must cope with biochemical and disease recurrence. For that reason, postoperative radiotherapy (RT) to the prostatic bed is used either to reduce the possibility of local recurrence (i.e., as adjuvant, or early, postoperative RT) or treat tumour relapse (i.e., as salvage, or late, postoperative RT), thus improving the curative intent of surgery. In this way, these therapies are used to consolidate disease control after surgery or control tumour growth at the time of diagnosis of recurrence (3, 4).
In recent years, as the costs and benefits of RT have been considered, debates have surfaced regarding the best timing to treat postoperative patients who have pathological risk factors suggestive of disease recurrence as well as a non-detectable PSA level (3). Two major arguments have been made: Early postoperative RT exposes potentially cured patients to RT toxicities, whilst late postoperative RT can have a negative impact on disease control.
In 2020, the results of the phase 3 RADICALS-RT trial showed comparable outcomes between patients treated with adjuvant RT and those treated with salvage RT at the time of disease relapse (5). The authors concluded that while adjuvant RT increased the risk of urinary morbidity, salvage RT should be the current standard of care after radical prostatectomy. The results of the GETUG-AFU 17 trial led to the same conclusions as the RADICALS-RT study, with the authors agreeing on favouring late postoperative RT in patients with non-detectable PSA levels (6). Moreover, in 2020, the ARTISTIC meta-analysis compared adjuvant to salvage RT in men with prostate cancer and confirmed the results obtained from the RADICALS-RT and GETUG-AFU 17 trials on biochemical control (7). However, despite the growing number of publications, a series of questions about the management of patients eligible for adjuvant RT remain unanswered. Amongst these questions, one important issue to address is represented by the PSA value at which late postoperative RT should be planned to avoid having a negative impact on disease control and, ultimately, on patient survival (5-7).
Considering the previous studies on postoperative RT, the present monocentric, retrospective study aimed to investigate differences in time to biochemical recurrence between patients treated with salvage RT and those treated with adjuvant RT considering different PSA cut-off values.
Patients and Methods
This study reports a retrospective experience from Pisa University Hospital on 249 men treated with either adjuvant or salvage RT. All patients underwent prostatectomy, had a pathological diagnosis of prostate cancer, and PSA value assessment every 3 months after surgery. No patient received neoadjuvant or adjuvant hormone therapy. Each patient underwent prostatectomy with or without lymphadenectomy (in our analysis, the term lymphadenectomy refers to the removal of at least 12 lymph nodes) and was evaluated according to the following criteria: Gleason score, age, type of surgery, risk group, PSA value at diagnosis and at 30 days after surgery, number of lymph nodes removed, pathological TNM stage and surgical margin status (8, 9). Table I presents the characteristics of the study patients. The present retrospective, monocentric analysis was approved by the local Ethics Committee (Pisa 2015/8424). All procedures were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Clinical data of patients analysed in the present study.
From January 2011 to December 2019, 158 patients were treated at Pisa University Hospital with adjuvant RT, whilst 91 were treated with salvage RT. We grouped the patients treated with salvage RT using their PSA values at the time of salvage RT: PSA >0.5 ng/ml, PSA between 0 and 0.5 ng/ml, and PSA between 0 and 0.2 ng/ml. Adjuvant RT was performed within 6 months of surgery. The prostatic bed was treated with 70-72 Gy, using a standard regimen, or 63-65.80 Gy as a hypofractionated regimen in all patients, whilst the lymph node chains were treated only in selected patients with 50.40 Gy in 28 fractions using a simultaneous integrated boost. The treatment plan was carried out after computed tomographic acquisition of the anatomical volume of interest. RT was delivered with the volumetric-modulated arc therapy technique (VMAT) once daily, with five sessions per week from Monday to Friday.
At the clinician’s discretion, medium-, high-, and very high-risk patients were also treated with hormone therapy for up to 2 years, beginning before RT and continuing during and after RT treatment (4).
After RT, all patients were monitored using PSA measurement every 3 months for the first 5 years, then every 6 months. Patients with biochemical relapse after surgery were assessed with a clinical and rectal examination, endorectal magnetic resonance and choline or prostate-specific membrane antigen, or positron-emission tomography/computed tomography (functional imaging was only scheduled for patients with PSA values greater than 1.0 ng/ml).
Statistical analysis. Categorical data are described by absolute and relative frequency, and continuous data by the mean and standard deviation. Survival curves were calculated with the Kaplan–Meier method, and the log-rank test was used to evaluate the differences between curves. The primary endpoint was biochemical recurrence-free survival (the time between surgery and biochemical recurrence after RT).
In accordance with the GETUG-AFU 17 trial, we decided to consider biochemical recurrence after RT as a PSA level of 0.4 ng/ml, or higher at least 6 months after completion of adjuvant or salvage RT, or a PSA level of 1 ng/ml or greater at any time (6).
Survival analysis of risk factors was performed by Cox regression as multivariate analysis using the stepwise method. The results of the Cox regression are expressed by the hazard ratio (HR) with its 95% confidence interval (CI) and regression coefficient. Significance was set at p=0.05 and all analyses were carried out with IBM SPSS Statistics for Windows, Version 27.0 (IBM Corp., Armonk, NY, USA).
Results
Statistical analysis of the data was performed in November 2021; the minimum and maximum follow-up were 18 and 116 months, respectively (median follow-up=63 months).
The median PSA level before the start of salvage RT was 0.71 ng/ml (range=0.09-6.42 ng/ml). Considering all 249 patients, salvage RT led to significantly shorter BFS compared to adjuvant RT (HR=3.195, 95% CI=1.534-6.655, p=0.002), as it also did for the group of patients with PSA ≤0.5 ng/ml (HR=3.763, 95% CI=1.509-9.380; p=0.004). Figure 1 shows that the survival rate after 5 years was approximately 67% for patients treated with salvage RT, while it was 88% for those treated with adjuvant RT. However, analysing only the group of patients with PSA ≤0.2 ng/ml at the time of salvage RT, salvage RT led to BFS similar to that achieved with adjuvant RT (p=0.35).
Biochemical recurrence-free survival (BFS) of patients treated with adjuvant and with salvage radiotherapy. CI: Confidence interval; HR: hazard ratio.
In the analysis of all 249 patients, the median duration of biochemical recurrence-free survival for those treated with salvage RT was 112 months, while that for patients treated with adjuvant RT, and those with PSA ≤0.5 ng/ml who had undergone salvage RT, the median survival time was not reached.
Discussion
The present study reports a monocentric analysis carried out on patients treated with postoperative RT (either early or late) for prostate cancer. Biochemical recurrence-free survival was used as a primary endpoint. To assess the PSA value to be used for planning salvage RT instead of adjuvant RT, we grouped the patients treated with salvage RT using their PSA levels at the time of salvage RT: PSA >0.5 ng/ml, PSA between 0 and 0.5 ng/ml, and PSA between 0 and 0.2 ng/ml. All patients included in the present analysis were treated with VMAT. Our results confirm that the outcomes of salvage RT overlap with those of adjuvant RT only when the PSA value at the time of recurrence is 0.2 ng/ml or less.
We performed this analysis to confirm the results obtained through randomised studies in a series of clinical cases outside a prospective trial. Our data are consistent with the literature, showing that there is no difference between the efficacy of adjuvant or salvage RT treatment if salvage RT is planned when the PSA value does not exceed 0.2 ng/ml.
In order to avoid toxicities strongly impacting the quality of life, such as urinary incontinence, urethral stricture and sexual impotence, in recent years, a series of studies have examined the best time for postoperative RT in patients with prostate cancer after radical prostatectomy (7, 10). In 2016, in a retrospective study, Fossati et al. assessed the best timing for early salvage RT in patients with increased PSA after radical prostatectomy (11). They found that salvage RT at the earliest sign of increased PSA improved cancer control. In addition, they observed that patients with more adverse pathological features had an increased risk of biochemical recurrence within 5-years of 10% per 0.1 ng/ml increase of PSA. However, a comparison in terms of biochemical recurrence-free survival with patients treated with adjuvant RT was not evaluated in that study. Briganti et al. in 2012 reported the results of a retrospective match-controlled multi-institutional analysis aimed at evaluating biochemical-free survival associated with adjuvant RT versus observation followed by salvage RT for patients undergoing radical prostatectomy for pT3, pN0, R0-R1 prostate cancer (12). Using a cut-off of 0.5 ng/ml, the authors reported encouraging results regarding the possibility of considering salvage RT in patients operated with a post-operative PSA level <0.10 ng/ml. In 2020, the results of the phase 3 RADICALS-RT trial showed comparable results between patients treated with adjuvant RT versus patients at risk of local recurrence and non-detectable PSA treated with salvage RT at the time of disease relapse (5). The authors concluded that whilst adjuvant RT increased the risk of urinary morbidity, salvage RT for biochemical progression should be the current standard therapy after radical prostatectomy. The results of the GETUG-AFU 17 trial in 2020 led to the same conclusions as those of the RADICALS-RT study, with the authors agreeing that they preferred to apply late postoperative RT in patients with non-detectable PSA (6). Furthermore, in 2019, the ARTISTIC meta-analysis included the most recent randomised trials on this topic. The authors did not show any benefit of adjuvant RT compared to salvage RT planned when the first signs of biochemical progression appeared; thus, suggesting that RT can be postponed at the time of possible biochemical progression (7). In addition, evaluating our results for operated patients considered to be at high risk for local relapse, follow-up instead of adjuvant RT can be proposed, but only if there is the chance of identifying a biochemical relapse using PSA values below 0.2 ng/ml; otherwise adjuvant RT must be mandatory.
Two of the strong points of the present study are represented by the number of patients examined and the homogeneity of the case series and the RT technique (all patients were treated with VMAT technique over a few years). The main limitations of the study are its retrospective design and the lack of data on patients who received only systemic therapy or stereotactic RT (due to disease dissemination outside the prostatic bed) after disease relapse (13-16). In addition, in the present analysis, all patients were referred to the Radiotherapy Service of Pisa University Hospital for recurrent prostate cancer, regardless of positive margins or extra-capsular extension revealed by pathological analysis. Moreover, through this analysis, it was possible to analyse only the impact of the PSA value as a determinant of the success of salvage RT. Further investigation of the Gleason score, TNM stage and risk of lymph node involvement with a more significant number of patients might identify subgroups of patients who might benefit from early or late postoperative RT treatment.
Acknowledgements
This report was produced within a study funded by Bando AIRC IG 2017 Id. 20819 “Oligometastatic and Oligorecurrent Prostate Cancer: enhancing patients’ selection by new imaging biomarkers”.
Footnotes
Authors’ Contributions
All Authors made substantial contributions to the conception or design of the work, or the acquisition, analysis, or interpretation of data; or the creation of new software used in the work; drafted the work or revised it critically for important intellectual content; approved the version to be published; and agree to be accountable for all aspects of the work.
Conflicts of Interest
The Authors declare that they have no conflicts of interest.
- Received April 7, 2022.
- Revision received May 9, 2022.
- Accepted May 13, 2022.
- Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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