|Year : 2021 | Volume
| Issue : 6 | Page : 213-218
Is immediate adjuvant radiotherapy necessary for men with positive surgical margin after robotic-assisted radical prostatectomy?
Yu-Ting Chen1, Chung-Yi Liu2, Shih-Huan Su1, Kai-Jie Yu3, Ying-Hsu Chang2, Po-Hung Lin3, I-Hung Shao3, Hung-Cheng Kan3, Yuan-Cheng Chu3, Liang-Kang Huang3, Cheng-Keng Chuang3, See-Tong Pang3
1 Division of Urology, Department of Surgery, LinKou Chang Gung Memorial Hospital, Taoyuan, Taiwan
2 Department of Urology, New Taipei Municipal TuCheng Hospital, Chang Gung Memorial Hospital and Chang Gung University, New Taipei City; College of Medicine, Chang Gung University, Taoyuan, Taiwan
3 Division of Urology, Department of Surgery, LinKou Chang Gung Memorial Hospital, New Taipei City; College of Medicine, Chang Gung University, Taoyuan, Taiwan
|Date of Submission||15-May-2021|
|Date of Decision||30-Jun-2021|
|Date of Acceptance||04-Oct-2021|
|Date of Web Publication||30-Nov-2021|
Department of Urology, New Taipei Municipal Tu Cheng Hospital, Chang Gung Memorial Hospital and Chang Gung University, No. 6, Sec.2, JinCheng Road, Tucheng District, New Taipei City 236
Source of Support: None, Conflict of Interest: None
Background: The role of immediate adjuvant radiotherapy (ART) in the management of positive surgical margin (PSM) following radical prostatectomy (RP) for low-grade prostate cancer (PCa) remains unclear. We aim to investigate our experience on survival outcome between immediate ART versus active surveillance in PSM groups after robotic-assisted RP (RaRP).
Materials and Methods: The PSM cohort was divided into an adjuvant therapy group, consisting of immediate radiotherapy (RT) with or without androgen deprivation therapy (ADT) within six months after surgery, and observation group, consisting of close follow-up at the out-patient clinic. Salvage therapy was conducted using RT with/without ADT if biochemical recurrence (BCR) occurred (PSA level >0.2 ng/mL) during follow-up. 461 patients with PCa who underwent RaRP between December 2006 and June 2014 were included. Data of patients with PSM (n = 79) were extracted and followed up to June 2020. We aimed to compare the outcomes of immediate ART against observation or salvage RT in patients with PSM. Hence, we focused on those who had a PSA level <0.2 ng/mL after RaRP. Those with a PSA level >0.2 ng/mL were excluded.
Results: No significant differences in age or preoperative PSA levels were observed after stratification to immediate ART and observation groups. Three patients (5.6%) received immediate ART with/without ADT. Another 51 patients received active surveillance, of which 18 (35.3%) received salvage ART with/without ADT due to BCR (PSA ≥0.2 ng/mL). There was no significant difference between immediate ART and observation groups in 5-year BCR-free survival (P = 0.072), local recurrence-free survival (P = 0.490), distant metastasis-free survival (P = 0.225), and overall survival (P = 0.517).
Conclusion: Of the RaRP patients with PSM in the Asian population, we discovered that immediate ART following RaRP may not offer a significant advantage to active surveillance. Routine monitor of PSA levels had shown equally successful disease control. Salvage ART could be used on detection of BCR.
Keywords: Adjuvant radiotherapy, positive surgical margin, prostate cancer, robotic-assisted radical prostatectomy
|How to cite this article:|
Chen YT, Liu CY, Su SH, Yu KJ, Chang YH, Lin PH, Shao IH, Kan HC, Chu YC, Huang LK, Chuang CK, Pang ST. Is immediate adjuvant radiotherapy necessary for men with positive surgical margin after robotic-assisted radical prostatectomy?. Formos J Surg 2021;54:213-8
|How to cite this URL:|
Chen YT, Liu CY, Su SH, Yu KJ, Chang YH, Lin PH, Shao IH, Kan HC, Chu YC, Huang LK, Chuang CK, Pang ST. Is immediate adjuvant radiotherapy necessary for men with positive surgical margin after robotic-assisted radical prostatectomy?. Formos J Surg [serial online] 2021 [cited 2022 Jan 16];54:213-8. Available from: https://www.e-fjs.org/text.asp?2021/54/6/213/331641
| Introduction|| |
For prostate cancer (PCa) with unfavorable pathological components following radical prostatectomy (RP), immediate adjuvant radiotherapy (ART) or surveillance followed by early-salvage radiotherapy for biochemical recurrence (BCR) may be used. The American Urological Association (AUA) defined BCR as prostate-specific antigen (PSA) ≥0.2 ng/mL postoperatively. However, there is no optimal timing for postoperative radiotherapy (RT). Positive surgical margin (PSM) after RP raises the risk of BCR, but its importance in disease-specific mortality has not been demonstrated. According to the NCCN and AUA guidelines, men following RP who do not have lymph node metastases with persistent PSA or adverse pathological features such as positive margin, seminal vesicle invasion, or extracapsular extension may consider receiving ART with or without androgen deprivation therapy (ADT). According to the EAU guideline, ART remains a recommended treatment option in only selected high-risk patients (pN0) with at least two of three high-risk features (ISUP grade group 4–5, pT3 with or without positive margins). However, systematic reviews reach diverse conclusions about the utility of immediate post-prostatectomy RT in patients with adverse features., Routine ART might not be justifiable for patients with PSMs because it represents overtreatment for most patients, resulting in risks of radiation complications. This study aims to explore the role of ART in PSMs after robot-assisted RP (RaRP).
| Materials and Methods|| |
After receiving approval from the Institutional Review Board (IRB No.: 201601008B0), medical records were reviewed at Chang-Gung Memorial Hospital (Linkou branch). Records of patients who underwent RaRP from all PCa patients treated between December 2006 and June 2014 were extracted. We excluded patients who had a positive bone scan and/or positive lymph node involvement and those with incomplete specimen pathological reports or laboratory data. The patients underwent regular outpatient clinic follow-up, and their medical records were collected until June 2020. The patient consent is waived by IRB.
All RaRP procedures of the study cohorts were performed by five urological surgeons at our medical center. Clinical and laboratory information - such as patients' age, preoperative and postoperative PSA levels, Gleason score, and pathological stages - were gathered.
Based on the pathologic results of the surgical specimen, patients were stratified into PSM and negative surgical margin (NSM) cohorts. A PSM was defined as the observation of a cancer cell at the inked margin of the resected specimen. BCR was defined as PSA >0.2 ng/mL after RP. The 7th edition of the American Joint Committee on Cancer staging system was used for cancer staging.
The PSM cohort was further divided into immediate ART group, which was defined as having received RT within 6 months after surgery, and observation group, which was defined as having close follow-up at the outpatient clinic. Salvage RT was conducted with ART with/without ADT if the PSA level was >0.2 ng/mL during follow-up. In the PSM cohort, the location of PSMs, level of postoperative PSA, duration of follow-up, number of patients with BCR, duration of being BCR free, number of patients with local recurrence (LR), distant metastasis (DM), and number of deaths were recorded. Patients without the event of interest were censored at their last contact date or last PSA assessment date. We aimed to compare the outcomes of immediate ART group against observation/salvage RT group in patients with PSM. Therefore, we focused on those who had a PSA level of <0.2 ng/mL after RaRP. Those with a PSA level >0.2 ng/mL postoperatively were excluded.
All analyses were performed using SPSS version 25 (IBM Corp. Released 2017. IBM SPSS Statistics for Windows, Version 25.0. Armonk, NY: IBM Corp.). A two-sided P < 0.05 was considered statistically significant. The Mann–Whitney U-test was used to compare continuous variables with nonnormal distribution. Pearson Chi-square test or Fisher's exact test was used for categorical variables. Kaplan–Meier survival methods were employed for survival results, and the differences were assessed using the log-rank test. Cox proportional-hazard regression model was performed for multivariate BCR-free survival analysis. All variables related to the risk of BCR-free survival and a P < 0.2 in univariate analysis were included in multivariate analysis.
| Results|| |
Of the 462 eligible patients, 79 patients (17.1%) had PSM and 383 patients had NSM. After excluding those with a postoperative PSA level >0.2 ng/mL, 54 PSM patients (11.7%) remained. The demographic, laboratory, and pathologic characteristics of the 54 patients with PSMs are listed in [Table 1]. The mean age of the patients in the PSM cohort was 64.5 years old (SD: 6.8 years old); the preoperative mean PSA level was 15.367 ng/mL (SD: 11.698 ng/mL). Regarding the baseline pathologic characteristics, the disease stage was pT2a-c for 26 patients (48.1%), pT3a for 16 patients (29.6%), and pT3b or above for 12 patients (22.2%). After stratification into immediate ART and observation groups, no significant difference was observed between the two groups in terms of age, preoperative PSA level, pathologic TNM stages, BCR, LR, DM or death. However, the immediate ART group had a higher postoperative PSA level and a higher PSA level at last follow-up checkup.
|Table 1: Characteristics of patients with or without immediate adjuvant radiotherapy|
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The median follow-up time was 88 months. Following RaRP, 3 men (5.6%) received postoperative immediate ART. The remaining 51 men (94.4%) received active surveillance; among them, 18 men (35.3%) underwent salvage ART with/without ADT because of BCR detection (PSA rebound to >0.2 ng/mL). Furthermore, there was no significant difference between the two groups in disease LR, DM, or death. In the observation group, five patients died of other medical diseases, and one patient died by suicide.
As shown in [Figure 1], there was no significant difference between the two groups in 5-year BCR-free survival (P = 0.072), 5-year LR-free survival (P = 0.490), 5-year DM-free survival (P = 0.225), and 5-year overall survival (P = 0.517). Univariate and multivariate analysis of factors [Table 2] revealed that ADT and pathologic lymph node status were significantly associated with BCR-free survival. There was no significant association between ART and BCR-free survival.
|Figure 1: Kaplan-Meier survival curves in ART (+) and ART (–) groups. (a) 5-year biochemical recurrence (BCR)-free survival (P = 0.072). (b) 5-year local recurrence-free survival (P = 0.490). (c) 5-year distant metastasis-free survival (P = 0.225). (d) 5-year overall survival (P = 0.517)|
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|Table 2: Univariate and multivariate analysis for predictors of biochemical recurrence-free survival|
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| Discussion|| |
In this study, we investigated the survival outcomes between adjuvant therapy, salvage therapy or active surveillance in PSM groups after RaRP. We found that early post-RaRP adjuvant therapy might not offer a significant benefit compared to active surveillance in PSA progression, LR free-survival metastasis-free survival, or overall mortality.
PCa is relatively less prevalent in Asia compared to that in the West. In Taiwan, however, a rising trend has been observed over the past 4 decades in both the incidence and mortality rates of PCa. In Western countries, more than 90% of PCa cases found during the period when PSA screening was available were organ-confined at diagnosis. By contrast, PCa may not be detected at early stages in Taiwan, as demonstrated in the findings of latent PCAs in a Taiwanese pathologic study of 49 non-PCa indicated cystoprostatectomy specimens. Unsuspected PCa was identified in 32.7% and high-grade prostate intraepithelial neoplasia in 49% of prostate specimens. Furthermore, in previous studies, the mean age of patients in contemporary Western RP cohorts, was 60–62 years, and the median PSA level was 5.9–7 ng/mL (median: 7.1 and 8.1 ng/mL in solitary PSMs and multiple PSMs, respectively). However, the mean age of our patient cohort at the time of diagnosis was 65.1 years, approximately 3–5 years older than that reported in previous studies, and the median preoperative PSA level was 13.25 ng/mL, which was relatively higher than that observed in Western men. Additionally, in Taiwan, a series reported by Ou et al. suggested similar trends of older age and higher preoperative PSA levels at the time of diagnosis than those observed in Western men. PSA levels were higher because they increase with age; this had been confirmed by a Taiwanese epidemiological study reporting that serum PSA levels correlated with age even in men without PCa.
The overall PSM after RaRP ranged from 9.3% to 33%, according to a review by Coelho et al. Despite the possible delay in diagnosis and surgical intervention, PSM rates in pT3 cancers in previously published cohorts were between 26% and 67%, stratified according to pathological stages., In our case series, the PSM rate after RaRP was 17.10%, and 60.8% of the patients with PSMs had a pathological stage of pT3.
Once PSM is detected after RP, surgeons encounter a dilemma between administering an adjuvant therapy or active surveillance until BCR occurs as a salvage therapy indication. In a randomized study, Thompson et al. (Southwest Oncology Group's SWOG 8794) demonstrated a significant improvement in BCR-free survival rate after administering early RT to patients with pathologically advanced PCa (including PSMs). However, no difference was observed in the metastasis-free survival rate between the RT and observation groups. The actual metastasis-free survival period in the observation group was considerably longer (13.2 years) than the anticipated period (6 years). In their study, approximately 33% (70 of 211) of patients eventually received salvage RT. Another study, conducted by Savdie R. et al., discovered that the higher the Gleason grade at the site of a PSM, the greater the chance of BCR. As a result, PSM patients following RaRP with a high Gleason grade (4 or 5) should be considered to be candidates for aggressive, immediate ART.
In the European Organization for Research and Treatment of Cancer trial 22911, which was performed in a similar setting, the benefit of clinical progression and survival outcome was not maintained in patients aged ≥70 years when the follow-up period was extended from 5 to 10 years. Wiegel et al. reported that early ART could reduce the rebound of PSA; however, additional follow-up data were not available in that study.
There are currently no prospective randomized studies available comparing adjuvant RT with salvage RT. Previous retrospective studies provided inconsistent conclusions with respect to ART benefits in BCR-free survival, progression-free survival, disease-specific survival, or OS.,,,,,, Our results indicate that routine ART might not benefit patients from delaying PSA progression than active surveillance. Besides, no advantage was observed in 5-year BCR-free survival, LR-free survival, metastasis-free survival, or reduced overall mortality. Routine ART would potentially reflect the consumption of extra healthcare resources and might possibly have adverse effects on the urinary tract, intestine, and sexual function., Therefore, post-RaRP treatment strategies should be individualized after evaluating the costs, risks, and benefits.
This study had some limitations; the retrospective nature of our study, the small population size, and the limited follow-up period might distort the real impact of adjuvant and salvage RT on patient outcomes. Prolonged follow-up is required, and further review is warranted at regular intervals. This is an ongoing research, and we are continually gathering more clinical data for long-term follow-up.
| Conclusion|| |
Of the RaRP patients with PSM in the Asian population, we discovered that immediate ART following RaRP might not offer a significant advantage to active surveillance. Routine monitor of PSA levels had shown an equally successful control of the disease. Salvage ART could be used on detection of BCR.
Financial support and sponsorship
Conflicts of interest
Dr. See-Tong Pang, an editorial board member at Formosan Journal of Surgery, had no role in the peer review process of or decision to publish this article.
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[Table 1], [Table 2]