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REVIEW ARTICLE
Year : 2022 | Volume
: 59
| Issue : 2 | Page : 170-177
Adjuvant versus early Salvage radiation therapy for prostate cancer with adverse pathological features on radical prostatectomy—Do we finally have an answer?
Saurabh Jain1, Indranil Mallick2, Ashwin Sunil Tamhankar3, Gagan Gautam4
1 Department of Gen. Surgery, Gandhi Medical College, Bhopal, Madhya Pradesh, India
2 Department of Radiation Oncology, Tata Medical Centre, Kolkata, West Bengal, India
3 Department of Urology, East and North Hertfordshire NHS Trust, Lister Hospital, UK
4 Department of Surgical Oncology, Division of Urologic Oncology, Max Institute of Cancer Care, Saket, New Delhi, India
Correspondence Address:
Gagan Gautam
Department of Surgical Oncology, Division of Urologic Oncology, Max Institute of Cancer Care, Saket, New Delhi
India
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/ijc.IJC_516_20
Background: The presence of adverse pathological features like extraprostatic extension, seminal vesicle involvement, or positive margins at radical prostatectomy incurs a high risk of postoperative recurrence. Currently, adjuvant radiotherapy (ART) is the standard of care in these patients, while early salvage radiotherapy (eSRT) is a potential alternative strategy.
Aims: The purpose of this paper is to review the latest evidence comparing outcomes of adjuvant versus early SRT in this clinical scenario.
Materials and Methods: A systematic review of Google Scholar, PubMed/Medline, and EMBASE was done to identify relevant studies published in the English language, regarding outcomes of adjuvant radiotherapy and early SRT in post radical prostatectomy patients. Twelve studies, including six randomized trials, four retrospective studies, one systematic review, and one metanalysis were included in the final analysis.
Results: We found that initial randomized trials demonstrated better event-free survival with adjuvant radiotherapy when compared to observation alone. However, ART was associated with increased risk of overtreatment and thus increased radiation-related toxicity rates.
Conclusion: Preliminary evidence from recently reported RCTs suggests that eSRT may provide equivalent oncological outcomes to ART in prostate cancer patients with adverse pathology on radical prostatectomy while decreasing unnecessary treatment and radiation-related toxicity in a significant proportion of patients. However, the final verdict would be delivered after the long-term metastasis-free survival and overall survival outcomes are available.
Keywords: Adjuvant radiotherapy, biochemical recurrence post radical prostatectomy, early salvage radiotherapy, high-risk prostate cancer, positive surgical margins
Postoperative decision making for patients who have undergone radical prostatectomy (RP) is based on the International Society of Urological Pathology (ISUP) grading of prostate cancer and histopathological features of the specimen. Patients with ISUP grade 3 or above, positive surgical margins, or pathological stage >pT2 (non-organ confined disease) have a higher risk of relapse and may be candidates for additional treatment. In recent times, the incidence of relapse after RP and subsequent development of the metastatic disease is increasing. This is likely attributable to the increasing number of radical prostatectomies being performed for high-risk localized prostate cancer.[1]
Adjuvant radiotherapy (ART) has been strongly recommended as a standard of care for locally advanced prostate cancer patients post RP. ART, however, is associated with a potential risk of overtreatment and a consequent increase in complication rates. An alternate strategy is to delay radiotherapy and treat only those patients with a rising prostate-specific antigen (PSA) after prostatectomy, starting early when the PSA is still low. Thus, ART is defined as radiotherapy delivered at an undetectable PSA level, whereas salvage radiation therapy refers to radiotherapy delivered at a detectable PSA level between and inclusive of 0.1 to 0.5 ng/mL, including those with a persistently detectable PSA level after surgery.[2],[3],[4],[5],[6] Though eSRT is an effective alternative in these patients, it carries the risk of disease progression before optimal intervention is done. This window of opportunity to minimize disease progression needs to be balanced and weighed against the side effects of ART. Hence, whether to offer ART or eSRT to prostate cancer patients with adverse pathology on RP is still a dilemma. To explore this further, we have reviewed the available literature to compare ART with eSRT. The scope of this review only includes pathologically lymph node-negative patients as patients with positive lymph nodes on RP have been excluded in ART/eSRT trials.
MethodsStudy design
We have performed a review of English literature to describe and discuss the current state of ART and eSRT in the management of prostate cancer with adverse pathology on RP (non-organ confined lymph node-negative disease and/or positive surgical margins). While conducting this review, we followed the Preferred Reporting Items for Systematic reviews and Meta-analysis (PRISMA) guidelines.[7]
Search Strategy
Searches were performed using Google Scholar, PubMed/Medline, and EMBASE to identify relevant studies using the following keywords: “high-risk prostate cancer, adjuvant radiotherapy for prostate cancer, early salvage radiotherapy (SRT) for prostate cancer, biochemical recurrence after radical prostatectomy, positive surgical margins after radical prostatectomy and locally advanced prostate cancer, timing of salvage radiation therapy.” We limited our search to studies published between January 2007 and December 2019.
Selection criteria
All the studies which were not published in the English language were excluded from this review. Titles and abstracts of these articles were then reviewed by two of the authors for inclusion in this review. Studies comparing the outcome of ART vs Observation, eSRT vs observation, ART vs eSRT, and timing of SRT in patients with adverse pathological features on radical prostatectomy were preferred for inclusion in this review.
ResultsUsing the described keywords, 58 studies were identified which matched the search criteria. Out of them, 46 studies were excluded for various reasons and only 12 studies were identified by the designated two authors for final inclusion in this review. These twelve studies included six randomized trials, four retrospective studies, one metanalysis, and one systematic review. The outcome of the above six randomized control trials is elaborated in [Table 1] and [Table 2].
Table 1: Comparing outcomes of adjuvant radiotherapy versus observation alone in patients with adverse pathological features post-radical prostatectomy as reported in three randomized trials
Table 2: Comparing outcomes of adjuvant radiotherapy (ART) versus early salvage radiotherapy (eSRT) in patients with adverse pathological features post-radical prostatectomy Discussion Defining high-risk prostate cancer, adverse pathological features, ART, and eSRT
As per the D'Amico classification, high-risk prostate cancer is defined as having a clinical T-stage ≥T2c, a Gleason score ≥8, or a PSA >20 ng/mL.[8] Traditionally, according to western literature, high-risk prostate cancer roughly accounts for about 15% of all cases.[9] However, with routine PSA screening being discouraged by various authorities such as the United States Preventive Services Task Force (USPSTF), the proportion of high-risk prostate cancer cases undergoing RP has been steadily increasing. Using the National Cancer Data Base, in a study of 127,391 men with high-risk prostate cancer, Weiner et al. reported an increase in the use of RP from 26% in 2004 to 42% in 2013 (P < 0.001).[10]
This is even more significant in countries like India, where routine PSA screening has never existed, and prostate cancer is more likely to be diagnosed in relatively advanced stages. These patients are more likely to have adverse pathology in the form of positive surgical margins (PSMs) and/or non-organ confined disease with the extraprostatic extension (pT3a) or seminal vesicle infiltration (pT3b).[11]
ART to the surgical bed is offered to patients with undetectable serum PSA and adverse pathological features after recovery of urinary function, typically within the first 6 months post-surgery.[12] These patients can also be kept under clinical and biochemical surveillance followed by eSRT before the PSA exceeds 0.5 ng/mL.[4] In the absence of a robust prospective comparison, the choice between immediate ART and eSRT has mostly been based on local protocols and the personal preference of the patient and his oncologist.
Evidence supporting adjuvant radiotherapy
Currently, the recommendations of the American Urological Association and the American Society for Radiation Oncology advise offering ART to patients at increased risk of local relapse (pT3N0 either because of extracapsular extension or invasion of the seminal vesicles, or resection with positive surgical margins).[13] These recommendations are based on three randomized controlled trials (RCTs)—European Organization for Research and Treatment of Cancer (EORTC) 22911, Southwest Oncology Group (SWOG) 8794, and Arbeitsgemeinschaft Radiologische Onkologie (ARO) 9602—investigating the role of adjuvant radiotherapy (ART) versus observation in patients with these high-risk features.[14],[15],[16] A comparative analysis of these three trials is shown in [Table 1].
Bolla et al., in EORTC 22911 trial, randomized 1005 post-RP prostate cancer patients (with either one of the following: capsule perforation, positive surgical margins, or seminal vesicle invasion) to a wait-and-see policy until biochemical progression or postoperative irradiation (60 Gy of conventional irradiation to the surgical bed for 6 weeks).[14] Biochemical progression was defined as an increase in PSA to >0·2 μg/L confirmed twice at least two weeks apart. This study included untreated prostate cancer patients younger than 75 years of age across 37 European institutions. These patients were followed up for a median of 10·6 years (range 2 months to 16·6 years). At five years follow up, significant improvement in biochemical progression-free survival was seen in the postoperative irradiation arm. However, clinical progression-free survival showed no improvement. [Table 1]
In the S8794 trial, 425 eligible men with prostate cancer having adverse pathology (either one of the three: extracapsular tumor extension, positive margins, or seminal vesicle invasion) post-prostatectomy were randomized into observation arm and ART arm.[15] The authors reported that ART significantly improves survival and reduces metastasis in patients with adverse pathological features post RP. One interesting finding in their study was that the number of men with pathologic T3 disease who must be treated with ART to prevent one death at a median follow up of 12.6 years is 9.1. [Table 1]
Wiegel et al. reported the results of a multicentric, phase III ARO 9602 trial.[16] This trial was initiated to study the biochemical progression-free survival after ART in patients with pT3-4 pN0M0 prostate cancer patients with positive or negative surgical margins with undetectable PSA after RP. It randomized 192 patients to the ART group and 193 patients to the observation group. They reported a significantly improved 5-year biochemical progression-free survival in the RT group (72%; 95% CI: 65% to 81%) when compared to observation group (54%; 95% CI: 45% to 63%) (hazard ratio = 0.53; P =0.0015). The primary endpoint of this study was biochemical recurrence-free survival only, and it did not include metastases-free and overall survival (OS).
To summarize, adjuvant radiotherapy has been shown to reduce biochemical failure rates by 50%, with limited evidence that immediate ART also translates into better OS and metastasis-free survival. Only SWOG 8794 was designed to detect an OS advantage and decreased metastasis rates.[15][Table 1].
Why consider early salvage radiotherapy?
Based on the results of the above three trials, there is a concern of overtreatment in about 50% of patients receiving ART. In a retrospective analysis of the American National Cancer Data Base, Sineshaw et al. reported a steady declining pattern in the use of ART after RP in patients with adverse pathologic features.[17] This phenomenon can be understood possibly by the concern of overtreatment, increased risk of radiation toxicity, the tendency to choose eSRT after biochemical failure, and patient's preference. This declining interest in the use of ART has led to the exploration of eSRT as an alternative option in these patients. Nowadays, recurrence in prostate cancer can be monitored with currently available ultra-sensitive PSA tests. This allows us to deliver early salvage treatment at low volumes of recurrence. Subset analysis of the EORTC 22911 and the ARO 9602 studies revealed that adjuvant radiotherapy in those with detectable PSA led to a similar magnitude of benefit as those with undetectable PSA.[14],[16] Therefore, there is a case for examining eSRT as an alternative to ART for better patient selection and resource utilization.
Evidence supporting eSRT
In a multi-institutional cohort, Briganti et al. studied 472 node-negative patients who experienced biochemical recurrence (BCR) after RP.[18] These patients received eSRT to the prostate and seminal vesicle bed at PSA ≤0.5 ng/mL. They reported a 73.4% 5-year biochemical recurrence (BCR)-free survival rate after eSRT. On multivariable analysis, pathologic stage, Gleason score, positive surgical margins, and pre-radiotherapy PSA were significantly associated with BCR after eSRT. Trock et al. did a retrospective analysis of 635 men who experienced biochemical and/or local recurrence after radical prostatectomy and received no salvage treatment (n = 397), SRT alone (n = 160), or SRT combined with hormonal therapy (n = 78).[19] In their study, 22% of patients who received no salvage treatment, 11% of patients who received SRT alone, and 12% of patients who received SRT and hormonal therapy, died after a median follow-up of 6 years after recurrence. SRT alone was associated with a significant 3-fold increase in prostate cancer-specific survival relative to those who received no salvage treatment. There was no additional increase in disease-specific survival benefit by adding hormonal therapy to SRT. They concluded that independent of pathological prognostic features if SRT was administered within two years of BCR with a prostate-specific antigen doubling time of fewer than 6 months, a significant increase in prostate cancer-specific survival was observed.
How early to start salvage radiotherapy?
King CR reviewed 41 published studies of SRT after radical prostatectomy to identify the pathologic, clinical, and treatment factors associated with relapse-free survival after SRT.[20] He concluded that the PSA level before SRT (P < 0.0001) and a dose of delayed postoperative RT (P =0.0052) had a significant and independent association with relapse-free survival. This study provided level 2a evidence for initiating SRT at the lowest possible PSA. Relapse-free survival was about 64% if SRT was initiated at a PSA level of 0.2 ng/mL or less. Their study reported a very important finding that, with each increment of 0.1 ng/mL PSA at the time of SRT, there was an average 2.6% loss of relapse-free survival (95% CI ∼2.2–3.1).
Fossati et al., in a retrospective study of 716 node-negative patients with undetectable postoperative PSA after RP, studied the association between pre-eSRT PSA levels and biochemical failure after eSRT.[21] They found an interesting variation in BCR after eSRT when patients were stratified according to the number of risk factors present in the final pathology out of the following three features: pT3b/pT4 prostate cancer, pathologic Gleason score ≥8, and negative surgical margins. They reported a significant increase in 5-year BCR in patients with two or more pathological risk factors (10% BCR per 0.1 ng/mL rise of pre-eSRT PSA level) when compared to patients with one or no risk factors (1.5% BCR per 0.1 ng/mL rise of pre eSRT PSA level).
Similarly, Tendulkar et al. reported highest (71%) 5-year freedom from biochemical failure (FFBF) rate at pre-eSRT PSA level of 0.01–0.2 ng/mL.[22] The 5-year FFBF progressively declined with rise in pre-eSRT PSA levels (63% for pre-eSRT PSA level of 0.21–0.50 ng/mL, 54%for pre-eSRT PSA of 0.51–1.0 ng/mL, 43%for pre-eSRT PSA of 1.01–2.0 ng/mL, and 37% for pre-eSRT PSA >2.0 ng/mL) (P < 0.001).
Thus, the above studies have highlighted that eSRT gave better BCR-free survival when administered at the very first sign of PSA rise. In clinical practice, due to the perceived risk of overtreatment, many physicians consider PSA levels of 0.2 ng/mL as a trigger to offer radiotherapy. However, currently, there is ample evidence to initiate eSRT at the earliest sign of a rise in post-prostatectomy PSA level and it should not be delayed till 0.2 ng/mL.
Nomograms predicting outcomes of post-prostatectomy radiotherapy
Although, majority of recurrences after RP are seen within 3 years,[23] a considerable number of patients may present with bony metastases during their lifetime after RP.[24] Thus, a nomogram is very critical for patient counseling and predicting the clinical outcome after RP. To address this, various prediction tools have been designed to predict the probability of BCR, distant metastasis, and life expectancy after RP. In the past, many nomograms were designed to predict the 5-year, 10-year, and 20-year probability of post-prostatectomy BCR and probability of metastatic progression after RP in men with rising PSA levels respectively.[25],[26],[27],[28] Similarly, various nomograms were designed to predict the life expectancy after definitive therapy in a patient of prostate cancer, but they were unable to differentiate disease-specific mortality from mortality due to other causes.[29],[30],[31],[32]
Shariat et al. critically reviewed these nomograms in 2009 and concluded that the predictions of these nomograms are more accurate than individual clinician's predictions, regardless of his expertise, but they are not perfect and need further upgradation using novel biomarkers.[33]
In 2007, Stephenson's nomogram was updated with the ability to predict BCR in post-prostatectomy patients who received SRT.[4] Though this nomogram is widely used to predict the outcomes of eSRT, the trigger PSA level for initiating SRT in this study was >0.2 ng/mL.
Trials comparing adjuvant radiotherapy (ART) to early salvage radiotherapy (eSRT)
Whether ART is superior to eSRT after prostatectomy with regards to patient survival, remains an open question. Three major randomized trials have compared the outcomes of ART with eSRT. Of these Radiotherapy and Androgen Deprivation in Combination after Local Surgery (RADICALS-RT) and French Genitourinary Tumor Group-17 (GETUG-AFU 17) are superiority trials, whereas Radiotherapy- Adjuvant versus Early Salvage (RAVES) is a non-inferiority trial.[2],[3],[34] Details of these three randomized trials are elaborated in [Table 2].
In 2019, the outcome of the RADICALS-RT trial was presented at the European Society for Medical Oncology (ESMO) Congress.[2] This study is a 1:1 randomized trial of 1396 men with localized prostate cancer of ART versus eSRT. In the eSRT arm, only 33% of men received radiotherapy. No statistically significant difference was found in biochemical progression-free survival between ART and eSRT, however, results on survival and freedom from distant metastases require longer follow up. Using Radiation Therapy Oncology Group scales, ART was associated with higher incidence urethral strictures (8% vs 5%, P = 0.03).[35] This was expected due to the higher numbers of patients receiving RT in this group. Thus, early findings of this trial suggested no added advantage of post-prostatectomy adjuvant radiation over eSRT.
The RAVES trial is a non-inferiority randomized multi-institutional trial across Australia and New Zealand, comparing eSRT to ART with respect to biochemical failure in patients with locally advanced disease on RP.[3] Patients were randomized 1:1 to either arm. The median follow-up was 6.1 years. About 50% of patients in the eSRT arm received radiotherapy. The 5-year and 8-year freedom from biochemical failure rates were comparable in both the groups [Table 2]. By eight years, the incidence of local, regional, or distant failure was 6% in the ART arm compared with 5% in the eSRT group. The eSRT group was associated with significantly lower levels of genitourinary toxicity, although the overall rate of toxicity was low in both arms. Their study showed the non-inferiority of eSRT when compared to ART in locally advanced post-prostatectomy patients, with lower toxicity levels in the eSRT group.
GETUG-AFU 17 trial is a multicentric phase-III randomized trial, evaluating whether the outcome of immediate post-prostatectomy radiotherapy along with hormonal therapy (triptorelin) is more effective than radiation and hormonal therapy (Triptorelin) given after post-prostatectomy biochemical failure.[34] Results of this trial are not published yet, however, the early event-free survival data were included in the collaborative ARTISTIC meta-analysis.[35]
An ARTISTIC meta-analysis confirmed the findings of the RADICALS trial. This meta-analysis included results of randomized trials comparing ART with eSRT following prostatectomy for men with localized prostate cancer: RADICALS (ISRCTN40814031), GETUG-AFU 17 (NCT00667069), and RAVES (NCT00860652).[2],[3],[34] All 2,151 men included in the three trials, were randomized to ART (n = 1074) versus eSRT (n = 1077). In the eSRT group, 37% of men received RT to date. No evidence of event-free survival advantage of ART was found over eSRT in this study (HR 1.12; 95% CI 0.88–1.42; P = 0.37).
So where do we stand today?
The current evidence suggests that in patients at a high risk of recurrence after RP, ART reduces biochemical failure rates by 50% as compared to observation alone. Three RCTs have demonstrated a biochemical progression-free survival benefit, but only SWOG 8794 has found an OS advantage. When early outcomes of ART were compared to eSRT in randomized trials, ART does not demonstrate any improvement in event-free survival over eSRT. Additionally, eSRT spares more than 60% of men from potentially unnecessary radiotherapy, thus reducing the radiation-related toxicity events. However, we need to wait for long term clinical outcomes (metastasis-free survival and OS), the primary endpoints of these studies before drawing firm conclusions on this subject. Future versions of the ARTISTIC meta-analysis may be able to identify subgroups where ART may be beneficial.
ConclusionIn post RP patients with adverse pathological features, the event-free survival outcome of eSRT is comparable to ART, with additional advantages of less radiation-related toxicity events and reduced risk of overtreatment in the eSRT strategy. It is important to emphasize that prima facie eSRT is as effective as ART when delivered at or before a PSA of 0.2 ng/mL. While waiting for further follow-up data to emerge from these trials, it is important to keep the current information in mind while counseling patients regarding further treatment options after radical prostatectomy.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
References
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