ROs were much more likely to recommend ART for patients with positive margins, extracapsular extension, seminal vesicle invasion (SVI), pT4, and pN+ disease (P<0.0001); proportions recommending this for GS-10 disease were equal. The most popular indication for ROs was positive margins; for urologists, positive margins, SVI, and pT4 were tied. In terms of recommending concurrent ADT with ART, the most popular indications were pN+, GS 8 to 10, and pT4 (P<0.0001 for pN+ and GS 8 to 10 comparisons). Significantly more urologists felt ADT was not appropriate outside the scope of a clinical trial (P<0.0001). Similar patterns of responses were seen in the setting of ADT with SRT, though the nominal magnitude of differences was narrower for all pathologic features. With regards to nodal RT with either ART or SRT, a majority of both ROs and urologists supported this in the context of pN+ disease, though significantly more ROs shared that opinion (P<0.0001). The next most popular indications were GS 8 to 10 disease (P<0.0001) and pT4 disease (P>0.1). Significantly more urologists felt that nodal irradiation had no role outside of the context of a clinical trial (P<0.0001).
Robust specialty-specific differences were elucidated with regards to various facets of postoperative RT for HR-CaP. In general, ROs were more likely to prefer a strategy of ART, feel that ART and SRT are underutilized, and recommend SRT earlier (P<0.0001 for all comparisons). Between 59% and 80% of ROs would recommend ART in the setting of positive margins, extracapsular extension, SVI, pT4 disease or pN+ disease in isolation—in comparison, only 32% to 47% of urologists would do so (P<0.0001 for all). Significantly more ROs would recommend concurrent ADT or pelvic nodal RT in the setting of pN+ or GS 8 to 10 disease (P<0.0001). Urologists were more likely to feel that concurrent ADT and nodal RT are not appropriate outside the context of a clinical trial (P<0.0001), though a large plurality of urologists would still recommend these for patients with pN+ disease in particular. These differences were found after adjusting for training level/experience, practice setting, percentage of consultation caseload consisting of CaP, and nationality. With 1253 responses, this survey is the largest of its kind and captures contemporary practice ethos, underscoring the significant specialty-specific differences underlying postoperative RT for HR-CaP.
Three randomized trials investigating ART versus observation following RP have suggested improved biochemical control with ART, with the SWOG 8794 trial reporting improvements systemic control and overall survival (Table 3).8–10 The EORTC 22911 and SWOG trials have been retrospectively criticized for including a fair percentage of patients (20% to 30%) with postoperative PSA>0.2 ng/mL at randomization; our results suggest that, for patients with HR-CaP, 86% of urologists and 93% of ROs would consider SRT in this setting. Neither trial had uniform SRT protocols for the observation arm, and the median PSA at the time of initiating SRT in the observation arm ranged from 0.75 ng/mL for the subset in SWOG trial who received SRT for PSA relapse only, to 1.2 ng/mL among patients receiving “active” treatment after relapse in the EORTC trial; many patients in the observation arms never received SRT. The ARO 9602 analysis excluded the ∼20% of patients who were randomized but ultimately had a “detectable” PSA (with thresholds as low as 0.03 ng/mL), but SRT utilization in the observation arm was not reported. Since the initiation of these studies, multiple series have suggested that SRT is effective11 and, specifically, that delivered at lower PSAs may be just as effective as ART.12,13
Nonetheless, utilization rates of postoperative RT remain low.6,17,19,20 Recently National Cancer Database analyses suggest utilization rates as low as 10% to 20% among ideal candidates.16,17 One study reported that among 57,447 men with pT3 disease and/or positive margins treated with RP from 2004-2009, only 7.5% received ART and 2.8% received SRT; a small increase in SRT in 2008 was offset by a commensurate decrease in ART.6 Another study of 97,270 men with pT3/4 disease or pT2 disease with positive margins reported that the rate of postoperative RT utilization actually dropped from 9.1% to 7.3% from 2005 to 2011.17 Both studies found higher rates among men with positive margins, higher T-stage, and higher GS disease, consistent with the results of our study. However, the proportion of physicians recommending postoperative RT for any of these indications in our study by and far exceeds practice patterns.
This disconnect may in fact be explained, at least partially, by the very specialty-specific differences unearthed by this study as well as previous survey studies.18,21 An analysis of men enrolled in the RAVES trial (Table 4) revealed that men strongly desire an active role in decision making with regards to postoperative RT.22 However, the analysis also revealed that men enrolled on the study by urologists had a different understanding of the relative merits of ART and SRT than men enrolled by ROs. Indeed, our results suggest that ROs are much more likely to favor ART and early SRT approaches, whereas urologists are more likely to favor either early or delayed SRT; however, urologists tend to pick higher PSA thresholds for triggering SRT. A hesitation to deliver postoperative RT, particularly ART, can be explained by concerns for toxicity and overtreatment.12 Urinary toxicity in particular was higher in the ART group in all 3 randomized trials.8–10 However, if ART is not delivered, one might expect early SRT to be more effective than delayed SRT or observation.11–13 Our results suggest that a sizable and equal proportion of both urologists and ROs actually appear to favor early SRT. However, there is no guarantee that any given patient will have both a RO and a urologist that feel this way—and even if the specialists treating a particular case did, in principle, agree on a general strategy, our data clearly suggest that they might not agree on the thresholds, indications, role of ADT, and radiation target volumes. This is likely to create a confusing situation for patients and when faced with such controversy over receiving a treatment or not, it is unsurprising that they may opt not to, particularly if the urologist (who treated the patient) is opposed to it. This, of course, presumes the patient is even referred to the RO for a discussion of postoperative RT—this process is necessarily at the mercy of the urologist’s own viewpoints regarding postoperative management. However, more urologists responded that they would consider postoperative RT than would be expected based on practice patterns, so a lack of referral is likely not the sole explanation.
Indeed, our results suggest differences related to not only the timing of postoperative RT, but also the appropriate pathologic indications ART, concurrent ADT, and nodal RT (with ART or SRT). These facets of postoperative RT are all subjects of randomized trials, which themselves have varied designs (Table 4). Three highly anticipated trials—RADICALS-RT, GETUG-17, and RAVES—randomize patients between ART and SRT. The RADICALS-RT trial allows SRT initiation at PSAs lower than 0.2 ng/mL (considered early SRT in our survey), whereas RAVES and GETUG-17 do not. The GETUG-17 trial requires 6 months of ADT, whereas the RADICALS-HD trial examines different ADT durations. The ongoing RTOG 0534 study is the only study to assess the role of pelvic nodal RT in a randomized fashion, though others allow nodal RT at the physician’s discretion. The long-term results from RTOG 9601 support an overall survival benefit to combining long-term ADT with SRT, whereas interim results of GETUG-16 support a biochemical control benefit—but no overall survival benefit—to 6 months of ADT.23,24 Interestingly, most physicians regardless of specialty were comfortable recommending ADT and nodal RT off-trial, particularly for patients with pN+ disease, GS 8 to 10 disease, and pT4 disease. The role of postoperative RT in general for patients with pN+ disease is particularly controversial, with a recent study supporting a prostate cancer-specific mortality benefit in selected patients.25 Patients with pN+ disease are largely excluded from the aforementioned trials, as the current standard of care for these patients is life-long ADT26; however, pN+ disease was a popular indication among both specialty groups for ART, concurrent ADT, and nodal RT.
The reasons for the apparent schism between urologists and ROs remain unclear, though hypotheses can be proposed. As mentioned above, urinary toxicity in particular was higher in the ART arm of all three randomized trials.8–10 Moreover, not all men with poor pathology will experience a BCR and the natural history of a BCR can be variable, raising the possibility of overtreatment.12 It is conceivable that urologists, who are the primary physician managing patients who have undergone RP, are thus less likely to recommend what they perceive to be a potentially toxic treatment until the disease has “declared itself,” which might translate to a proclivity for recommending SRT at higher PSAs. In contrast, ROs may consider the relative added toxicity of postoperative RT to be meager when compared with the implications of aggressive disease. In addition, the efficacy of the postoperative RT in many ways reflects on the RO delivering the RT, rather than the urologist who performed the RP. Thus, the RO may strongly prefer to deliver SRT at a lower PSA because it is known to be more effective, and may place more stock in the randomized trials that show a benefit to ART. Indeed, the aforementioned analysis of men enrolled in the RAVES trial revealed that men enrolled by urologists had a different understanding of the relative merits of ART and SRT than men enrolled by ROs, likely reflecting the specialty-specific perceptions of the toxicity versus efficacy of these treatments.22 Emerging data suggest that molecular and histopathologic biomarkers found at the time of RP can stratify patients into different risk levels with regards to recurrence following RP.27–31 Although a review of this intriguing possibility is beyond the scope of this report, the potential of obtaining patient-specific risk stratification will clearly facilitate a nuanced discussion of the risks and benefits of postoperative RT.
As with all survey studies, there are some limitations to our study. Because we attempted to maximize absolute response number in an effort to capture contemporary practice ethos, our study design precluded determination of the relevant response rate. This could introduce nonresponse bias, particularly as demographics data were only available for responders. However, nonresponse bias is less of a concern in physician surveys.32 In addition, Internet-based surveys have lower RRs than other surveys32 and our multivariate analysis controlled for factors that might potentially be associated with nonresponse bias. Another weakness, inherent to nearly all survey studies, relates to having simple answer choices. Further, a physician’s response on the survey may not mirror delivery of care for other reasons, such as access to certain technology or institutional/practice biases not captured by the survey. Finally, our study was underpowered to fully evaluate differences on the basis of primary practice location within the United States versus outside the United States (defined here as “nationality”). This is because only 2% of urologists who responded were confirmed to practice outside the United States. We did adjust for nationality in our multivariate model that showed a significant effect for specialty. When independently assessing the effect of nationality, we did not note significant differences in provider preference.
In conclusion, our data indicate robust specialty-specific differences regarding multiple aspects of postoperative RT for HR-CaP. Such marked disparities between recommendations offered by different specialist might explain why postoperative RT is underutilized. Certainly, from a patient perspective, hearing dissonant recommendations might wane enthusiasm for postoperative RT. Multidisciplinary clinics afford an opportunity to ameliorate the situation, as patients seen in these clinics should receive recommendations from urologists and ROs who have reviewed the case together. Such clinics improve outcomes and allow shared decision making, reducing treatment regret.33,34 Continuing medical education has also been shown to increase physician performance and patient outcomes35 and increased cross-specialty training in this context and during residency training may also help to abrogate the effects of specialty bias.
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Keywords:Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
specialty bias; high-risk prostate cancer; radiation therapy; radical prostatectomy; local salvage; postoperative radiation