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Discord Among Radiation Oncologists and Urologists in the Postoperative Management of High-Risk Prostate Cancer

Kishan, Amar U., MD*; Duchesne, Gillian, MD; Wang, Pin-Chieh, PhD*; Rwigema, Jean-Claude M., MD*; Kishan, Arun U., MS*; Saigal, Christopher, MD; Rettig, Matthew, MD§,∥; Steinberg, Michael L., MD*; King, Christopher R., MD, PhD*

American Journal of Clinical Oncology: August 2018 - Volume 41 - Issue 8 - p 739–746
doi: 10.1097/COC.0000000000000381
Original Articles: Genitourinary

Objective: To query specialty-specific differences regarding postoperative radiotherapy (RT) for high-risk prostate cancer.

Materials and Methods: Electronic mail survey of radiation oncologists (ROs) and urologists. We sought to maximize absolute response number to capture contemporary practice ethos. The outcome of interest was association between response and specialty. Training level/expertise, practice setting, percentage of consultation caseload consisting of high-risk prostate cancer, and nationality were set as effect modifiers for multivariate logistic regression.

Results: In total, 846 ROs and 407 urologists responded. ROs were more likely to prefer adjuvant radiotherapy (ART). ART or early salvage radiotherapy (SRT, with early SRT defined as that delivered at prostate-specific antigen<0.2), whereas urologists were more likely to prefer early or delayed SRT (P<0.0001). ROs were more likely to prefer lower PSA thresholds for initiating SRT (P<0.0001), and more likely to recommend ART in the setting of adverse pathologic features or node-positive disease (P<0.0001). Significantly more ROs would recommend concurrent androgen deprivation therapy or pelvic nodal RT in the setting of node-positive or Gleason score 8 to 10 disease (P<0.0001).

Conclusions: Specialty-specific differences were readily elucidated with respect to timing and indications for ART and SRT, as well as for indications for androgen deprivation therapy and nodal RT. These differences are likely to create a sense of dissonance for patients, which may in turn explain the underutilization of postoperative RT in general practice.

Departments of *Radiation Oncology

Urology

§Internal Medicine, Division of Hematology and Oncology, David Geffen School of Medicine, University of California, Los Angeles

Division of Hematology-Oncology, VA Greater Los Angeles Healthcare System, Los Angeles, CA

Sir Peter MacCallum Department of Oncology, the University of Melbourne, Vic., Australia

The authors declare no conflicts of interest.

Reprints: Amar U. Kishan, MD, Department of Radiation Oncology, University of California, Los Angeles, 200 UCLA Medical Plaza Suite B265, Los Angeles, CA 90095. E-mail: aukishan@mednet.ucla.edu.

Nearly 238,590 men are diagnosed with prostate cancer (CaP) in the United States every year, with 15% having high-risk disease (defined as clinical T-stage ≥3, initial prostate-specific antigen (PSA)>20 ng/mL, or Gleason score [GS], 8 to 10).1–3 The percentages of men with high-risk CaP (HR-CaP) undergoing radical prostatectomy (RP) have increased from 30.6% to 41.3% between 2004 and 2011.4 Because up to 20% to 40% of these men will ultimately experience biochemical recurrences,5–7 optimizing postoperative management has been an important goal. Three randomized trials investigating adjuvant radiotherapy (ART) versus observation for patients with adverse pathologic features (typically pT3 disease and/or positive margins) following RP demonstrated improved biochemical control with ART, with 1 reporting an overall survival benefit.8–10 Notably, the trials did not uniformly require rigorous postoperative PSA analysis to identify patients who might have already experienced a BCR at randomization, and salvage therapy was not standardized. Data suggest that salvage radiotherapy (SRT) is effective, particularly if delivered at lower PSA thresholds,11–13 and the optimal timing of postoperative radiotherapy remains controversial.14,15 Indeed, 2 recently published National Cancer Database analyses demonstrate that only 10% to 20% of patients with adverse pathologic features receive postoperative radiotherapy (RT).16,17 Specialty-specific differences in preferred postoperative RT strategies may contribute to this controversy; a previous survey of 641 ROs and urologists finding that ROs were more likely to recommend ART for a variety of pathologic findings, whereas urologists were more likely to favor SRT.18 Divergent recommendations may also create a sense of dissonance that is readily perceived by patients.

Three ongoing randomized trials are comparing ART and SRT. These trials have nonuniform inclusion criteria and thresholds for initiating SRT. Furthermore, the radiation target volumes (ie, inclusion of pelvic nodal RT) and role of androgen deprivation therapy (ADT) are variable. Other randomized trials are exploring the benefit of ADT and nodal RT. Given the controversies surrounding these important facets of postoperative RT, we sought to query a large pool of ROs and urologists to understand the role that specialty-specific differences play in rendering treatment recommendations for postoperative RT. We hypothesized that specialty-specific differences would be prominent.

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MATERIALS AND METHODS

Survey Design

The survey instrument (hosted online by SurveyGizmo) included questions about postoperative management of HR-CaP, as well as question about the general management of HR-CaP. Questions relevant to postoperative RT are presented in Table 2. We operationally distinguished between “early SRT” and “delayed SRT” because data suggest that SRT at lower PSA thresholds may be more effective12,13; early SRT refers to SRT delivered at postoperative PSA values <0.2 ng/mL (the formal threshold for biochemical recurrences).

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Survey Deployment

No general directory of genitourinary oncologists was known and many patients with CaP are managed in community settings by practitioners who may not self-identify as such. To best capture contemporary practice ethos, we therefore sought to maximize absolute response number by targeting excess numbers of ROs and urologists; this strategy was known a priori to preclude a determination of the relevant response rate, since the majority of physicians who would receive an invitation would not treat CaP regularly. We queried members of the American Society for Radiation Oncology, the American Urological Association, the Society for Urologic Oncology, the Trans-Tasman Radiation Oncology Group, and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group. Physicians were contacted by electronic mail, with a reminder sent 2 weeks later. All participants who completed the survey were eligible for a raffle to win up to $500 in credit at Amazon.com.

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Statistical Analysis

Distribution of 4 responder characteristics—“training level/expertise,” “practice setting,” “percentage of patients seen in consultation who have CaP,” and “nationality”—was compared between specialists using the Mantel-Haenszel χ2 test. Multivariate logistic regression was used to measure associations between selected categorical responses and specialty, setting responder characteristics as effect modifiers. Binary, ordinal, or multinomial logistic regression was used as appropriate to statistically estimate odds ratios. All analyses were performed with SAS, version 9.4 (SAS Institute, Cary, NC), and P-values ≤0.05 for 2-sided tests were considered statistically significant.

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RESULTS

Respondent characteristics are shown in Table 1. The absolute response number was 1253. Results of multivariate analyses and raw response patterns are presented in Table 2, and pictorial representations of response distributions are shown in Figures 1 and 2. ROs tended to favor ART or early SRT, whereas urologists favored early or delayed SRT (P<0.0001 by logistic regression). Significantly more ROs felt that ART and SRT were underutilized (P<0.0001), whereas significantly more urologists felt that these were overutilized (P<0.0001). A plurality (30%) of ROs felt that ≥2 consecutive rises in PSA were sufficient to initiate SRT, regardless of the magnitude of these PSA values, while 29% favored a threshold of 0.2 ng/mL and 15% supported initiating SRT at any detectable PSA. In contrast, 35% of urologists favored a threshold of 0.2 ng/mL, with 20% favoring a threshold of ≥2 consecutive rises in PSA and only 7% favoring initiating SRT at any detectable PSA. Overall, ROs were more likely to select a lower PSA threshold for SRT (P<0.0001). ROs were also more likely to offer SRT for cases with immediately detectable postoperative PSAs (P<0.0001).

TABLE 1

TABLE 1

TABLE 2

TABLE 2

FIGURE 1

FIGURE 1

FIGURE 2

FIGURE 2

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).

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DISCUSSION

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

TABLE 3

TABLE 3

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.

TABLE 4

TABLE 4

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.

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CONCLUSIONS

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:

specialty bias; high-risk prostate cancer; radiation therapy; radical prostatectomy; local salvage; postoperative radiation

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