RADIOTHERAPY AFTER PROSTATECTOMY: AUA/ASTRO ......NOT TO BE COPIED, DISSEMINATED, OR REFERENCED 3 Radiotherapy After Prostatectomy: AUA/ASTRO Guideline – DRAFT 2-5-13 50 INTRODUCTION

NOT TO BE COPIED, DISSEMINATED, OR REFERENCED

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Radiotherapy After Prostatectomy: AUA/ASTRO Guideline – DRAFT 2-5-13

RADIOTHERAPY AFTER PROSTATECTOMY: AUA/ASTRO GUIDELINE 1

2

Purpose: The purpose of this guideline is to provide a clinical framework for the use of 3

radiotherapy after prostatectomy in patients with and without evidence of prostate cancer 4

recurrence. 5

Methods: A systematic review of the literature using the Pubmed, Embase, and Cochrane 6

databases (search dates 1/1/90-12/15/12) was conducted to identify peer-reviewed 7

publications relevant to the use of radiotherapy after prostatectomy. The review yielded an 8

evidence base of 301 articles after application of inclusion/exclusion criteria. These 9

publications were used to create the guideline statements. When sufficient evidence existed, 10

the body of evidence for a particular treatment was assigned a strength rating of A (high quality 11

evidence; high certainty), B (moderate quality evidence; moderate certainty), or C (low quality 12

evidence; low certainty) and evidence-based statements of Standard, Recommendation, or 13

Option were developed. Additional information is provided as Clinical Principles and Expert 14

Opinion when insufficient evidence existed. See text for definitions and detailed information. 15

Guideline Statements: 16

1. CLINICAL PRINCIPLE. Patients who are being considered for management of localized 17

prostate cancer with radical prostatectomy should be informed of the potential for adverse 18

pathologic findings that portend a higher risk of cancer recurrence and that these findings 19

may suggest a benefit of additional therapy after surgery. 20

2. CLINICAL PRINCIPLE. Patients with adverse pathologic findings including seminal vesicle 21

invasion, positive surgical margins, and extracapsular extension should be informed that 22

adjuvant radiotherapy, compared to observation, reduces the risk of biochemical (PSA) 23

recurrence, local recurrence, and clinical progression of cancer. They should also be 24

informed that the impact of adjuvant radiation on subsequent metastases and overall 25

survival is less clear; one of two randomized controlled trials that addressed these 26

outcomes indicated a benefit but the other trial findings were equivocal. 27

3. STANDARD. Physicians should offer adjuvant radiotherapy to patients with adverse 28

pathologic findings at prostatectomy including seminal vesicle invasion, positive surgical 29

margins, or extraprostatic extension. (Body of Evidence Strength Grade A) 30

4. CLINICAL PRINCIPLE. Patients should be informed that the development of a PSA 31

recurrence after surgery is associated with a higher risk of development of metastatic 32

prostate cancer or death from the disease. Congruent with this clinical principle, physicians 33

should regularly monitor PSA after radical prostatectomy to enable early administration of 34

salvage therapies if appropriate. 35


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5. RECOMMENDATION. Clinicians should define biochemical recurrence as a detectable or 36

rising PSA value after surgery that is ≥ 0.2 ng/ml with a second confirmatory level ≥ 0.2 37

ng/ml or as a consistently rising serum PSA level. 38

6. OPTION. A restaging evaluation in the patient with a PSA recurrence may be considered. 39

(Body of Evidence Strength Grade C) 40

7. RECOMMENDATION. Physicians should offer salvage radiotherapy to patients with PSA or 41

local recurrence after radical prostatectomy in whom there is no evidence of metastatic 42

disease. (Body of Evidence Strength Grade C) 43

8. CLINICAL PRINCIPLE. Patients should be informed that the effectiveness of radiotherapy for 44

PSA recurrence is greatest when given at lower levels of PSA. 45

9. CLINICAL PRINCIPLE. Patients should be informed of the possible short-term and long-term 46

urinary, bowel, and sexual side effects of radiotherapy as well as of the potential benefits of 47

controlling disease recurrence. 48

49


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INTRODUCTION 50

51

Purpose 52

This guideline’s purpose is to provide direction to clinicians and patients regarding the 53

use of radiotherapy after prostatectomy in patients with and without evidence of prostate 54

cancer recurrence. The strategies and approaches recommended in this document were 55

derived from evidence-based and consensus-based processes. This document constitutes a 56

clinical strategy and is not intended to be interpreted rigidly. The most effective approach for a 57

particular patient is best determined by the individual clinician faced with a particular patient. 58

As the science relevant to the use of radiotherapy after prostatectomy evolves and improves, 59

the strategies presented here will require amendment to remain consistent with the highest 60

standards of clinical care. 61

Methodology 62

63

A systematic review was conducted to identify published articles relevant to the use of 64

radiotherapy (RT) after prostatectomy, including its efficacy in patients with detectable and 65

undetectable prostatic specific antigen (PSA) levels, its toxicity and quality of life (QoL) impact, 66

and optimal imaging strategies to determine the appropriateness of RT use in patients 67

suspected of recurrence. Literature searches were performed on English-language publications 68

using the Pubmed, Embase, and Cochrane databases from 1/1/1990 to 12/15/2012. Data from 69

studies published after the literature search cut-off will be incorporated into the next version of 70

this guideline. Preclinical studies (e.g., animal models), commentary, and editorials were 71

excluded. Only studies in which PSA data were provided for 75% or more patients were 72

included. Review article references were checked to ensure inclusion of all possibly relevant 73

studies. Multiple reports on the same patient group were carefully examined to ensure 74

inclusion of only nonredundant information. The review yielded an evidence base of 301 75

articles from which to construct a clinical framework for the use of radiotherapy after 76

prostatectomy. 77

78

Quality of Individual Studies and Determination of Evidence Strength. 79

80

Quality of individual studies that were randomized controlled trials (RCTs) or controlled 81

clinical trials (CCTs) was assessed using the Cochrane Risk of Bias tool (Higgins 2007). Case-82

control studies and comparative observational studies were rated using the Newcastle-Ottawa 83

Quality (NOQ) Assessment Scale (Wells 2009). Because there is no widely-agreed upon quality 84

assessment tool for single cohort observational studies, the quality of these studies was not 85

assessed except in the case of diagnostic accuracy studies. Diagnostic accuracy studies were 86

rated using the QUADAS (Whiting et al., 2003, 2004). 87

88


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The categorization of evidence strength is conceptually distinct from the quality of 89

individual studies. Evidence strength refers to the body of evidence available for a particular 90

question and includes consideration of study design, individual study quality, consistency of 91

findings across studies, adequacy of sample sizes, and generalizability of samples, settings, and 92

treatments for the purposes of the guideline. The AUA categorizes body of evidence strength 93

(ES) as Grade A (well-conducted and highly-generalizable RCTs or exceptionally strong 94

observational studies with consistent findings), Grade B (RCTs with some weaknesses of 95

procedure or generalizability or moderately strong observational studies with consistent 96

findings), or Grade C (observational studies that are inconsistent, have small sample sizes, or 97

have other problems that potentially confound interpretation of data). By definition, Grade A 98

evidence is evidence about which the Panel has a high level of certainty, Grade B evidence is 99

evidence about which the Panel has a moderate level of certainty, and Grade C evidence is 100

evidence about which the Panel has a low level of certainty (Faraday, Hubbard et al., 2009). 101

102

For some clinical issues, there was little or no evidence from which to construct evidence-103

based statements. Where gaps in the evidence 104

existed, the Panel provides guidance in the 105

form of Clinical Principles or Expert Opinion with 106

consensus achieved using a modified Delphi 107

technique if differences of opinion 108

emerged(Hsu and Sandford 2007). A Clinical 109

Principle is a statement about a component of 110

clinical care that is widely agreed upon by 111

urologists or other clinicians for which there 112

may or may not be evidence in the medical 113

literature. Expert Opinion refers to a 114

statement, achieved by consensus of the Panel, 115

that is based on members' clinical training, 116

experience, knowledge, and judgment for 117

which there is no evidence. 118

119

AUA Nomenclature: Linking Statement 120

Type to Evidence Strength. The AUA 121

nomenclature system explicitly links statement 122

type to body of evidence strength, level of 123

certainty, and the Panel’s judgment regarding 124

the balance between benefits and 125

risks/burdens (Faraday, Hubbard et al. 2009). 126

Standards are directive statements that an action should (benefits outweigh risks/burdens) or 127

should not (risks/burdens outweigh benefits) be undertaken based on Grade A (high level of 128

certainty) or Grade B (moderate level of certainty) evidence. Recommendations are directive 129

Table 1: AUA Nomenclature Linking Statement Type to Level of Certainty and

Evidence Strength

Standard: Directive statement that an action should (benefits outweigh risks/burdens) or should not (risks/burdens outweigh benefits) be taken based on Grade A (high quality; high certainty) or B (moderate quality; moderate certainty) evidence

Recommendation: Directive statement that an action should (benefits outweigh risks/burdens) or should not (risks/burdens outweigh benefits) be taken based on Grade C (low quality; low certainty) evidence

Option: Non-directive statement that leaves the decision regarding an action up to the individual clinician and patient because the balance between benefits and risks/burdens appears equal or appears uncertain based on Grade A (high quality; high certainty), B (moderate quality; moderate certainty), or C (low quality; low certainty) evidence

Clinical Principle: a statement about a component of clinical care that is widely agreed upon by urologists or other clinicians for which there may or may not be evidence in the medical literature

Expert Opinion: a statement, achieved by consensus of the Panel, that is based on members' clinical training, experience, knowledge, and judgment for which there is no evidence


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statements that an action should (benefits outweigh risks/burdens) or should not (risks/burdens 130

outweigh benefits) be undertaken based on Grade C (low level of certainty) evidence. Options 131

are non-directive statements that leave the decision to take an action up to the individual 132

clinician and patient because the balance between benefits and risks/burdens appears relatively 133

equal or appears unclear; Options may be supported by Grade A (high certainty), B (moderate 134

certainty), or C (low certainty) evidence. 135

136

Limitations of the Literature. The Panel proceeded with full awareness of the 137

limitations of the radiotherapy after prostatectomy literature. A major limitation of this 138

literature is the lack of a large number of randomized controlled trials (RCTs) to guide decision-139

making in patients with and without evidence of recurrence and to indicate the appropriate use 140

of androgen deprivation therapies in these patients. Further, a major limitation of all 141

randomized trials in localized prostate cancer with long-term follow-up is the change in 142

chacteristics of contemporary patients; because of increased prostate cancer screening via 143

prostatic specific antigen (PSA) testing and consequent detection of disease and initiation of 144

therapy at earlier disease stages, patients recruited into trials decades ago have a greater risk of 145

adverse outcomes than do contemporary patients. However, the Panel is fully aware that these 146

issues will always be present in trials of therapies for localized prostate cancer because disease 147

events (e.g., metastases and death) generally occur one to two decades after treatment. 148

Additional limitations include: the preponderance of non-randomized studies; poorly-defined 149

or heterogeneous patient groups; in studies that compared RT administered to patients with 150

and without recurrence, the lack of group equivalence in terms of pathological risk factors; 151

variability in PSA assay sensitivity and in failure criteria across studies and over time; the 152

paucity of studies with follow-up duration longer than 60 mos; and, the overwhelming focus of 153

the literature on biochemical recurrence with less information available regarding metastatic 154

recurrence, cancer-specific survival, and overall survival. In addition, relatively few studies 155

focused on quality of life outcomes that are of critical importance to patients, such as erectile 156

function. 157

158

Process. The Radiotherapy after Prostatectomy Panel was created in 2011 by the 159

American Urological Association Education and Research, Inc. (AUA) and the American Society 160

for Radiation Oncology (ASTRO). The AUA Practice Guidelines Committee (PGC) and the ASTRO 161

Guidelines Committee (GC) selected the Panel Chairs and the additional panel members with 162

specific expertise in this area. 163

AUA and ASTRO conducted a thorough peer review process. The draft guidelines 164

document was distributed to 73 peer reviewers, of which XX reviewers provided comments. 165

The panel reviewed and discussed all submitted comments and revised the draft as needed. 166

Once finalized, the guideline was submitted for approval to the AUA PGC and the ASTRO GC. 167

Then it was submitted to the AUA and ASTRO Boards of Directors for final approval. Funding of 168

the panel was provided by the AUA and ASTRO; panel members received no remuneration for 169

their work. 170

171


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BACKGROUND 172

General Background. 173

In 2012, an estimated 241,740 men were diagnosed with prostate cancer (American 174

Cancer Society 2012). The most common primary treatment for localized disease is radical 175

prostatectomy (Miller 2006). In approximately two-thirds of men, prostatectomy constitutes a 176

cure but within 10 years up to one-third of patients will present with recurrent disease (Amling 177

2000; Chun 2006; Han 2001; Bianco 2005). Recurrence after prostatectomy is thought to result 178

from residual subclinical disease in the operative site that later manifests as a rising prostatic-179

specific antigen (PSA) level, a local tumor recurrence, or metastatic disease. The risk of 180

recurrence is greater among men with adverse pathology such as positive margins, seminal 181

vesicle invasion (SVI), extracapsular extension (ECE), and higher Gleason scores (e.g., 182

Stephenson 2006; Swindler 2005; Hawkins 1995; Kupelian 1997; Epstein 1993; Zietman 1994; 183

Lee 2004; Ohori 1995; Lowe 1997; Pound 1999; Catalona 1994). 184

185

Clinicians, therefore, frequently face two scenarios in the patient for whom 186

prostatectomy is the primary prostate cancer treatment. In the high-risk patient, revealed to 187

have adverse pathological features at prostatectomy, clinicians and patients face the question 188

of whether an adjuvant therapy should be considered to prevent possible future recurrence. In 189

the post-prostatectomy patient who later presents with a detectable PSA level, appropriate 190

salvage therapies may be considered. 191

192

This guideline focuses on the evidence for use of radiotherapy (RT) in the adjuvant and 193

salvage contexts. Adjuvant radiotherapy (ART) is defined as the administration of radiotherapy 194

to post-prostatectomy patients at a higher risk of recurrence because of adverse pathological 195

features prior to evidence of disease recurrence. Salvage radiotherapy (SRT) is defined as the 196

administration of radiotherapy to the prostatic bed in the patient with a PSA recurrence after 197

surgery but no evidence of metastatic disease. Biochemical (PSA) recurrence after surgery is 198

defined as a detectable or rising PSA level > 0.2 ng/mL with a second confirmatory level > 0.2 199

ng/mL or a consistently rising PSA. 200

201

The most commonly-reported post-prostatectomy outcome in the peer-reviewed 202

literature is biochemical (PSA) recurrence and biochemical recurrence-free survival (bRFS). 203

Other reported outcomes include local recurrence and local recurrence-free survival, 204

metastatic recurrence and metastatic recurrence-free survival (mRFS), clinical progression-free 205

survival (no evidence of local or metastatic progression, excluding evidence of biochemical 206

recurrence), cancer-specific survival, and overall survival. Clinicians generally use regularly-207

obtained PSA levels over time in post-RP patients to detect recurrence, to trigger the 208

administration of additional therapies, and/or to guide further diagnostic evaluations. 209

210


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Adjuvant radiotherapy (ART). The highest-quality evidence that addresses the use of 211

radiotherapy after prostatectomy is provided by three randomized controlled trials (RTCs) that 212

have examined the effect of radiotherapy delivered primarily in an adjuvant context. Findings 213

from the three trials are reviewed below and in Table 2. 214

215

Overall Findings. Biochemical recurrence. Three RCTs (SWOG 8794, EORTC 22911, and 216

ARO 96-02), two with more than 10 years of follow-up, documented significant improvements 217

in biochemical recurrence-free survival (bRFS) among patients with adverse pathological 218

features (i.e., seminal vesicle invasion, positive surgical margins, and/or extraprostatic 219

extension) with the use of adjuvant RT in comparison with observation only post-prostatectomy 220

(Thompson 2006; Bolla 2012; Wiegel 2009). A meta-analysis of biochemical recurrence data 221

performed as part of the literature review yielded a pooled hazard ratio of 0.48 (95% 222

confidence interval: 0.42 – 0.56; p <0.00001; random effects model; see Figure 1 below). 223

224

225

Locoregional recurrence. Two RCTs demonstrated a reduction in locoregional failure in 226

ART patients compared to RP only patients; ARO 96-02 did not assess locoregional failure. This 227

difference was statistically significant in EORTC 22911 (Bolla 2012) at median 10.6 years of 228

follow-up with 8.4% of ART patients having locoregional failure compared to 17.3% of RP only 229

patients. In SWOG 8794, also at 10.6 years of follow-up, locoregional recurrence was 8% in the 230

ART group and 22% in the RP only group (Thompson 2006). A p level was not presented but the 231

proportions are similar to those reported in EORTC 22911. 232

233

Hormonal-therapy free survival. SWOG 8794 also reported a statistically significant 234

improvement in hormonal therapy-free survival in ART patients compared to RP only patients 235

with approximately 84% of ART patients remaining hormone-therapy free at 10 years compared 236

to approximately 66% of RP only patients. EORTC 22911 reported that by year 10, 21.8% of 237

patients in the ART group had started an active salvage treatment (including salvage 238

Figure 1: Meta-analysis of biochemical recurrence data from SWOG 8794 (Thompson 2009), EORTC

22911 (Bolla 2012), and ARO 96-02 (Wiegel 2009).


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radiotherapy or ADT) compared to 47.5% of patients in the RP only group -- a statistically 239

significant difference. 240

241

Clinical progression. SWOG 8794 and EORTC 22911 also both demonstrated improved 242

clinical progression-free survival (defined as clinical or imaging evidence of recurrence or death 243

but not including biochemical progression) in patients who had ART compared to those who 244

had RP only. This difference was statistically significant in SWOG 8794 at median 10.6 years of 245

follow up and borderline significant (p = 0.054) in EORTC 22911 at the same follow-up point. 246

The weaker effect in EORTC 22911 may have been the result of the higher rate of non-prostate 247

cancer mortality among the ART group (17.1%) compared to the RP only group (12.3%) or 248

possibly because salvage treatments in the RP only group were initiated at lower PSA levels 249

than in the ART group. 250

251

Metastatic recurrence and overall survival. Only SWOG 8794 demonstrated significantly 252

improved overall survival (74% in ART patients compared to 66% for RP only patients) and 253

significantly improved metastatic recurrence-free survival (43.5% for ART patients compared to 254

54% for RP only patients) with the use of ART compared to RP only at more than 12 years of 255

follow-up (Thompson 2009). These findings did not replicate in EORTC 22911 at median 10.6 256

years of follow-up (Bolla 2012). There are several differences between the two trials that may 257

be relevant to the disparate findings. These include the fact that the overall survival rate of the 258

RP only group in SWOG 8794 was much lower (66.0%) than the RP only group in EORTC 22911 259

(80.7%); the reason for the lower survival rate in SWOG 8794 is not clear. The trials used 260

identical patient selection criteria. Patient demographics were reported differently in the two 261

trials, making it somewhat difficult to compare recruited patient characteristics that might be 262

relevant to the disparate findings. The proportion of patients administered preoperative 263

hormonal therapies was similar, however (SWOG 8794 – 8% of Observation group, 9% of ART 264

group; EORTC 22911 – 10% of each group). More patients had SVI in EORTC 22911 265

(approximately 25% of each group) than in SWOG 8794 (10-11% of each group). In SWOG 266

8794, 68% of the Observation group and 67% of the ART group had ECE or positive margins. 267

EORTC 22911 reported that 78.9% of the Observation group and 75.1% of the ART group had 268

ECE and 63% of the Observation group and 62.2% of the ART group had positive margins. The 269

proportion of patients with post-RP PSA values ≤ 0.2 ng/ml also was relatively similar across 270

trials (SWOG 8794 – 68% of Observation group, 65% of ART group; EORTC 22911 – 68.6% of 271

Observation group, 70.3% of ART group). None of these patient-level differences, however, 272

clearly explain the outcome differences. It also is possible that salvage treatments in SWOG 273

8794 were not used as extensively as in EORTC 22911; the trials had similar rates of salvage 274

treatment despite higher relapse rates in SWOG 8794. A definitive answer has yet to be 275

identified. 276

277

Subgroup Findings. The three RCTs also reported outcomes for various patient 278

subgroups (see Table 3). Not all trials reported on all subgroups and subgroup analyses were 279


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not performed for all outcomes. These analyses are summarized below. The Panel notes that 280

the trials did not stratify randomization by subgroups and that these comparisons were 281

unplanned, internal analyses for which the trials did not necessarily have sufficient statistical 282

power. Subgroup analyses, therefore, should be interpreted with caution and their utility is 283

primarily to guide new research directions. 284

285

Positive surgical margins: All three trials reported a statistically significant improvement 286

in biochemical RFS among patients with positive surgical margins who received radiotherapy 287

compared to patients who did not. In addition, both SWOG 8794 and EORTC 22911 reported a 288

significant improvement in clinical RFS among patients who received radiotherapy (this 289

outcome was not addressed by ARO 96-02). Only EORTC 22911 reported overall survival data 290

for this subgroup; there were no differences in overall survival between patients who did or did 291

not receive radiotherapy. 292

293

Patients with positive surgical margins comprised the majority in EORTC 22911 (62.2% 294

of the ART group; 63% of the RP only group) and in ARO 96-02 (68% of the ART group; 61% of 295

the RP only group). SWOG 8794 did not report the number of patients with positive margins 296

separately but reported that 67% of patients in the ART group and 68% in the RP only group 297

had disease that extended beyond the capsule or had positive margins. 298

299

Negative surgical margins: Among patients with negative surgical margins, EORTC 300

22911 reported that the use of radiotherapy did not improve clinical RFS rates and significantly 301

decreased overall survival (HR 1.68; 95% CI 1.10-2.56). Although EORTC 22911 reported a 302

significant improvement in biochemical RFS with radiotherapy in this subgroup, ARO 96-02 303

reported no improvement with radiotherapy. SWOG 8794 did not address outcomes among 304

patients with negative margins. 305

306

Seminal vesicle invasion (SVI): In patients with SVI, SWOG 8794 and EORTC 22911 307

reported significantly improved bRFS with radiotherapy. However, RT did not improve clinical 308

RFS in either trial, metastatic RFS in SWOG 8794, or overall survival in EORTC 22911. Further, 309

ARO 96-02 reported no difference in bRFS with RT among patients with SVI. 310

311

Absence of SVI: Only EORTC 22911 reported on patients without SVI and the findings 312

are exactly the same as for patients with SVI – improved bRFS but no difference in clinical RFS 313

or overall survival. 314

315

Extracapsular extension (ECE): EORTC 22911 and ARO 96-02 reported significantly 316

improved biochemical RFS with use of RT among patients with ECE. EORTC 22911 reported no 317

differences, however, in clinical recurrence-free survival or overall survival. SWOG 8794 did not 318

report on this subgroup. 319

320


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Absence of ECE: Only EORTC 22911 reported on outcomes among patients without ECE. 321

Similar to patients with ECE, use of RT among patients without ECE significantly improved bRFS 322

but not clinical recurrence-free survival or overall survival. 323

324

Gleason score subgroups: Gleason 2-6. EORTC 22911 and ARO 96-02 both reported 325

significantly improved biochemical RFS with use of RT among Gleason 2-6 patients. SWOG 8794 326

reported no differences, however, in metastatic RFS with use of RT in this subgroup. 327

328

Gleason 7-10. ARO 96-02 reported significant improvement in bRFS with use of RT 329

among Gleason 7-10 patients. EORTC 22911 reported improved bRFS among Gleason 7 330

patients that did not reach statistical significance and no difference with RT among Gleason 8-331

10 patients. SWOG 8794 reported a statistically significant improvement in metastatic RFS with 332

RT, however, among Gleason 7-10 patients. 333

334

Patient age. EORTC 22911 reported on outcomes for patients younger than age 65 335

years, age 65 to 69 years, and age 70 years and older. In patients younger than age 65 years, 336

the use of RT resulted in significant improvements in biochemical RFS and clinical RFS. Among 337

patients aged 65 to 69 years, the use of RT resulted in significant improvements in bRFS but not 338

clinical RFS. Among patients aged 70 years and older, the use of RT did not improve bRFS or 339

clinical RFS and, in fact, appeared to worsen overall survival (HR 2.94; CI 1.75-4.93, p<0.05). 340

341

Observational studies also have evaluated the use of ART; because of the confounds to 342

interpretation and to causal attribution inherent in designs that lack randomization and other 343

controls for bias, the Panel based its judgments regarding ART primarily on the findings from 344

the RCTs. 345

346

Interpretation. The Panel interpreted the findings from the RCTs to indicate that 347

adjuvant radiotherapy after prostatectomy may benefit patients with high-risk pathological 348

features. The most consistent findings were an improvement in biochemical RFS across all 349

three trials and improvements in locoregional and clinical RFS in the two trials that reported 350

these outcomes, with less consistent findings across trials for other outcomes. The most 351

consistent finding for subgroup benefit was for positive margin patients with all three trials 352

reporting improved outcomes with RT. 353

354

The Panel is fully aware that the apparent benefits associated with RT are the result, in 355

part, of a subset of patients treated with RT who never would have presented with recurrence. 356

It is the nature of adjuvant therapies to treat high-risk patients with full knowledge that this 357

decision will result in some patients who are over-treated. It should be noted that primary 358

therapy for localized prostate cancer (e.g., radical prostatectomy) also is employed for the 359

benefit of an unknown minority of patients with the understanding that this strategy will result 360


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in over-treatment of a large number of men who never would have experienced an adverse 361

event from their tumor. 362

363

To put these issues in context, it is useful to consider the efficacy of radical 364

prostatectomy compared to watchful waiting relative to the efficacy of prostatectomy in 365

combination with ART compared to prostatectomy only. The number needed to treat (NNT) is 366

a helpful statistic for this purpose; the lower the NNT, the more effective the treatment in 367

preventing the designated outcome. 368

369

With regard to prostatectomy compared to watchful waiting, Bill-Axelson (2011; SPCG-4 370

trial) reported that at 15 years post-RP, the NNT for overall survival was 15. That is, 371

approximately 15 men would have to undergo prostatectomy in order to prevent one death 372

from any cause compared to watchful waiting. Using data from approximately 45,000 patients 373

from the SEER database, Abdollah (2012) stratified patients into high-risk (pT2c or Gleason 8-374

10) vs. low-intermediate risk (all other patients) and reported an NNT at 10 years of follow-up 375

of 13 for death from prostate cancer for high-risk patients and an NNT of 42 for low-376

intermediate risk patients. 377

378

With regard to RP plus ART compared to RP only, SWOG 8794 reported an NNT of 9.1 379

for overall survival, indicating that approximately 9 men would need to be treated with RP+ART 380

compared to RP only to prevent one death from any cause at median 12.6 years of follow up 381

(Thompson 2009)1. With regard to preventing metastatic disease, SWOG 8794 reported an 382

NNT of 12.2. EORTC 22911 did not replicate these findings and reported a higher overall death 383

rate among RP+ART patients (25.9%) compared to RP only patients (22.9%) – these data yield a 384

negative NNT, indicating a lack of benefit for the active treatment. With regard to cancer-385

specific survival, for which EORTC 22911 also did not document a treatment benefit, the NNT 386

calculated from the raw data provided in Table 2 (Bolla 2012) is 55.6, indicating that 387

approximately 56 men would need to be treated with RP+ART to prevent one case of death 388

from prostate cancer at 10.6 years of follow-up compared to RP only (the other two trials did 389

not report cancer-specific data). As a point of comparison, a pooled NNT for preventing 390

biochemical recurrence derived from combining SWOG 8794 and EORTC 22911 (which each had 391

follow-up durations >10 years) is 4.2. Combining local recurrence data from SWOG 8794 and 392

1 Note that NNTs from papers that compared RP to watchful waiting appear to have been calculated using

cumulative incidence rates whereas the NNTs from SWOG 8794 reported in Thompson (2009) and calculated from data provided in EORTC 22911 (Bolla 2012) and ARO 96-02 (Wiegel 2009) for purposes of comparison were calculated using raw event data; these different calculation methods will yield somewhat different NNTs because they use different denominators (use of cumulative incidence rates will lead to higher NNTs). As an example, using raw event data from Bolla (2012) yielded an NNT of 55.6 for cancer-specific survival; using cumulative incidence data provided in the text of the same paper yielded an NNT of 66.7 for cancer-specific survival.


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EORTC 22911 yields an NNT of 9.8. Combining clinical progression data from SWOG 8794 and 393

EORTC 22911 yields an NNT of 13.8. 394

395

Given the findings from the RCTs, the nature of adjuvant treatments to inevitably result 396

in over-treatment for some patients, and the contextual information provided by NNTs, the 397

Panel emphasizes that ART should be offered to all patients at high risk of recurrence because 398

of adverse pathological features. The offering of ART should occur in the context of a thorough 399

discussion of the potential benefits and risks/burdens associated with ART (see Guideline 400

Statements 2 and 3). Ultimately, whether ART is likely to benefit a particular patient and should 401

be administered is a decision best made by the multidisciplinary treatment team and the 402

patient with full consideration of the patient’s history, values, and preferences. 403


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404 Table 2: Outcomes from Randomized Controlled Trials

(yellow highlighting = statistically significant comparison; green highlighting = borderline significant comparison)

SWOG 8794 EORTC 22911 ARO 96-02

RT Observ. RT Observ RT Observ

Biochemical recurrence and Biochemical recurrence-free survival

60/172 (34.9%) recurrence 5 y bRFS: 71.0% 10 y bRFS: 53.0%

112/175 (64%) recurrence 5 y bRFS: 44.0% 10 y bRFS: 26.0%



38/148 (25.7%) recurrence 5 year bRFS: 72%

67/159 (42.1%) recurrence 5 year bRFS: 54%

Comparison: HR = 0.43 (95% CI: 0.31-0.58; p<0.001)

Comparison: HR = 0.49 (95% CI: 0.41-0.59; p<0.001)

Comparison: HR = 0.53 (95% CI: 0.37 – 0.79; p=0.0015)

Local recurrence, local recurrence-free survival, cumulative local relapse

15/190 (8%) local recurrence at median 10.6 y

40/184 (22%) local recurrence at median 10.6 y

42/502 (8.4%) w/ locoregional failure 10 y cumulative local relapse rate: 7.3% (95% CI: 4.9-9.8%)

87/503 (17.3%) locoregional failure 10 y cumulative local relapse rate: 16.6% (95% CI: 13.1-20.1%)

NR NR

Comparison: NR Comparison: HR = 0.45 (95% CI: 0.32 – 0.68; p<0.0001)

NR

Hormonal therapy-free survival (hTFS)

5 y hTFS: 90.0% 10 y hTFS: 84.0%

5 y hTFS: 79.0% 10 y hTFS: 66.0%

NR NR NR NR

Comparison: HR = 0.45 (95% CI: 0.29 – 0.68; p<0.001)

NR NR

Metastases, Metastases-free survival (mRFS), cumulative metastatic rate

93/214 (43.5%) had metastases or died of any cause 20/214 (9.3%) had metastases 5 y mRFS: 88% 10 y mRFS: 71%

114/211 (54%) had metastases or died of any cause 37/211 (17.5%) had metastases 5 y mRFS: 84% 10 y mRFS: 61%

55/502 (11.0%) had distant metastases 10 y cumulative metastatic rate: 10.1% (95% CI: 7.2-13.0%)

57/503 (11.3%) had distant metastases 10 y cumulative metastatic rate: 11% (95% CI: 8.0-14.0%)

4/148 (2.7%) had distant metastases at median 4.5 y

5/159 (3.1%) had distant metastases at median 4.5 y



NR

Clinical progression and clinical progression-free survival (cPFS); does not include bRFS

84/214 (39.3%) clinical progression or death at median 10.6 y 10 y cPFS: 70%

111/211 (52.6%) clinical progression or death at median 10.6 y 10 y cPFS: 49%

157/502 (31.3%) clinical progression or death at median 10.6 y 10 y cPFS: 70.3%

181/503 (36.0%) clinical progression or death at median 10.6 y 10 y cPFS: 64.8%

NR NR



NR

Deaths from cancer and cancer-specific survival

NR

NR 25/502 (5.0%) deaths from prostate cancer 10 y cumulative prostate cancer mortality rate: 3.9% (95% CI: 2.0-5.7%)

34/503 (6.8%) deaths from prostate cancer 10 y cumulative prostate cancer mortality rate: 5.4% (95% CI: 3.2-7.5%)

NR NR

NR Comparison: HR = 0.78 (95% CI: 0.46 – 1.33; p=0.34)

NR

Overall survival (OS)

88/214 (41.1%) deaths at median 12.7 y







14


10 y OS estimate: 74.0%






NR

405


15


406 Table 3: Risk Factor Subgroup Findings from RCTs

(all comparisons statistically significant unless otherwise noted)

SWOG 8794 EORTC 22911 ARO 96-02

Gleason 2-6 Met RFS: Obs. = RT2 (HR

approx. 0.90, CI 0.55-1.50) Biochem RFS: Obs < RT

4

(HR approx. 0.44; CI 0.26-0.82)

Biochem RFS: Obs < RT5

(HR 0.42, CI 0.20-0.89)

Gleason 7-10 Met RFS: Obs. < RT2 (HR

approx. 0.58, CI 0.35-0.92)

Biochem RFS: -Gleason 7: Obs < RT

4 but

dif n.s. (HR approx. 0.63; CI 0.38-1.00) -Gleason 8-10: Obs < RT

4

but dif n.s. (HR approx. 0.52; CI 0.26-1.20)


(HR 0.59, CI 0.37-0.95)

No SVI Not reported Biochem RFS: Obs. < RT3

(HR 0.43, CI 0.35-0.54) Clin RFS: Obs. = RT

3 (HR

0.8; CI 0.61-1.04) Overall survival: Obs. = RT

3 (HR 1.30, CI 0.95-1.77)

Not reported

SVI Biochem RFS: Obs < RT1

(HR 0.23, CI 0.06 to 0.84) Met RFS: Obs. < RT

2 but

dif ns (HR approx. 0.68, CI 0.42-1.07) Clin RFS: Obs = RT

1 (HR

0.76, CI 0.33 to 1.74)

Biochem RFS: Obs. < RT3


3 (HR


3 (HR 1.00, CI 0.66-1.52)

Biochem RFS: Obs = RT5

but dif n.s. (pT3c: HR 0.77, CI 0.42-1.40)

Negative margins Not reported Biochem RFS: Obs. < RT3


3 (HR

1.08; CI 0.78-1.55) Overall survival: Obs. > RT

3 (HR 1.68, CI 1.10-2.56)

Biochem RFS: Obs = RT5

(HR 0.95, CI 0.47-1.93)

Positive margins Biochem RFS: Obs. < RT1

(HR 0.44, CI 0.3 to 0.65)) Clin RFS: Obs < RT

1 (HR

0.64, CI 0.45 to 0.93)

Biochem RFS: Obs. < RT3

(HR 0.44, CI 0.35-0.75) Clin RFS: Obs. < RT

3 (HR


3 (HR 0.98, CI 0.72-1.34)


(HR 0.41, CI 0.25-0.66)

No ECE Not reported Biochem RFS: Obs. < RT3


3 (HR


3 (HR 1.21, CI 0.70-2.08)

Not reported

ECE Not reported Biochem RFS: Obs. < RT3


3 (HR

0.83; CI 0.65-1.05)


(pT3a/b: HR 0.34, CI 0.19-0.64)


16


Overall survival: Obs. = RT

3 (HR 1.16, CI 0.88-1.54)

ECE or Positive margins Met RFS: Obs. < RT2 but

dif n.s. (HR approx. 0.73, CI 0.52-1.08)

Not reported Not reported

SVI and Positive margins Biochem RFS: Obs < RT1

(HR 0.40, CI 0.20-0.77) Clin RFS: Obs < RT

1 (HR

0.47, CI 0.27-0.81)

Not reported Not reported

Age Not reported Biochem RFS: -<65 y: Obs. < RT

3 (HR

0.43, CI 0.33-0.56) -65-69 y: Obs. < RT

3 (HR

0.46, CI 0.34-0.61) -≥70 y: Obs. < RT

3 but dif

n.s. (HR 0.75, CI 0.52-1.08) Clin RFS: -<65 y: Obs. < RT

3 (HR

0.57, CI 0.40-0.79) -65-69 y: Obs. = RT

3 (HR

0.81, CI 0.57-1.15) -≥70 y: Obs. > RT

3 (HR

1.78, CI 1.14-2.78) Overall survival: -<65 y: Obs. = RT

3 (HR

0.91, CI 0.60-1.39) -65-69 y: Obs. = RT

3 (HR

0.97, CI 0.65-1.44) -≥70 y: Obs. < RT

3 (HR

2.94, CI 1.75-4.93)

Not reported

407 408 1 Thompson 2006; median 10.6 years follow-up; all bRFS analyses conducted in patient subset of 348 409 who had post-RP PSA </= 0.4 ng/ml 410 2 Thompson 2009; median 12.7 years follow-up for RT group; median 12.5 years follow-up for Observ 411 group; all bRFS analyses conducted in patient subset of 348 who had post-RP PSA </= 0.4 ng/ml 412 3 Bolla 2012; median 10.6 years follow-up 413 4 Van der Kwast 2007; patient subset (n=552) of total eligible sample (n=972) who had central pathology 414 review; included here are data from Fig. 2 which consists of only patient with post-RP PSA ≤ 0.2 ng/ml 415 5 Wiegel 2009; median 4.5 years follow-up; 1992 AJCC – pT3a/b – ECE; pT3c - SVI 416 417

418


17


Salvage radiotherapy (SRT). Evidence regarding the efficacy of SRT in the post-RP 419

patient is available in the form of a large literature composed of observational studies; 420

however, only a few studies compared patients who received SRT to RP only patients with PSA 421

or local recurrence who did not receive further therapy (e.g., Boorjian 2009; Trock 2008). 422

Generally, these studies indicate that SRT improves outcomes compared to RP only patients but 423

the benefits may be specific to certain risk groups (see Discussion under Guideline Statement 424

7). In addition, two of the three RCTs (SWOG 8794 and EORTC 22911) enrolled patients with 425

detectable PSA levels post-RP – salvage patients by definition. These two trials also generally 426

revealed better outcomes among SRT patients compared to RP only patients with evidence of 427

PSA recurrence (see Discussion under Guideline Statement 7). 428

429

ART vs. SRT. One of the most pressing clinical questions regarding the care of the post-430

RP patient is whether it is better to administer RT before evidence of recurrence – RT as 431

adjuvant therapy – or to wait until recurrence manifests and then administer RT – RT as salvage 432

therapy. It is acknowledged that the use of ART may involve irradiation of some patients who 433

never would have had recurrent cancer, thus exposing them unnecessarily to the risks, toxicity, 434

and quality of life impact of RT. Waiting to administer RT as a salvage therapy limits its use to 435

patients with recurrence but, particularly in patients with high-risk disease, could be less 436

effective and could allow the emergence of metastatic disease. 437

438

The literature review attempted to address this issue by examining the large number of 439

observational studies that reported outcomes for ART and SRT patients in the PSA era. Study 440

arms were categorized as adjuvant if post-RP patients administered RT had no evidence of 441

recurrence based on the PSA failure threshold used by the authors. Study arms were 442

categorized as salvage if post-RP patients had evidence of PSA or local recurrence at the time of 443

RT administration. A third group of studies in which outcomes for ART and SRT patients were 444

combined also was retrieved. Mixed studies were considered with regard to toxicity and 445

quality of life outcomes (see below) but not for efficacy outcomes. 446

447

The search yielded 45 ART study arms reporting outcomes for 2844 patients (Arcangeli 448 2009; Bastide 2011; Boorjian 2009; Budiharto 2010; Caraffini 2006; Catton 2001; Cheng 1993; Choo Hruby Hong 449 Hong 2002; Cozzarini 2009; Do 2002; Eggener 2005; Hagan2004; Kalapurakal 2002; Kamat 2003; Lee Solan 2004; 450 Leiibovich 2000; MacDonald 2007; Mayer 2002; McCarthy 1994; Neulander 2005; Nudell 1999; Ost 2009; Ost De 451 Troyer 2011; Pacholke 2004; Pai 2009; Peschel 2000; Petroski 2004; Schaefer 2000; Schafer 2003; Schild 2001; 452 Taylor 2003; Teh 2006; Trabulsi 2008; Tsien 2003; Valicenti 1998a, 1998b, 1999; 2004; Vargas 2005; Vicini 1999; 453

Wadasaki 2007). The search yielded 129 SRT study arms reporting outcomes for 11,893 patients 454

(Anscher 2000; Bastide 2010; Bernard 2010; Boorjian 2009; Borg 2006; Brodak 2011; Brooks 2006; Budiharto 2010; 455 Buskirk 1996, 2006; Cadeddu 1998; Caraffini 2006; Catton 2001; Chawla 2002; Cheung 2005; Choo 2005; Choo 456 Hruby Hong Bahk 2002; Coetzee 1996; Cozzarini 2004; Cremers 2010; De La Taille 2002; De Meerleer 2008; 457 Delongchamps 2009; Do 1998, 2001, 2002; Eggener 2005; Forman 1997; Garg 1998; Haab 1995; Hagan 2004; 458 Hugen 2010; Jacinto 2007; Jereczek-Fossa 2009; Kalapurakal 2002; Katz 2003; Kim 2004; King & Spiotto 2008; King 459 2004; King Presti 2008; Koppie 2001; Kruser 2011; Kundel 2004; Lee McBain 2004; Lee Solan 2004; Leventis 2001; 460 Liauw 2008; Loeb 2008; MacDonald 2004, 2008; Maier 2004; Matsui 2004; Mayer 2002; McCarthy 1994; Medinn 461


18


1996; Monti 2006; Mosbacher 2002; Nagda 2007; Neuhof 2007; Nudell 1999; Numata 2005; Ost De Troyer 2011; 462 Ost Lumen 2011; Pacholke 2004; Pai 2009; Patel 2005; Pazona 2005; Perez 2003; Peschel 2000; Petroski 2004; 463 Peyromaure 2003; Pisansky 2000; Quero 2008; Rogers 1998; Sasaki 2006; Schaefer 2000; Shafer 2003; Schild 464 Buskirk 1996; Schwartz 2005; Siegmann 2011; Song 2002; Song 2009; Spiotto 2007; Stephenson 2004, 2007; 465 Stockdale 2007; Swanson 2011; Symon 2006; Taylor 2003; Tefelli 1998; Terai 2005; Tomita 2009; Trabulsi 2008; 466 Trock 2008; Tsien 2003; Valicenti 1998a, 1998b; Van Der Poel 2008; Vanuytsel 2001; Vargas 2005; Vicini 1999; 467

Wadasaki 2007; Ward 2004; Wiegel 2009; Wilder 2000; Wu 1995; Xu 2005; Yoshida 2011; Youssef 2002). 2 468

469

When this literature 470

is examined as a whole, it 471

appears that ART patients 472

generally have better 473

outcomes compared to SRT 474

patients. For example, 475

when the percentage of 476

patients who had 477

biochemical recurrence are 478

plotted against follow-up 479

duration post-RT for all 480

observational studies that 481

reported this outcome, the 482

ART study arms generally 483

report lower rates of 484

biochemical recurrence3 485

and metastatic recurrence 486

than do SRT study arms 487

(see Figures 2 and 3). 488

Patterns with regard to 489

cancer-specific survival and 490

overall survival are less 491

clear because few ART 492

studies reported these 493

outcomes (data not 494

shown). 495

496

Overall, the interpretation that ART leads to superior outcomes is difficult to make with 497

certainty in the absence of randomization and given that SRT studies focus only on patients 498

2 Multiple reports on the same patient group were extracted as a composite report. Some publications

contributed more than one study arm. 3 It should be noted that authors varied considerably in how biochemical recurrence was defined, including what

constituted a detectable PSA level, whether one or more than one detectable values were required, whether values had to be rising, and/or whether values were evaluated with reference to the post-RT nadir.

Figure 2: Scatterplot of biochemical recurrence percentages by follow-up duration (mos) from observational studies

of adjuvant and salvage radiotherapy


19


who have already relapsed, making direct comparisons with ART studies problematic. ART and 499

SRT studies also differ across numerous factors, any of which potentially confound 500

interpretation. These include differences in patient characteristics (e.g., ART patients generally 501

have more adverse pathological profiles), RT protocols (e.g., SRT studies often used higher RT 502

doses than ART studies), failure 503

definitions, follow-up durations, 504

and in other key factors. In 505

addition, most of the published 506

literature reports findings from 507

the use of older RT techniques 508

(e.g., EBRT protocols), making it 509

unclear whether newer 510

techniques might result in fewer 511

apparent differences between 512

ART and SRT outcomes. 513

514

Given these issues, the 515

Panel concluded that is not 516

possible from the available 517

evidence to address the 518

question of the superiority of 519

ART vs. SRT. Currently, two RCTs 520

are actively accruing patients to 521

address this important question 522

– the RADICALS trial (MRC PR10, 523

NCIC PR13) and the RAVES trial 524

(TROG 08.03) (see more detailed discussion in Research Needs and Future Directions. 525

526

Radiotherapy techniques and protocols in the post-prostatectomy patient. 527

528

The Panel’s literature review attempted to address the question of which radiotherapy 529

techniques and doses produced optimal outcomes in the adjuvant and salvage context. It was 530

not possible to answer these questions, however, from the available data. 531

532

Specifically, approximately one-third of the ART and SRT observational studies treated 533

patients with conventional external beam modalities which have since been replaced by more 534

sophisticated approaches using three-dimensional conformal radiation therapy (3D-CRT) or 535

intensity-modulated radiation therapy (IMRT) methods. The published literature has lagged 536

well behind the implementation of these newer methods, with only one-quarter of the 537

reviewed studies reporting use of 3D-CRT techniques and less than 5 percent reporting use of 538

IMRT techniques. The remaining studies used either a mix of techniques, without separating 539

Figure 3. Scatterplot of metastatic recurrence percentages by follow-up duration (mos) from observational studies of adjuvant

and salvage radiotherapy


20


patient outcomes based on technique, or did not report enough information to determine the 540

type of RT used. The lack of studies using newer RT methods made it difficult to definitively 541

address the question of optimal methods in general and whether these might differ in the 542

adjuvant vs. salvage contexts. 543

544

With regard to the randomized controlled trials of ART, the men treated in SWOG 8794 545

and EORTC 22911 were administered RT using EBRT techniques (Thompson 2006; Bolla 2009); 546

patients in ARO 96-02 were administered 3D-CRT (Wiegel 2009). Although there were no clear 547

differences in toxicity, biochemical recurrence, or local recurrence among the three RCTs, a 548

broader literature suggests that patients treated with 3D-CRT and IMRT would be expected to 549

experience less treatment-related toxicity and better biochemical and local control compared 550

to men irradiated with traditional techniques (e.g., Zelefsky 1998; Ost 2009). 551

552

Among the observational studies, the RT dosages varied from 50 to 78 Gy with most 553

studies administering doses in the 60 to 70 Gy range and with SRT studies administering 554

somewhat higher radiation dosages than ART studies (median ART dose – 61 Gy; median SRT 555

dose – 65 Gy). Although RT dose-escalation has been shown in multiple randomized trials to 556

improve freedom from biochemical relapse when used as primary treatment for localized 557

prostate cancer, the optimal post-prostatectomy radiation dose is less clear and has never been 558

tested in a prospective fashion. However, the clinical data suggest that doses above 65 Gy can 559

be safely delivered and may lead to improved tumor control as determined by a reduction in 560

biochemical progression (e.g., Bernard 2010; Cozzarini 2009; King & Spiotto 2008; Siegmann 561

2011). In the three RCTs, the majority of patients were treated with radiation doses of 60 Gy, 562

which was lower than the dose used in most observational studies. 563

564

Given the difficulties in interpreting findings from the observational studies and the lack 565

of high-quality evidence regarding optimal RT dosing and protocols in the adjuvant and salvage 566

contexts, it is not possible at this time to identify the best RT strategies for these patients. 567

568

Use of androgen-deprivation therapies in conjunction with RT in the post-RP patient. 569

570

One of the questions faced by the clinician and post-prostatectomy patient is whether, 571

when, for how long, and in what form androgen-deprivation therapy (ADT) should be 572

administered. The systematic review attempted to address these questions by retrieving the 573

literature that focused on the use of ADT in patients who underwent prostatectomy and then 574

adjuvant or salvage radiotherapy. The Panel’s conclusion after reviewing the available evidence 575

(see brief review below) was that, given the methodological weaknesses of this literature, it is 576

not possible at this time to provide guidance regarding the use of ADT in conjunction with 577

adjuvant or salvage radiotherapy. These weaknesses include: observational, non-randomized 578

study designs; small sample sizes and consequent lack of statistical power to reliably detect 579

differences between RT only and RT+ADT groups; lack of equivalence of RT and RT+ADT groups 580


21


on pathological risk factors; large differences in ADT protocols, including when it was 581

administered (e.g., pre-RP, pre-RT, during RT, post-RT) and for how long (e.g., weeks vs. months 582

vs. years); and, other differences across studies that may be relevant to efficacy such as 583

differences in RT techniques, targets, and total Gy administered. 584

585

Randomized controlled trials are needed to provide definitive evidence regarding these 586

issues. At the time of this writing, RTOG 9601 was examining the effects of salvage RT with and 587

without 24 mos of bicalutamide in patients with biochemical failure who had pT3N0 or pT2N0 588

disease with positive margins; to-date, findings from this trial had been reported only in 589

abstract form. At median follow-up 7.1 years, patients who received SRT plus ADT had 590

significantly improved freedom from biochemical progression and significantly fewer 591

metastases (Shipley 2011). These findings are promising; publication of full trial results is 592

awaited to provide more detailed guidance regarding the use of ADT in combination with 593

salvage RT. In addition, currently RTOG 0534 is actively recruiting patients post-RP with a rising 594

PSA to participate in a trial of short-term ADT with pelvic lymph node or prostate bed only RT. 595

Findings from this trial, once mature, also will help to answer these important questions. 596

597

ADT in the adjuvant setting. Only four observational studies compared RP patients who 598

received adjuvant radiotherapy to those who received ART in combination with some form of 599

ADT (Bastide 2011; Ost 2009; Ost, de Troyer 2011; Pai 2009). Although all four studies reported 600

findings suggesting that patients who received ADT in combination with ART had better 601

outcomes, only one study reported a statistically significant difference between groups. 602

Specifically, Bastide (2011) reported at median follow-up 60.3 mos that the ART+ADT group had 603

significantly higher biochemical recurrence-free survival (bRFS) rates at five and seven years 604

than did the ART only group (82.8% vs. 44.4%, respectively, at 5 years; 62.1% vs. 28.6%, 605

respectively, at 7 years). bRFS rates for two additional comparison groups (patients who had RP 606

only and patients who had RP+ADT but did not have ART) were similar to rates for the ART only 607

group. All patients in this study had SVI but the distribution of other risk factors (i.e., Gleason 608

scores, positive margins) differed somewhat across groups. The ADT administered was an LHRH 609

analog; it was initiated on the first day of RT with median duration 12 mos. These findings 610

require replication in a randomized trial. 611

612

ADT in the salvage setting. Twenty-one observational studies evaluated RP patients 613

who received salvage RT compared to those who received SRT in combination with some form 614

of ADT. Overall, this literature arrived at mixed conclusions. Six studies documented 615

statistically significantly better outcomes for SRT+ADT patients compared to SRT only patients 616

(De La Taille 2002; King Presti 2008; Pai 2009; Spiotto 2007; Stephenson 2007; Taylor 2003). 617

The Panel notes that findings from the study with the largest sample size (Stephenson 2007; 618

1325 SRT patients; 214 SRT+ADT patients) derived from a multi-institutional retrospective 619

cohort are particularly promising. Stephenson and colleagues (2007) used the sample to 620

develop an SRT nomogram and demonstrated a significant advantage in progression-free 621


22


survival for patients who had SRT+ADT compared to SRT only patients. ADT (type not specified) 622

was administered either before RT or during RT for median 4.1 months. 623

624

Seven studies reported that SRT+ADT patients had better outcomes than SRT only 625

patients but either did not report a p level or the comparison did not reach statistical 626

significance (De Meerleer 2008; Katz 2003; Liauw 2008; Monti 2006; Ost, de Troyer 2011; Trock 627

2008; Wadasaki 2007). Eight studies indicated that SRT only patients had better outcomes than 628

did SRT+ADT patients or that the outcomes were indistinguishable (Anscher 2000; Buskirk 2006; 629

Do 1998; Neuhof 2007; Ost, Lumen 2011; Song 2002; Stephenson 2004; Yoshida 2011). 630

631

Although the majority of studies suggested better outcomes for patients who had SRT in 632

combination with some type of ADT, studies differed in when ADT was administered (pre-RT 633

only, pre- and during RT, post-RT only; during RT only; during and post-RT), for how long 634

(weeks, months, years), and in ADT type. In addition, studies varied in patient risk factors, RT 635

protocols, and follow-up durations. Overall, the Panel’s conclusion was that, in the absence of 636

randomized trials, the role of ADT in the ART or SRT context remains unclear. 637

638

Toxicity and quality of life (QoL) impact of RT post-prostatectomy. 639

640

A key concern of clinicians and patients when adjuvant or salvage RT is contemplated is 641

the toxicity and quality of life effects of RT in patients who have already undergone 642

prostatectomy. The Panel’s systematic review retrieved the literature relevant to these issues; 643

findings are reviewed below. In addition to ART and SRT studies, studies that reported on 644

mixed groups of ART and SRT patients were included given the importance of understanding 645

toxicity effects. It was not possible to delineate differences in RT toxicity and QoL effects 646

between ART and SRT studies given the many confounds to interpretation. These included: the 647

absence of pre-RP information regarding genitourinary (GU), gastrointestinal (GI), and sexual 648

functioning; large differences in the RP to RT interval, with consequent differential recovery 649

from prostatectomy in ART vs SRT patients; the greater incidence of adverse pathology among 650

ART patients; the use of somewhat higher radiation doses in SRT studies; and, the paucity of 651

published studies using newer radiotherapy delivery modes such as 3D-CRT and IMRT that 652

might minimize toxicity. 653

654

Toxicity. The most commonly-used measures to report toxicity information were the 655

Radiation Therapy Oncology Group (RTOG) measure for acute effects (through day 90) and the 656

RTOG/European Organisation for Research and Treatment of Cancer (EORTC) measure for late 657

RT effects (persisting beyond day 90 or developing after day 90). The second most commonly-658

used measure was the Common Toxicity Criteria Adverse Event (CTCAE) measure which uses 659

the same time frames. Both systems use a rating system of 0 to 5: a score of 0 indicates no 660

change in function; 1 indicates a minor change in function that generally does not require any 661

clinical action; 2 indicates a moderate change in function that may require medication; 3 662


23


indicates a major change in function sufficient to require more aggressive medication use or 663

outpatient procedures; 4 indicates severe symptoms requiring hospitalization and surgical 664

procedures; and, 5 indicates death. A total of 94 study arms reported at least one measure of 665

toxicity; these arms included 10 ART study arms reporting on a total of 856 patients, 55 SRT 666

study arms reporting on a total of 4,985 patients, and 29 mixed ART-SRT study arms reporting 667

on a total of 4,146 patients (Alongi 2009; Anscher 2000; Bastasch 2002; Bolla 2005; Borg 2006; Brodak 2011; 668 Brooks 2005; Buskirk 1996, 2006; Caraffini 2006; Catton 2001; Chawla 2002; Cheng 2008; Choo 2005, 2008; Choo 669 Hruby Hong Bahk 2002; Choo Hruby Hong Hong 2002; Cozzarini 2003, 2004, 2009; Cremers 2010; De La Taille 670 2002; De Meerleer 2008; Do 2002; Duchesne 2003; Feng 2007; Fontaine 2004; Forman 1997; Goenka 2011; 671 Goldner 2008; Hagan 2004; Jacinto 2007; Jereczek-Fossa 2009; Jung 2006; Kalapurakal 2002; Katz 2003; Kruser 672 2011; Kundel 2004; Lee McBain 2004; Lee Solan 2004; MacDonald 2004, 2007; Maier 2004; Matsui 2004; Monti 673 2006; Nath 2010; Neuhof 2007; Numata 2005; Ost 2009, 2011; Ost Lumen 2011; Pacholke 2004; Pearse 2008; 674 Perez 2003; Perna 2010; Peterson 2009; Petroski 2004; Peyromaure 2003; Pinkawa 2008; Pisansky 2000; QUero 675 2008; Sasaki 2006; Schild 2001; Schild Buskirk 1996; Schwartz 2005; Sharma 1997; Siegmann 2011; Song 2002; 676 Stockdale 2007; Suzuki 2010; Symon 2006; Tefelli 1998; Teh 2001; Tomita 2009; Tisien 2003; Valicenti 1998, 2004; 677

Wadasaki 2007; Ward 2004; WIegel 2009a, 2009b; Wilder 2000; Wu 1995; Yoshida 2011; Zelefsky 1997). 678

679

Acute toxicity. Of the 94 study arms that reported any toxicity information, 30 reported 680

at least one measure of acute genitourinary (GU) toxicity (4 ART arms, 12 SRT study arms, and 681

14 mixed study arms) and 28 reported at least one measure of acute gastrointestinal toxicity (2 682

ART arms, 13 SRT arms, 13 mixed arms). 683

684

Acute GU toxicity symptoms include: 685

- Grade 1 – presence of the following symptoms without the requirement for 686

medications - urinary frequency or nocturia that is twice pre-treatment levels, 687

dysuria, urgency; 688

- Grade 2 – urinary frequency or nocturia that is <1/hour, dysuria, urgency, bladder 689

spasm requiring local anesthetic (e.g., Pyridium); 690

- Grade 3 – urinary frequency with urgency and nocturia hourly or more frequently 691

with dysuria, pelvis pain or bladder spasm requiring regular frequency narcotics or 692

gross hematuria with/without clot passage; 693

- Grade 4 – hematuria requiring transfusion, acute bladder obstruction not secondary 694

to clot passage; ulceration or necrosis 695

696

Acute GI toxicity symptoms include: 697

- Grade 1 – presence of the following symptoms without the requirement for 698

medications - anorexia with ≤5% weight loss; nausea, abdominal discomfort, 699

increased frequency or change in bowel habits, rectal discomfort; 700

- Grade 2 – anorexia with ≤15% weight loss, nausea and/or vomiting or abdominal 701

pain requiring medication, diarrhea requiring parasympatholytics, mucus discharge 702

not requiring sanitary pads, rectal/abdominal pain requiring analgesics; 703

- Grade 3 – anorexia with >15% weight loss or nausea/vomiting or diarrhea requiring 704

nasogastric (NG) tube or parenteral support; abdominal pain that is severe despite 705


24


medications, hematemesis or melena, abdominal distension; severe mucus/blood 706

discharge requiring sanitary pads; 707

- Grade 4 – ileus, subacute or acute obstruction, fistula, perforation, GI bleeding 708

requiring transfusion, abdominal pain requiring tube decompression or bowel 709

diversion. 710

711

The ranges for proportions of patients experiencing Grade 1-2 and Grade 3-4 acute 712

toxicities are presented in Table 4; no grade 5 toxicities were reported. Grade 1-2 acute 713

toxicities were characterized by extremely wide ranges, with a great deal of variability across 714

studies, and high percentages in many study arms, suggesting that these effects are relatively 715

common. Grade 3-4 toxicities, however, were relatively uncommon. 716

717 Table 4: Acute Toxicity Effects of Radiotherapy After Prostatectomy

(Ranges based on RTOG or CTCAE Grading Systems)

Genitourinary Gastrointestinal

Study Arm Type Grade 1-2 Grade 3-4 Grade 1-2 Grade 3-4

Adjuvant 10.5 - 26% 2.0 - 7.0% 22.0 – 25.0% 0.0 – 2.0%

Salvage 3.0 - 82.0% 0.0 – 3.8% 2.9 – 96.0% 0.0 – 2.2%

Mixed 5.0 – 92.0% 0.0 - 2.3% 4.3 – 87.0% 0.0 – 1.3%

718

719

With regard to acute GU effects, two studies compared patients treated with 3D-CRT to 720

patients treated with IMRT (Alongi 2009; Goenka 2011). Both studies reported that use of 3D-721

CRT resulted in higher rates of grade 2 or greater toxicities (12.3% and 20.8%, respectively) 722

compared to IMRT (6.6% and 13.4%, respectively). 723

724

Additional acute GU toxicity information was reported by Bolla (2005), one of the three 725

RCTs that evaluated adjuvant RT, using the World Health Organization (WHO) scale for acute 726

effects. The WHO scale breaks down functioning into 0 – no change, 1 – slight disturbance, 2 – 727

greater disturbance but without influence on daily life; 3 – toxicities requiring treatment, and 4 728

- severe toxicities requiring vigorous treatment or hospitalization. Grade 1 and 2 frequency 729

symptoms (44.9% and 17.3%, respectively), were the most frequently reported acute GU 730

toxicities. Grade 3 frequency was uncommon (3.3%) and grade 4 frequency was rare (0.4%). 731

Grade 1 and 2 dysuria occurred in 37.9% and 10.3% of patients, respectively, with only 1.1% 732

reporting grade 3 dysuria and no reports of grade 4. Hematuria was uncommon, with 3.7% of 733

patients exhibiting grade 1, 0.9% exhibiting grade 2, and no patients exhibiting the higher 734

grades. 735

736

With regard to acute GI effects, Goenka (2011) reported that 3D-CRT patients had 737

higher levels of grade 2 or greater toxicities (13.2%) compared to IMRT patients (7.6%). Alongi 738

(2009) divided toxicities into lower and upper GI and reported that patients treated with 3D-739


25


CRT had higher lower GI toxicity rates (8.6%) and higher upper GI toxicity rates (22.2%) than did 740

patients treated with IMRT (lower: 3.3%; upper: 6.6%). 741

742

Using the WHO scale, Bolla (2005) reported that rates of diarrhea were grade 1 – 38.3%, 743

grade 2 – 17.7%, grade 3 – 5.3%, and grade 4 – 0%. Nausea/vomiting symptoms were 744

uncommon, with grade 1 levels manifested in 4.2% of patients, grade 2 in 0.2%, and no patients 745

exhibiting grade 3 or 4. 746

747

Late toxicity. Of the total 94 study arms that reported any toxicity information, 40 748

reported at least one measure of late genitourinary (GU) toxicity (6 ART arms, 23 SRT study 749

arms, and 11 mixed study arms) and 32 reported at least one measure of late gastrointestinal 750

(GI) toxicity (2 ART arms, 20 SRT arms, 10 mixed arms). 751

752

Late GU toxicity symptoms include: 753

- Grade 1 – slight bladder epithelial atrophy, minor telangiectasia (microscopic 754

hematuria) 755

- Grade 2 – moderate frequency, generalized telangiectasia, intermittent macroscopic 756

hematuria 757

- Grade 3 – Severe frequency and dysuria, severe generalized telangiectasia (often 758

with petechiae), frequent hematuria, reduction in bladder capacity (<150 cc) 759

- Grade 4 – Necrosis, contracted bladder (capacity <100 cc), severe hemorrhage, 760

cystititis 761

762

Late GI toxicity symptoms include: 763

- Grade 1 – mild diarrhea, mild cramping, bowel movement 5/day, slight rectal 764

discharge or bleeding 765

- Grade 2 – moderate diarrhea and colic, bowel movement >5/day, excessive mucus 766

or intermittent bleeding 767

- Grade 3 - Obstruction or bleeding requiring surgery 768

- Grade 4 – Necrosis, perforation, fistula 769

770

The ranges for proportions of patients experiencing Grade 1-2 and Grade 3-4 late 771

toxicities are presented in Table 5; no grade 5 toxicities were reported. Similar to acute toxicity 772

data, Grade 1-2 late toxicities were characterized by extremely wide ranges, with a great deal of 773

variability across studies (except for ART study arms for which only 2 values were available), 774

and high percentages in many study arms, suggesting that these effects are relatively common. 775

Grade 3-4 toxicities, however, were relatively uncommon. 776

777

778

779

780


26


Table 5: Late Toxicity Effects of Radiotherapy After Prostatectomy (Ranges based on RTOG/EORTC or CTCAE Grading Systems)

Genitourinary Gastrointestinal

Study Arm Type Grade 1-2 Grade 3-4 Grade 1-2 Grade 3-4

Adjuvant 2.0 – 22.0% 0.0% 1.0 – 7.0% 0.0%

Salvage 1.0 – 49.0% 0.0 – 6.0% 0.0 – 66.0% 0.0 – 18.0%

Mixed 1.3 – 79.0% 0.0 – 11.7% 2.0 – 59.0% 0.0 – 3.0%

781

Late toxicity over time. In contrast to acute toxicities, late toxicities may manifest 782

cumulatively for several years post-RT and persist for many years. 783

784

Ost Lumen (2011) noted that the probability of late grade 2-3 GU toxicity rose from 12% 785

at 24 mos post-SRT to 22% at 60 mos post-SRT. Pearse (2008) reported a similar pattern with 786

13% of patients manifesting grade 2 or higher GU toxicity at 12 mos post-SRT, rising to 28% at 787

48 mos post-SRT, and remaining at 28% at 60 mos post-SRT. Feng (2007) reported in a mixed 788

group of patients that grade 2 or higher toxicities occurred in 4% of patients at 12 mos post-RT 789

rising to 12% at 60 mos post-RT. Goenka (2011) reported on patients who were administered 790

3D-CRT or IMRT and noted that the probability of late grade 2 or higher toxicities for 3D-CRT 791

patients ranged from 5% at 24 mos post-SRT to 25% at 96 mos post-SRT. For IMRT, 9% of 792

patients exhibited grade 2 or higher toxicities at 24 mos post-SRT with the proportion rising to 793

16.8% at 60 mos post-SRT and remaining at 16.8% through 120 mos of post-SRT follow-up. 794

795

Late GI toxic effects are less common. Ost Lumen (2011) also reported that the 796

probability of late grade 2-3 GI toxicity rose from 3% at 24 mos post-SRT to 8% at 48 mos post 797

RT and remaining at 8% at 60 mos post-SRT. Pearse (2008) reported a similar pattern with 3% of 798

patients manifesting grade 2 or higher GU toxicity at 12 mos post-SRT, rising to 7% at 36 mos 799

post-SRT, and remaining at 7% at 60 mos post-SRT. Feng (2007) reported in a mixed group of 800

patients that grade 2 or higher toxicities occurred in 2% of patients at 12 mos post-RT rising to 801

4% at 60 mos post-RT. Goenka (2011) reported on patients who were administered 3D-CRT or 802

IMRT and noted that the probability of late grade 2 or higher toxicities for 3D-CRT patients 803

ranged from 4.5% at 24 mos post-SRT to 10.2% at 96 mos post-SRT. For IMRT, 1% of patients 804

exhibited grade 2 or higher toxicities at 24 mos post-SRT with the proportion rising to 4.0% at 805

72 mos post-SRT and remaining at 4.0% through 120 mos of post-SRT follow-up. 806

807

Additional late toxicity information is provided by Thompson (2006), one of the three 808

RCTs (SWOG 8794). At median 127 mos follow-up, urethral stricture was more common among 809

RT patients (17.8%) than among RP only patients (9.5%). Proctitis also was more common 810

among RT patients (3.3%) than among RP only patients (0%). Moinpour (2008) reported on 811

frequency symptoms defined as >8 voids/day among a subset of patients from SWOG 8794. 812

Before RT, rates of frequency were similar between groups (21% of patients who then received 813

RT; 22% of RP only patients). Frequency rates rose post-RT for RT patients (12 mos – 27.5%; 24 814

mos – 23%; 36 mos – 26%; 48 mos – 28%) but decreased for RP only patients (12 mos – 14%; 24 815


27


mos – 12%; 36 mos – 13%; 48 mos – 15%). By 60 mos post-RT, however, the two groups had 816

similar frequency rates that were indistinguishable from pre-RT values (RT – 22%; RP only – 817

19.5%). Rates of bowel movement tenderness, although similar between groups post-RP and 818

pre-RT, became elevated among RT patients post RT and remained elevated through 60 mos of 819

follow up (6 mos post-RT/RP: RT – 18%; RP only – 5%; 60 mos post RT/RP: RT – 18.5%; RP only 820

11%). 821

822

Urinary incontinence. To understand the impact of RT on urinary incontinence (UI) post 823

prostatectomy, the Panel focused on studies that provided either pre-RT baseline information 824

and/or reported findings for a comparison group. 825

826

Five ART studies reported in six papers provided information on urinary incontinence 827

(Choo 2002; Formenti 1996, 2000; Hoffman 2003; Van Cangh 1998; Thompson 2006). One 828

study provided pre-RT information (25 of 69 patients with UI) and reported at median 50.4 mos 829

follow-up that one additional patient had developed UI (Choo 2002). Three reports compared 830

ART patients to RP only patients; at follow-up durations ranging from one to three years, ART 831

and RP only patients had indistinguishable and low rates of UI and pad use (ART: 12-23%; RP 832

only: 14 – 19%) (Formenti 1996, 2000; Hoffman 2003). Two reports focused on patients from 833

the RCTs (Van Cangh 1998 – EORTC 22911; Thompson 2006 – SWOG 8794). Van Cangh (1998) 834

noted that among patients from the Belgian arm of EORTC 22911, there were no statistically 835

significant differences between ART and RP only patients in Grade 2-3 UI (grade 2 – use of 1-4 836

pads soaked; grade 3 – more than 4 pads) pre-RP (ART 8.3%; RP only 9.6%) or at 24 mos post 837

RP/RT (ART – 8.3%; RP only 2%). Thompson (2006) reported a non-significant difference in total 838

UI between ART patients (6.5%) and RP only patients (2.8%) at median 127 mos follow up. 839

840

Seven SRT studies that included pre-RT baseline information and/or a comparison group 841

reported information regarding UI (Borg 2006; Chawla 2002; Choo 2005; Duchesne 2003; Hagan 842

2004; Katz 2003; Pearse 2008). As a group, these studies reported either isolated cases of new 843

onset UI and/or mild worsening of UI in small numbers of patients (usually one or two patients). 844

845

Quality of Life (QoL). Few studies focused on the QoL impact of urinary and GI 846

symptoms and on overall QoL post-RT. No ART studies and only two SRT studies reported 847

urinary and GI-related QoL information using a validated measure. Using the EPIC (score range 848

0-100 with higher scores indicating better QoL), Pinkawa (2008) reported that pre-RT, SRT 849

patients had urinary-related function and bother scores that ranged from 75 to 87. Although 850

urinary function and bother scores worsened immediately after RT, scores returned to pre-RT 851

levels by 2 mos post-RT and remained at those levels at >1 year post-RT. Pre-RT, mean bowel 852

function score was 92 and bowel bother score was 94. Post-RT, there was a significant 853

decrease in function and bother scores (indicating worse QoL) that did not recover to pre-RT 854

levels until 1 year post-RT. Similar patterns were evident for individual symptoms of rectal 855

urgency, fecal incontinence, painful bowel movements, and having a moderate/big problem 856


28


from bowel dysfunction. Hu (2006) reported responses to the UCLA Prostate Cancer Index in 857

SRT patients and noted that urinary and bowel function and bother scores did not change from 858

pre-RT to 12-18 mos post-RT. 859

860

One ART study reported overall quality of life data. Moinpour (2008; data subset from 861

SWOG 8794) reported that pre-RT, similar proportions of ART patients (47%) and RP only 862

patients (52%) reported having a normal health-related quality of life. These proportions 863

increased over time for the ART group, with 69% of patients reporting a normal quality of life at 864

60 mos post-RT. In contrast, for the RP only patients, the proportions remained the same, with 865

51% reporting a normal quality of life at 60 mos post-RP. For up to 36 mos post-RT, ART 866

patients had higher symptom distress scores than did RP only patients but by 48 and 60 mos 867

post-RT, ART patients had lower distress scores than RP only patients. For the RAND Medical 868

Outcomes subscales (Physical Function, Emotional Function, Social Function, and Role 869

Function), the groups were indistinguishable throughout follow-up. 870

871

One SRT study reported overall QoL data (Hu 2006). SRT patient scores on the RAND 872

physical component summary and mental component summary did not change from pre-RT to 873

12-18 mos post-RT. The population mean on these scales is 50; SRT patient mean scores 874

ranged from 46.0 to 54.0. 875

876

Erectile Function. ART studies. Five studies reported information in six publications 877

regarding erectile function in ART patients (Choo 2002; MacDonald Lee 2007; Do 2002; 878

Formenti 1996, 2000; Moinpour 2008). Given the limited number of studies, the lack of 879

validated measures, the absence of key data over time (particularly pre-RP baseline data), and 880

potential confounding variables such as unequal use of ADT across patient groups and lack of 881

full recovery from RP (RP to RT interval < 6 mos), it is not possible to determine the impact of 882

RT on erectile function when given for adjuvant purposes to post-RP patients. It is noteworthy 883

that the percentages of patients who had intact erectile function post-RP but pre-RT were low, 884

ranging from 7% to 33.3% with the most rigorous data from SWOG 8794 (Moinpour 2008) 885

indicating that only 7% of men had intact function pre-RT. 886

887

SRT studies. The impact of salvage RT on erectile function also is difficult to determine. 888

Thirteen studies reported erectile function information in SRT patients (Bastach 2002; Borg 889

2006; Buskirk 1996; Do 2002; Duchesne 2003; Petroski 2004; Wilder 2000; Wu 1995; Zelefsky 890

1997; Cremers 2010; Hu 2006; Goenka 2011; Pinkawa 2008). Nine of these studies reported 891

only proportions of patients with ED at various time points and provide contradictory 892

information (three studies reported no change post-RT and six reported increased proportions 893

of patients with ED post-RT). In most of these studies: sample sizes were extremely small (<50); 894

pre-RP functioning was not reported; the type of RP was not reported or varied (some patients 895

had nerve-sparing procedures and others did not); the RP to RT interval was less than 2 years, 896

making it unclear whether erectile function had fully recovered post-RP; patients were followed 897


29


for less than 2 years; and data were obtained from physician chart notes rather than patient-898

reported. Four studies used some type of validated measure. Although the sample sizes were 899

larger, many of the same potential confounds remain. Three of these studies reported no 900

changes over time from the post-RP/pre-RT measurement point throughout follow-up; one 901

reported increased ED rates. 902

903

In addition, similar to the ART studies, post-RP patients who presented for salvage RT 904

had very low rates of adequate erectile function (3.8% to 35.7%; most studies reported that 905

<10% patients had full potency post-RP but pre-RT) and low scores on QoL measures of sexual 906

function/bother. The only study that included pre-RP data (Petroski 2004) reported that 74 of 907

110 patients (73%) were fully potent pre-RP, 9 (9%) were partially potent, and 18 (18%) were 908

impotent. Post-RP/Pre-RT, 7 of 74 previously potent patients remained potent (9.5%); 14 of 74 909

previously potent patients became partially potent (19%); 53 of 74 previously potent patients 910

became impotent (71.6%); in addition, all 9 patients who were partially potent pre-RP became 911

impotent. Post-RT (minimum follow-up 60 mos), of the 21 patients who were potent or 912

partially potent post-RP, 9 (43%) became impotent, 10 (47.6%) became or remained partially 913

potent, and 2 (9.4%) retained full potency; 1 of the 9 patients who lost partial potency post-RP 914

regained partial potency during follow-up. 915

916

Overall, given the paucity of available data and the potential confounds to 917

interpretation, the Panel interpreted these data to indicate that the impact of RT on erectile 918

function given in either the adjuvant or salvage context is not currently known. 919

920

Secondary malignancies. Findings from studies carried out to investigate the risk of 921

secondary malignancies resulting from the use of radiotherapy post-prostatectomy are 922

contradictory as pointed out by Guedea (2010). Specifically, Bhojani (2010) estimated that the 923

hazard ratio of developing a rectal tumour at 120 months was 2.2 in patients treated with 924

radiotherapy compared with the general population. In contrast, a Canadian study evaluated 925

all prostate cancer cases treated in British Columbia from 1984 to 2000 and found no significant 926

difference between observed and expected second cancer rates, regardless of whether 927

treatment included radiotherapy (Pickles 2002). In addition, none of the trials that focused on 928

ART or SRT have reported secondary malignancy data. Further, post-prostatectomy men may 929

not be an accurate control group for estimating the risk of secondary malignancies post-RT 930

because there is evidence that they have a lower risk of second cancers than the general 931

population (Eifler 2012). Finally, the risk of secondary cancers also may be related to co-932

existing factors such as the presence of past or current smoking (e.g., van Leeuwen 1995; 933

Koivisto-Korander 2012; Zelefsky 2012). The Panel concluded that at this time the risk of a 934

secondary malignancy as a result of the administration of RT in the adjuvant or salvage context 935

is not known. 936

937

Guideline Statement 1. 938


30


939

Patients who are being considered for management of localized prostate cancer with radical 940

prostatectomy should be informed of the potential for adverse pathologic findings that 941

portend a higher risk of cancer recurrence and that these findings may suggest a potential 942

benefit of additional therapy after surgery. Clinical Principle 943

944

Discussion. Patients should be counseled before radical prostatectomy that certain 945

pathology findings at prostatectomy are associated with higher risks for cancer recurrence. 946

These findings include positive surgical margins, the presence of seminal vesicle invasion (SVI), 947

and extracapsular extension (ECE). Rates of recurrence in post-RP patients with adverse 948

pathological features may be greater than 60% at 5 years post-RP in case series (e.g., 949

Stephenson 2006; Swindler 2005; Epstein 1993; Zietman 1994; Lee 2004; Ohori 1995; Lowe 950

1997; Pound 1999; Catalona 1994; Karakiewicz 2005; Han 2001, 2003). In addition, two 951

randomized controlled trials with more than 10 years of follow-up reported recurrence rates of 952

>60% in high-risk patients who had RP only (Thompson 2009; Bolla 2012). 953

954

The most definitive evidence for an increased probability of disease recurrence 955

associated with specific high-risk pathologic features is provided by a recent report on 956

approximately 4,400 radical prostatectomies with median follow-up of 10 years (and follow-up 957

of up to 29 years in subset of patients) (Mullins 2012). Approximately 3,300 of these patients 958

were treated during the PSA era (from 1992 to 2011). These data reveal reduced rates of 959

biochemical recurrence-free survival and reduced rates of metastatses-free survival at 15 years 960

post-RP in men with a variety of pathological risk factors (see Tables 6 and 7). 961

962

Patients also should be informed that if these adverse pathological features are 963

detected, then additional therapy after surgery, such as radiotherapy, may be beneficial. 964

965 Table 6: 15-Year Biochemical Recurrence-Free Survival (%)

in Men Treated with Radical Prostatectomy in the PSA era (adapted from Mullins 2012)

Pathology Finding

Pathological Gleason Score

3 + 3 3 + 4 ≥ 4 + 3

Organ-confined 99 86 79

No ECE; Margin + 94 75 67

ECE; Margin - 89 72 41

ECE; Margin + 75 45 27 (at 14 years)

SVI 39 39 15

Table 7: 15-Year Metastatic Recurrence-Free Survival (%) in Men Treated with Radical Prostatectomy in the PSA era (adapted from Mullins 2012)

Pathology Finding

Pathological Gleason Score

3 + 3 3 + 4 ≥ 4 + 3

Organ-confined 100 98 92

No ECE; Margin + 100 100 50

ECE; Margin - 100 97 75

ECE; Margin + 100 88 73


31


SVI 86 93 38

ECE – extraprostatic extension; SVI – seminal vesical invasion

966

967

968


Patients with adverse pathologic findings including seminal vesicle invasion, positive surgical 970

margins, and extracapsular extension should be informed that adjuvant radiotherapy, 971

compared to observation, reduces the risk of biochemical (PSA) recurrence, local recurrence, 972

and clinical progression of cancer. They should also be informed that the impact of adjuvant 973

radiation on subsequent metastases and overall survival is less clear; one of two randomized 974

controlled trials that addressed these outcomes indicated a benefit but the other trial 975

findings were equivocal. Clinical Principle 976

977

Discussion. Patients with adverse pathologic findings at prostatectomy should be 978

counseled regarding the most up-to-date findings from the randomized controlled trials that 979

have evaluated the use of ART. This counseling should emphasize that high-quality evidence 980

indicates that the use of ART in patients with adverse pathological findings reduces the risk of 981

biochemical recurrence, local recurrence, and clinical progression of cancer. Patients also 982

should be informed that the impact of ART on subsequent metastases and overall survival is 983

less clear, with benefits reported in one of two trials with long-term data on these outcomes. 984

Clinicians also should counsel patients regarding the potential benefits and risks/burdens of the 985

available treatment alternatives if biochemical recurrence, local recurrence, and/or clinical 986

progression occur. 987

988


990

Physicians should offer adjuvant radiotherapy to patients with adverse pathologic findings at 991

prostatectomy including seminal vesicle invasion, positive surgical margins, or extraprostatic 992

extension. Standard 993

994

Discussion. (Evidence strength – Grade A; Benefits outweigh risks/burdens). Three 995

randomized controlled trials (SWOG 8794, EORTC 22911, and ARO 96-02), two with more than 996

10 years of follow-up, evaluated the effects of ART on outcomes among patients with adverse 997

pathologic features at prostatectomy [Thompson 2006, 2009; Bolla 2012; Wiegel 2009; for 998

detailed discussion of RCT findings, see Adjuvant Radiotherapy (ART) section in General 999

Background]. All three trials documented significant improvements in biochemical recurrence-1000

free survival (bRFS) with use of ART compared to RP only (pooled hazard ratio of 0.48; 95% CI 1001

0.42 – 0.56; p <0.00001; see Figure 1 above). The Panel notes that prevention of biochemical 1002


32


progression is an important clinical endpoint because biochemical progression may trigger 1003

salvage therapy, with its associated toxicities and quality of life impact. In addition, patients 1004

with biochemical recurrence are more likely to manifest metastatic recurrence. Therapies for 1005

metastatic recurrence, such as androgen deprivation therapies, can have profound quality of 1006

life impact and their efficacy has not yet been convincingly demonstrated. 1007

1008

The two RCTs that evaluated locoregional failure (SWOG 8794; EORTC 22911) 1009

demonstrated a reduction in failure in ART patients compared to RP only patients at more than 1010

10 years of follow-up. This difference was statistically significant in EORTC 22911 (Bolla 2012; 1011

locoregional failure in 8.4% of ART patients compared to 17.3% of RP only patients) and similar 1012

in magnitude in SWOG 8794 (Thompson 2006; locoregional failure in 8% of ART patients 1013

compared to 22% in RP only patients; no p value reported). The Panel viewed reduction of 1014

locoregional failure as another important clinical endpoint because the occurrence of local 1015

failure also triggers the use of salvage therapies, with associated toxicities, and increases the 1016

probability of subsequent metastatic failure. 1017

1018

Both SWOG 8794 and EORTC 22911 also reported statistically significant reductions in 1019

the use of subsequent salvage therapies with ART compared to RP only at approximately 10 1020

years of follow up. SWOG 8794 reported improvement in hormonal therapy-free survival in 1021

ART patients (84%) compared to RP only patients (66%). EORTC 22911 reported that fewer ART 1022

patients (21.8%) had started an active salvage treatment (including salvage radiotherapy or 1023

ADT) compared to RP only patients (47.5%). The Panel viewed reduction in initiation of salvage 1024

therapies as a result of ART as another important clinical endpoint because of the avoidance of 1025

the negative consequences of these therapies. 1026

1027

SWOG 8794 and EORTC 22911 also both demonstrated improved clinical progression-1028

free survival (defined as clinical or imaging evidence of recurrence or death but not including 1029

biochemical progression) at more than 10 years of follow up in ART patients compared to RP 1030

only patients. This difference was statistically significant in SWOG 8794 and borderline 1031

significant (p = 0.054) in EORTC 22911. The Panel also judged improved clinical progression-1032

free survival as an important endpoint because it reflects lower rates of local and distant failure 1033

as well as lower death rates associated with the use of ART. 1034

1035

Two of the trials – SWOG 8794 and EORTC 22911 -- assessed metastatic recurrence and 1036

overall survival. Only SWOG 8794 demonstrated significantly improved metastatic recurrence-1037

free survival (43.5% for ART patients; 54% for RP only patients) and overall survival (74% in ART 1038

patients; 66% in RP only patients) at more than 12 years of follow-up (Thompson 2009). 1039

Several possible explanations for the discrepant findings across trials have been offered. These 1040

include the fact that the overall survival rate of the RP only group in SWOG 8794 was much 1041

lower (66.0%) than the RP only group in EORTC 22911 (80.7%); the reason for the lower survival 1042

rate in SWOG 8794 is not clear. It also is possible that salvage treatments in SWOG 8794 were 1043


33


not used as extensively as in EORTC 22911; the trials had similar rates of salvage treatment 1044

despite higher relapse rates in SWOG 8794. Therefore, in the context of offering ART to 1045

patients, it should be emphasized that there is less certainty regarding potential benefits in 1046

terms of preventing metastatic recurrence and improving overall survival. 1047

1048

Given the consistency of findings across trials regarding other clinically-important 1049

endpoints of reduced biochemical and locoregional failure, clinical progression, and the 1050

reduction in the need for initiation of salvage therapies in patients administered ART, the Panel 1051

concluded that patients with high-risk pathological features should be offered ART. 1052

1053

The Panel also notes that RT should be offered to patients with adverse pathology 1054

detected at prostatectomy who have a persistent post-prostatectomy PSA level. Although by 1055

the definitions used in the guideline this is a salvage context for RT, two of the trials (SWOG 1056

8794 and EORTC 22911) enrolled some patients with a detectable PSA in the early post-RP 1057

period (< 18 weeks). EORTC 22911 reported that RT improved biochemical recurrence-free 1058

point estimates similarly in patients with undetectable post-RP PSA levels (<0.2 ng/ml) and with 1059

detectable post-RP PSA levels (≥0.2 ng/ml) (Bolla 2012). SWOG 8794 reported that RT 1060

improved metastases-free survival point estimates similarly in patients with undetectable (< 0.2 1061

ng/ml) and detectable (≥ 0.2 ng/ml) post-RP PSA (Thompson 2009). It is important to note that 1062

in SWOG 8794, although the point estimate of benefit was similar, the Kaplan-Meier survival 1063

analysis revealed that men with a detectable PSA post-RP who received RT were more likely 1064

over time to develop metastases or to die than were men who had an undetectable PSA and 1065

received RT. 1066

1067

The Panel is fully aware that the apparent benefits associated with ART are the result, in 1068

part, of a subset of patients treated who never would have presented with recurrence. For this 1069

reason, the Panel emphasizes that ART should be offered to all patients at high risk of 1070

recurrence because of adverse pathological features. Whether ART is likely to benefit a 1071

particular patient and should be administered is a decision best made by the multidisciplinary 1072

treatment team and the patient with full and thoughtful consideration of the patient’s history, 1073

current functional status, values, and preferences, and his tolerance for the potential toxicities 1074

and quality of life effects of radiotherapy. 1075

1076

1077


1079

Patients should be informed that the development of a PSA recurrence after surgery is 1080

associated with a higher risk of development of metastatic prostate cancer or death from the 1081

disease. Congruent with this clinical principle, physicians should regularly monitor PSA after 1082

radical prostatectomy to enable early administration of salvage therapies if appropriate. 1083

Clinical Principle 1084


34


1085

Discussion. Prostate specific antigen (PSA) levels drawn following a radical 1086

prostatectomy should be undetectable. An increasing PSA level suggests the presence of 1087

residual disease and frequently heralds the eventual development of symptomatic metastases 1088

and death from prostate cancer. Pound et al (1999) were among the first to describe the time 1089

course of disease progression. They followed 1997 consecutive men undergoing radical 1090

prostatectomy at the Johns Hopkins Hospital and demonstrated that no man experienced 1091

either distant or local recurrence without also demonstrating a rising PSA level. Among 304 1092

men who developed detectable PSA values following surgery, the median time to the 1093

development of metastases was 8 years. Men with Gleason score 8-10 disease in the surgical 1094

specimen developed metastases more rapidly, usually within five years, while men with 1095

Gleason score 5-7 disease developed metastases more slowly, usually within ten years. 1096

Early PSA rise was associated with more rapid development of metastases. Specifically, 1097

men who developed a rise in their PSA value within 2 years of surgery developed metastases 1098

more rapidly -- usually within five years; men who developed a rise in their PSA values more 1099

than two years post surgery, however, developed metastases later, many more than ten to 1100

fifteen years later. The median PSA doubling time provided the most statistically significant 1101

prediction of time to distant progression. Men with a PSA doubling time less than 10 months 1102

usually developed metastases within five years of surgery, while men with a PSA doubling time 1103

greater than 10 months developed metastases much later. Men who developed metastatic 1104

disease usually died at median five years later (range two to twelve years later). 1105

Albertsen et al (2004) reported similar findings from a population based sample. They 1106

reported outcomes of 1136 men who underwent treatment in community practice following 1107

diagnosis of localized disease between 1990 and 1992. Among the 516 men who underwent 1108

surgery, the majority of men had post treatment PSA levels that remained undetectable or at a 1109

low, constant detectable level. For the remaining patients PSA levels increased immediately 1110

after surgery or after a time delay. Among the patients who did NOT die of prostate cancer 1111

within ten years of follow up, 40% showed no increase in post treatment PSA values, whereas 1112

10% had a PSA doubling time of six to seven months or longer. A doubling time of 1113

approximately twelve months provided the maximum separation between patients who died of 1114

prostate cancer within ten years of surgery and those who did not. PSA doubling times were 1115

correlated with patients’ biopsy Gleason score and their pretreatment PSA level. 1116

Overall, these data indicate that men with an increasing PSA after surgery are at risk for 1117

developing metastases and subsequently dying from their disease; this risk is particularly high 1118

among men with rapid PSA doubling times. Half of all men with PSA values doubling faster than 1119

every 10 to 12 months after surgery are dead from their disease within 10 to 13 years. Patients 1120

should be informed of the relationship between PSA recurrence post-surgery and the 1121

probability of metastastic recurrence and death from prostate cancer. 1122

1123


35



Clinicians should define biochemical recurrence as a detectable or rising PSA value after 1125

surgery that is ≥ 0.2 ng/ml with a second confirmatory level ≥ 0.2 ng/ml or as a consistently 1126

rising serum PSA level. Recommendation 1127

1128

Discussion. (Evidence strength – Grade C; Benefits outweigh risks/burdens). 1129

The vast majority of the published literature assessing the efficacy of radical prostatectomy 1130

uses a PSA threshold value of 0.2 ng/mL to define recurrence although some authors have 1131

advocated for the use of higher values (Amling 2001). Many adjuvant studies, including the 1132

three RCTs reviewed in detail in this guideline, and many salvage radiotherapy studies also use 1133

a PSA threshold of 0.2 ng/ml to define recurrence. Patients who have had a prostatectomy 1134

should be informed that a PSA value of 0.2 ng/ml or higher that has been confirmed by a 1135

second elevated PSA value constitutes evidence of a biochemical recurrence. The presence of a 1136

biochemical recurrence necessitates a thorough discussion of the available alternatives for 1137

salvage therapy, including the use of radiotherapy and other types of therapy. 1138

1139

The Panel notes that recurrences can be identified earlier and at much lower PSA levels 1140

(e.g., 0.07 ng/mL or less) using ultra-sensitive PSA assays (Pruthi 1997; Malik 2011). In addition, 1141

even more sensitive assays may add further clarity as to whether patients are at increased risk 1142

for clinical failure (Sarno 2012; Moul 2012). Data from retrospective and prospective trials 1143

tend to support the notion that more favorable biochemical outcomes are associated with very 1144

low PSA values at the time radiotherapy is offered (Swanson 2007). The salvage literature also 1145

generally reports that patients who receive radiotherapy at lower PSA levels have better 1146

outcomes than do patients who receive radiotherapy at higher PSA levels (see Discussion under 1147

Guideline Statement 8). However, a small percentage of patients may have detectable but 1148

stable PSAs for 10 years or more without evidence of clinical failure, which may reflect the 1149

presence of benign prostate glands in the surgical bed (Shinghal 2003). Currently, therefore, it 1150

is not clear whether the use of more sensitive assays would translate into improved outcomes 1151

for most patients or, alternatively, would result in an increase in unnecessary treatments (Malik 1152

2011; Eisenberg 2010; Chang 2010). Given the lack of evidence regarding the use of 1153

ultrasensitive PSA assays to guide care, the Panel judged that the use of the 0.2 ng/ml threshold 1154

value with a second confirmatory value to document recurrence or treatment initiated by a 1155

clearly rising PSA value is the optimal strategy currently. 1156

1157

Body of evidence strength is Grade C because the majority of the relevant literature is 1158

composed of observational studies and no randomized trials have focused on the impact of 1159

different PSA thresholds on outcomes. 1160

1161



36


A restaging evaluation in the patient with a PSA recurrence may be considered. Option 1163

Discussion. (Evidence strength – Grade C; Balance between benefits and risks/burdens 1164

uncertain). In the patient with evidence of recurrence manifested as a detectable or rising PSA, 1165

determining the site of recurrence (local vs. metastatic) may be relevant to select an 1166

appropriate salvage strategy. The guideline systematic review included retrieval of the 1167

literature regarding imaging strategies to detect recurrence location in the post-RP patient who 1168

has biochemical evidence of recurrence. 1169

1170

The Panel grappled with numerous challenges in interpreting this literature. The most 1171

difficult issue was the lack of a reliable and relatively error-free reference standard with which 1172

to evaluate new modalities. In many studies no recurrence location could be identified in a 1173

subset of patients with biochemical failure by either the reference standard or the modality 1174

under evaluation, making the true performance of the evaluated modality unclear. Other 1175

problems included the use of different reference standards within and across studies, failure to 1176

administer the reference standard to all patients, lack of independence of the reference 1177

standard from the evaluated modality, and lack of blinding for test interpreters. In addition, 1178

the majority of studies assessed relatively small sample sizes (<50 for the majority of study 1179

arms). For these reasons, body of evidence strength for this literature is Grade C. 1180

1181

Local recurrence. Thirty-one studies comprised of 51 study arms reported on the 1182

diagnostic performance of 19 modalities for local recurrence detection. The modalities 1183

evaluated included digital rectal exam (DRE; Abi-Aad 1992; Casciani 2008; Scattoni 2003), 1184

transrectal ultrasound (TRUS; Abi-Aad 1993; Drudi 2006; Foster 1993; Kapoor 1993; Leventis 1185

2001; Salomon 1993; Scattoni 2003; Sudakoff 1996), color Doppler TRUS (Sudakoff 1996), color 1186

power Doppler TRUS (Drudi 2006; Tamsel 2006), contrast-enhanced (CE) color power Doppler 1187

TRUS (Drudi 2006), body coil MRI (Huch Boni 1996), endorectal coil MRI without contrast 1188

(Casciani 2008; Cirillo 2009; Huch Boni 1996; Sella 2004), endorectal coil MRI with contrast 1189

(Cirillo 2009; Huch Boni 1996; Silverman 1997), 11C acetate PET/CT (Albrecht 2007), 11C choline 1190

PET/CT (Castelluci 2011; Reske 2008), 18FDG PET (Haseman 1996; Schoder 2005), 18FCH PET/CT 1191

(Panebianco 2012; Schillaci 2012), dynamic contrast-enhanced (DCE) MRI (Boonsirikamchai 1192

2012; Casciani 2008; Sciarra 2008), diffusion-weighted MRI with contrast (Giannanarini 2012), 1193 1H-MRSI (Sciarra 2008), 1H-MRSI with DCE MRI (Panebianco 2012; Sciarra 2008), CT with 1194

contrast (Kramer 1997), Prostascint (Haseman 1996; Kahn 1998; Koontz 2008; Nagda 2007; 1195

Texter 1998; Wilkinson 2004), and Prostascint fused with MRI or CT (Schettino 2004). For more 1196

than half of the modalities evaluated, only one or two study arms reported findings; the lack of 1197

a sufficient number of studies on each modality limited the interpretability of findings. In 1198

addition, many modalities exhibited highly variable sensitivities and specificities across studies; 1199

this lack of consistency further limited interpretability of the performance of specific 1200

modalities. 1201

1202


37


Overall, endorectal coil MRI with contrast, DCE-MRI, 1H-MRSI, and 1H-MRSI with DCE 1203

MRI yielded the highest and most consistent sensitivities and specificities for the detection of 1204

local recurrence. Sensitivities were all above 70% and endorectal coil MRI with contrast and 1H-1205

MRSI with DCE-MRI had sensitivities above 80%. The same set of modalities also yielded high 1206

specificities with all values above 70% except for one endorectal coil MRI with contrast study 1207

that reported a specificity of 66.7% (Huch Boni 1996). Specificities for 1H-MRSI were above 80% 1208

and those for DCE-MRI were above 85%. Two published systematic reviews on this topic come 1209

to similar conclusions (Beresford 2010; Martino 2011) 1210

1211

Other modalities exhibited excellent sensitivity but poor or variable specificity or vice 1212

versa. For example, nine study arms that evaluated TRUS reported sensitivities that ranged 1213

from 75% to 95.5% but specificities that ranged from 0 to 83.3%. Digital rectal exam (DRE), 1214

color power Doppler TRUS, and 11C choline PET/CT all exhibited specificities of 75% or higher 1215

but sensitivities that ranged from 32 to 50% for DRE, 41.6 to 93.3% for color power Doppler 1216

TRUS, and 53.8 to 69.7% for 11C choline PET/CT. 1217

1218

Overall, the decision regarding which modality to use to determine the presence or 1219

absence of local recurrence will depend on the availability of specific modalities and on the 1220

clinician’s goals for imaging. 1221

1222

Recurrence in nodes. Five studies reported on the diagnostic performance of 11C 1223

choline PET/CT (Rinnab 2008; Scattoni 2007; Schilling 2008; Winter 2010) and 18FDG PET/CT 1224

(Chang 2003) to detect recurrence in lymph nodes. The sensitivity of 11C choline PET/CT was 1225

100% across studies; three studies reported data per patient and one study reported data per 1226

node (Winter 2010). Scattoni (2007) also reported data per node with a sensitivity of 64%. The 1227

single 18FDG PET/CT study reported a sensitivity of 75%. In contrast to high sensitivity values, 1228

specificities were more variable; values for 11C choline PET/CT ranged from 0 to 100% and the 1229

single 18FDG PET/CT study reported a value of 100%. 1230

1231

Two additional studies reported on the use of MRI with lymphotropic 1232

superparamagnetic nanoparticles (LSN). One study was conducted in patients who had not yet 1233

undergone prostatectomy and reported values for sensitivity and specificity above 90% 1234

(Harisinghani 2003). The only study retrieved that used this modality in post-RP patients with 1235

biochemical failure did not biopsy sufficient patients so that diagnostic performance could be 1236

calculated (Ross 2009). 1237

1238

Overall, the Panel concluded that insufficient data are available to recommend specific 1239

techniques for the detection of recurrence in nodes. 1240

1241

Recurrence in bone. Four studies comprised of ten study arms reported on the use of 1242

bone scan with or without SPECT (Even-Sapir 2006; Kane 2003), 11C choline PET/CT (Fuccio 1243


38


2010; Luboldt 2008), 18F fluoride PET (Even-Sapir 2006), 18F fluoride PET/CT (Evan-Sapir 2006), 1244

DWE MRI with contrast (Luboldt 2008), conventional MRI-STIR (Luboldt 2008), and 1245

conventional MRI –T1 weighted (Luboldt 2008). It is difficult to draw firm conclusions from this 1246

literature given that most modalities were evaluated in only one study arm and that nine of ten 1247

study arms evaluated 25 or fewer patients. The sensitivities across techniques ranged from 1248

66.7% to 100% with five studies reporting values of 100% (MRI-STIR, DW-MRI with contrast, 18F 1249

fluoride PET, 18F fluoride PET/CT, and bone scan without SPECT). Two studies reported values 1250

above 90% (MRI-T1 weighted and bone scan with SPECT). Only six study arms provided 1251

specificity information; these values ranged from 64% to 100% with four of five study arms 1252

reporting values above 80% (bone scan with and without SPECT, 11C choline PET/CT, 18F fluoride 1253

PET, and 18F fluoride PET/CT). 1254

1255

An additional set of studies focused on bone scan findings in patients with various PSA-1256

related characteristics. This group of studies reported that scans were more likely to be 1257

positive among patients with higher PSA levels, shorter PSA doubling times (PSADTs), and faster 1258

PSA velocities (Cher1998; Choueiri 2008; Dotan 2005; Gomez 2004; Okotie 2004). For example, 1259

at PSA levels less than 10 ng/ml, less than 5% of patients had a positive bone scan (Dotan 2005). 1260

For PSADT greater than 6 mos, the probability of a positive bone scan was 3% (Okotie 2004). 1261

The yield of bone scans, given that most patients manifest biochemical failure at PSA values 1262

<1.0 ng/ml, will be low. 1263

1264

Metastatic recurrence. Six studies provided information regarding the detection of 1265

metastases outside of the prostate bed. Three studies reported on the use of ProstaScint (Raj 1266

2001; Kahn 1998; Nagda 2007). One study each focused on 11C choline PET/CT (Castelluci 1267

2011), 18FDG PET (Schoder 2005), and 18FCH PET/CT (Schillaci 2012). Sensitivity values for 1268

ProstaScint ranged from 30% to 100%. The other three scanning modalities had sensitivities 1269

above 95%. Specificities ranged from 0% to 58% for the ProstaScint studies and were above 1270

95% for the other modalities. In the absence of multiple studies assessing each modality, 1271

definitive conclusions regarding the best imaging strategy to detect metastatic recurrence are 1272

not possible, but these data suggest that 11C choline PET/CT, 18FDG PET, and 18FCH PET/CT are 1273

promising. 1274

Recurrence at all sites. Twenty-one studies provided diagnostic performance 1275

information regarding the detection of disease recurrence anywhere in the body using seven 1276

different imaging techniques (Kotzerke 2002; Sandblom 2006; De Jong 2003; Picchio 2003; 1277

Castelluci 2011; Garcia 2009; Giovacchini Picchio Coradeschi 2010; Richter 2010; Rinnab 2007, 1278

2009; Yoshida 2005; Schoder 2005; Seltzer 1999; Pelosi 2008; CImitan 2006; Heinsch 2006; 1279

Husarik 2008; Schillacci 2012; Proano 2006; Raj 2001; Mitchell 2012). A wide range of 1280

reference standards were employed including: other imaging modalities; biopsies of the 1281

prostate bed, nodes, and/or bone; PSA responses to salvage RT; and follow-up. In most cases, 1282

only a few study arms examined the same modality, making it difficult to arrive at definitive 1283


39


conclusions. Eight study arms reported findings from the use of 11C choline PET/CT, however. 1284

All sensitivities were above 60% and six of the eight study arms reported sensitivities at 80% or 1285

higher. Specificity was provided in five of the eight study arms and ranged from 36% to 100%. 1286

In three of the five arms, specificity was above 75% (Mitchell 2012; Castelluci 2011; Giovachinni 1287

Pichhio Coradeschi 2010); the lower specificity values occurred in studies from the same 1288

institution in which a single reference standard (biopsy) was used (Rinnab 2007, 2009). 1289

Mitchell (2012) summarized the recent Mayo Clinic experience with11C-choline PET/CT in 176 1290

patients who had biochemical recurrence (most patients had RP as primary treatment) and 1291

concluded that 11C-choline PET/CT not only performed well but substantially enhanced the rate 1292

of prostate cancer lesion detection by approximately 32% beyond what could be identified 1293

using conventional imaging technologies. This enhanced rate of cancer detection allowed 1294

decisions regarding appropriate care that were not possible with conventional imaging and 1295

included observation, surgical resection, anatomically targeted therapies, and systematic 1296

therapies. Given the body of data on 11C choline PET/CT, this imaging strategy appears 1297

promising. 1298

1299


Physicians should offer salvage radiotherapy to patients with PSA or local recurrence after 1301

radical prostatectomy in whom there is no evidence of metastatic disease. Recommendation 1302

1303

Discussion. (Evidence strength – Grade C; Benefits outweigh risks/burdens). Two of 1304

the RCTs included a subgroup of patients who had detectable PSA levels post-RP – patients that 1305

could be categorized as salvage patients. Subgroup analyses of these patients suggest a benefit 1306

of RT. In SWOG 8794, RT significantly reduced metastatic recurrence rates among patients with 1307

detectable PSA post-RP (Thompson 2009). In EORTC 22911, RT significantly reduced rates of 1308

biochemical failure among patients with detectable PSA post-RP; rates of clinical progression 1309

were lower among this group than among patients with detectable PSA post-RP who were 1310

observed but the difference was not significant (HR = 0.75; 95% CI: 0.52-1.08; Bolla 2012). 1311

1312

This statement also is supported by two observational studies that reported outcomes 1313

for patients who had SRT vs. post-RP patients with detectable PSA and/or local recurrence who 1314

did not have SRT. Boorjian (2009) reported on a cohort of 2,657 patients with biochemical 1315

failure post-RP; 856 of these patients had salvage RT. Median follow-up post-RP was 11.5 1316

years; median follow-up post biochemical failure was 6.9 years. SRT patients were followed for 1317

median 5.9 years post-RT. SRT significantly reduced the risk of local recurrence (by almost 90%) 1318

and systemic progression (by 75%) and delayed the need for ADT administration; these 1319

differences were present even after controlling for differences between groups in clinical and 1320

pathological features. No overall survival difference was documented, however. Trock (2008) 1321

reported outcomes for post-RP patients with biochemical failure and/or local recurrence who 1322


40


received no salvage treatment (n=397), received SRT alone (n=160), or who received SRT in 1323

combination with ADT (n= 78). At median follow-up of 6 years after recurrence and 9 years 1324

after RP, 22% of men who received no salvage therapy had died from prostate cancer – a 1325

significantly higher rate than men who had SRT (11% deaths from prostate cancer) and men 1326

who had SRT with ADT (12% deaths from prostate cancer); there were no differences between 1327

the two SRT groups. The authors note that the cancer-specific survival advantage associated 1328

with SRT (with or without ADT) was specific to certain clinical subgroups. These included men 1329

with a PSA doubling time of <6 mos with a recurrence to RT interval of <2 years. Men with a 1330

PSA level ≤ 2 ng/ml at the time of RT also had increased survival; however, among men with 1331

PSADT of <6 mos, SRT significantly increased survival regardless of PSA level at time of RT. SRT 1332

also significantly improved survival among men whose PSA became undetectable in response to 1333

RT but not in men whose PSA remained detectable. Overall, in men with PSADT <6 mos, 10-1334

year cancer-specific survival rates were significantly higher for men who received SRT 1335

compared to those who did not regardless of surgical margin status or Gleason score. For men 1336

with PSADT >6 mos, the cancer-specific survival advantage associated with RT was only evident 1337

among patients with positive margins and Gleason scores 8-10. Overall survival in men with 1338

pT3 cancer was significantly increased by SRT but only in men with PSADT <6 mos. 1339

1340

In the context of administering SRT, clinicians should be aware that a large number of 1341

observational studies have reported that patients in certain high-risk groups have poorer 1342

outcomes than patients without these risk factors or in lower risk groups. As a group, these 1343

studies focused primarily on biochemical recurrence-free survival. Generally, although all 1344

comparisons were not statistically significant, studies indicate that poorer bRFS is present in 1345

patients with higher Gleason scores, higher pT stages, with SVI, and with ECE compared to 1346

lower risk subgroups (Borg 2006; Buskirk 2006; Chawla 2002; Cremers 2010; De La Taille 2002; De Meerleer 1347 2008; Do 1998; Garg 1993; Jacinto 2007; King 2004; King Presti 2008; King & Spiotto 2008; Kruser 2011; Lee 1348 McBain 2004; Leventis 2001; Liauw 2008; MacDonald 2004; Monti 2006; Mosbacher 2002; Nagda 2007; Neuhof 1349 2007; Ost Lumen 2011; Petroski 2004; Peyromaure 2003; Pisansky 2000; Quero 2008; Rogers 1998. Schild-Buskirk 1350 1996; Song 2002; Song 2009; Stephenson 2004; Swanson 2011; Symon 2006; Taylor 2003; Tomita 2009; Tsien 1351

2003; Wiegel 2009; Yoshida 2011; Youssef 2002). 1352

1353

Body of evidence strength was Grade C because the analyses from the RCTS were 1354

internal subgroup analyses and because the remaining evidence was derived from 1355

observational studies. 1356

1357

1358


41


1359


1361

Patients should be informed that the effectiveness of radiotherapy for PSA recurrence is 1362

greatest when given at lower levels of PSA. Clinical Principle 1363

1364

1365

Discussion. Forty-five observational studies compared biochemical recurrence-free 1366

survival rates for salvage radiotherapy patients at lower vs. higher pre-RT PSA levels (Bernard 1367 2010; Buskirk 1996; Catton 2001; Chawla 2002; Cheung 2005; Cremers 2010; De La Taille 2002; De Meerleer 2008; 1368 Do 1998; Forman 1997; Garg 1998; Hugen 2010; Jacinto 2007; King & Spiotto 2008; King Presti 2008; Leventis 1369 2001; Liauw 2008; Loeb 2008; MacDonald 2004; Maier 2004; Monti 2006; Nagda 2007; Neuhof 2007; Nudell 1999; 1370 Ost De Troyer 2011; Ost Lumen 2011; Pai 2009; Pazona 2005; Perez 2003; Petroski 2004; Pisansky 2000; Rogers 1371 1998; Schild Buskirk 1996; Song 2002; Stephenson 2004; Stephenson 2007; Swanson 2011; Symon 2006; Taylor 1372

2003; Terai 2005; Tomita 2009; Vanuytsel 2001; Wiegel 2009; Wilder 2000; Youssef 2002). Thirty-nine studies 1373

used cut-off values to divide the low and higher groups of approximately 1.0 ng/ml or less. 1374

1375

All but one study reported that patients with lower pre-RT PSA levels had higher bRFS 1376

rates over time compared to patients with higher pre-RT PSA levels although the differences 1377

between groups were not always statistically significant. The exception was Tomita (2009), 1378

which divided patients into those with pre-RT PSA <0.25 ng/ml or ≥0.25 ng/ml – an extremely 1379

low threshold. This is the only study in which values for the low and high groups were reversed, 1380

with 51% of the pre-RT PSA <0.25 ng/ml free of biochemical recurrence at 36 mos compared to 1381

59% of the pre-RT PSA ≥0.25 ng/ml group – a non-significant difference. 1382

1383

Confirmatory subgroup analyses from SWOG 8794 presented in Swanson (2007) 1384

indicate that among patients with detectable PSA at the time of radiotherapy, those with PSA 1385

values ≤1.0 ng/ml had higher 5- and 10-year bRFS rates than those with pre-RT PSA values >1.0 1386

ng/ml. 1387

1388

Therefore, patients should be advised that if recurrence is detected without evidence of 1389

metastases, then radiotherapy should be administered at the earliest sign of PSA recurrence 1390

and, ideally, before PSA rises to 1.0 ng/ml. 1391

1392

1393


1395

Patients should be informed of the possible short-term and long-term urinary, bowel, and 1396

sexual side effects of radiotherapy as well as of the as well as of the potential benefits of 1397

controlling disease recurrence. Clinical Principle 1398

1399


42


Discussion. Patient counseling regarding the potential toxicity and quality of life (QoL) 1400

impact of radiotherapy is important to ensure that patients make informed treatment decisions 1401

and have appropriate expectations regarding the course and consequences of radiotherapy. 1402

Counseling should include the fact that the evidence base for toxicity and QoL effects of RT is 1403

based mostly on reports using older RT techniques; newer techniques appear to have fewer 1404

toxic effects. 1405

1406

Acute toxicity. Patients should be informed that during radiotherapy and in the 1407

immediate post-RT period of 2-3 mos, mild to moderate genitourinary and gastrointestinal 1408

effects that may require the use of medication for management have been frequently reported, 1409

with over 90% of patients experiencing these effects in some studies. Serious toxicity effects of 1410

radiotherapy, including those requiring aggressive medication management, outpatient 1411

procedures, or hospitalization, however, are uncommon or rare, with most studies reporting 1412

rates of 5% or less. The lowest acute toxicity rates have been reported with use of IMRT 1413

radiotherapy techniques (Alongi 2009; Goenka 2011). 1414

1415

Late toxicity. Patients should be informed that, similar to acute toxicities, mild to 1416

moderate late toxicities occurring more than 90 days post-RT are commonly reported with 1417

some studies reporting rates as high as 79%. Serious late toxicities, however, are relatively 1418

uncommon, with most studies reporting rates of 10% or less. Patients also should be told that 1419

in a small proportion of patients, late toxicities that are moderate to major may emerge for up 1420

to four to five years post-RT and may persist beyond that point. These toxicities are more likely 1421

to include GU symptoms (up to 28% of patients; Ost Lumen 2011) than to include GI symptoms 1422

(up to 10.2% of patients; Goenka 2011). The use of newer RT techniques such as IMRT, 1423

however, is associated with lower cumulative rates of late GU (up to 16.8% of patients) and GI 1424

(4.0% of patients) toxicities (Goenka 2011). 1425

1426

Urinary incontinence. Patients should be informed that rates and severity of urinary 1427

incontinence in patients who have had RP and then adjuvant RT are generally similar to rates 1428

for patients who have had RP only. Studies of SRT patients indicate possible mild worsening of 1429

UI in small numbers of patients and isolated cases of new onset UI. Overall, the Panel 1430

interpreted these data to indicate that RT is unlikely to have a major impact on UI. 1431

1432

Sexual function. Patients with intact erectile function post-RP should be informed that 1433

the impact of RT on erectile function in men who have already had a prostatectomy is not clear. 1434

This uncertainty derives from the fact that few studies have addressed the impact of RT on 1435

erectile function in post-RP patients and also from the fact that most men post-RP do not have 1436

intact erectile function, making it difficult to determine whether RT results in further loss of 1437

function. 1438

1439


43


Adjuvant RT may reduce the need for salvage therapies. Patients also should be 1440

informed that the use of ART, because it is associated with improved biochemical recurrence-1441

free survival compared to RP only, is likely to reduce the need for subsequent salvage therapies. 1442

Salvage therapies such as androgen deprivation can have debilitating side effects and also 1443

present increased risks for osteoporosis, cardiovascular disease, and other health problems. 1444

1445

Secondary malignancies. Clinicians should advise patients that the potential for 1446

developing secondary malignancies exists when postoperative radiotherapy is given, but that 1447

studies investigating the risk of developing secondary malignancies in men undergoing prostate 1448

cancer radiotherapy are contradictory (Bhojani 2010; Pickles 2002). Furthermore, in clinical 1449

trials of adjuvant and salvage radiotherapy no data have been reported on secondary 1450

malignancies. Finally, the risk of secondary cancers may be related to co-existing behavioral 1451

factors such as the presence of past or current smoking (e.g., van Leeuwen 1995; Koivisto-1452

Korander 2012; Zelefsky 2012). Therefore, the Panel concluded that at this time the risk of 1453

developing a secondary malignancy as a result of ART or SRT administration is not known. 1454

1455

1456

1457


44


Research Needs and Future Directions 1458

Ongoing Clinical Trials. Several ongoing clinical trials will help to clarify the magnitude 1459

and impact of adjuvant or salvage radiotherapy, the relative value of combining RT with 1460

hormonal and other therapies, and potentially make clear which patients are more likely to 1461

benefit from specific therapies, therapy combinations, and therapeutic contexts. 1462

1463

RTOG 0534 is randomizing post-prostatectomy patients (pT2N0/Nx or pT3N0/Nx) with 1464

Gleason scores ≤9, with or without positive margins, and with post-RP PSA of ≥ 0.1 1465

ng/ml to < 2.0 ng/ml to prostate bed radiotherapy, prostate bed radiotherapy plus 1466

short-term androgen deprivation (4-6 mos) therapy, or pelvic lymph node RT plus 1467

prostate bed RT plus short-term ADT. Patients are stratified by SV status, Gleason score 1468

≤7 or 8-9, pre-RT PSA of ≥0.1 to 1.0 ng/ml or >1.0 to <2.0 ng/ml, and pT2 with negative 1469

margins vs. all other patients. The trial includes assessments of biomarkers, quality of 1470

life, neurocognitive function, and urinary function. 3D-CRT or IMRT methods are used 1471

with 64.8-70.2 Gy administered to the prostate bed and 45 Gy administered to pelvic 1472

lymph nodes. 1473

1474

RTOG 9601 is examining the effects of radiotherapy with or without long-term androgen 1475

deprivation in men post-prostatectomy with pT3N0 disease or pT2N0 disease with a 1476

positive margin or positive prostate fossa/anastomosis biopsy with PSA ≥ 0.2 ng/ml to 4 1477

ng/ml. Radiation doses were 64.8 Gy to the prostate bed and anti-androgen therapy 1478

consisted of 24 months of bicalutamide (150 mg daily) monotherapy. While not yet 1479

published, results reported in abstract form indicate that the addition of 24 months of 1480

bicalutamide during and after RT significantly improved freedom from biochemical 1481

progression and reduced the incidence of metastatic disease without adding 1482

significantly to radiation related toxicity. There were no differences in overall survival 1483

with a median followup of 7.1 years (Shipley 2011). Implementation of these 1484

preliminary findings into clinical care awaits publication of the full trial results. 1485

1486

The RADICALS trial is a 3,000-subject study taking place in the UK, Canada, Denmark and 1487

Republic of Ireland recruiting post-prostatectomy patients who are within 22 weeks of 1488

RP with post-RP PSA ≤0.2 ng/ml with one or more of the following characteristics: pT3 1489

or pT4 disease; Gleason score 7-10; preoperative PSA ≥ 10 ng/ml; and/or positive 1490

margins. This trial is addressing two critical questions in post-protatectomy patients. 1491

The first question is the comparative efficacy of the ART vs SRT approach. Patients are 1492

randomized to either immediate adjuvant RT or to regular PSA testing and salvage RT if 1493

PSA becomes detectable. The second, concurrent randomization addresses the 1494

question of the role of androgen deprivation therapy. Patients receiving radiation 1495

(either ART or SRT) are further randomized to three treatment arms: radiation alone, 1496

radiation plus 6 months of hormonal therapy or radiation plus two years of hormonal 1497


45


therapy. This study will address perhaps the most contentious of issues regarding 1498

radiation after surgery: whether salvage radiation when PSA becomes detectable is 1499

equivalent to early adjuvant radiation. 1500

1501

The RAVES trial (TROG 08.03) is a phase III multi-center trial taking place in Australia and 1502

New Zealand comparing adjuvant RT with early salvage RT in patients with positive 1503

margins or ECE. The primary trial aim is to determine whether surveillance with early 1504

salvage RT results in equivalent biochemical control and improved quality of life when 1505

compared with adjuvant RT. Secondary outcomes include quality of life, toxicity, 1506

anxiety/depression, biochemical recurrence-free survival, overall survival, cancer-1507

specific survival, time to distant failure, time to local failure, time to initiation of ADT, 1508

quality adjusted life years, and cost-utility. This trial is actively recruiting. 1509

1510

1511

Improved imaging techniques. A major question among patients who are undergoing 1512

treatment for localized, higher-risk prostate cancer is the true extent of disease. For example, 1513

patients with high-volume, high-grade disease whose staging studies (generally bone and CT 1514

scans) are negative are those who are most likely to exhibit an immediate PSA relapse, 1515

demonstrating pre-existing disease beyond the prostate at the time of diagnosis and treatment. 1516

Another challenging class of patients is those who have locally-extraprostatic (e.g., positive 1517

margins or seminal vesicle invasion) disease or microscopic nodal disease. In both groups of 1518

patients, improved imaging techniques would help to better define appropriate therapies or 1519

modifications to existing therapies. Knowing the true extent of disease could lead to more 1520

rational nerve-sparing at the time of surgery or could lead to the extension of radiation to 1521

include nodal groups or replacement of local therapy (radiation or surgery) with systemic 1522

therapy for patients with occult distant metastases. In the realm of adjuvant or salvage 1523

radiation, better imaging could allow confirmation that residual disease is confined to the pelvis 1524

before embarking on therapy. A significant challenge will be the design of clinical trials to 1525

confirm the sensitivity and specificity of such imaging techniques as these studies are 1526

confounded by the very long natural history of the disease and the fact that in almost all cases, 1527

histologic confirmation that scans are true positive or true negative is lacking. Advances in this 1528

field are most likely to be achieved by study designs with clinically-practical outcomes. 1529

1530

New PET imaging tracers appear more accurate in the assessment of prostate cancer 1531

than conventional 18F deoxyglucose PET imaging. Further research in 11C or 18F Choline or 11C 1532

acetate for assessment of local and regional disease is required to validate their utility in the 1533

postoperative setting. Similarly, improved bone metastases imaging with 18F sodium fluoride 1534

will allow clinicians to avoid futile local therapy in men with documented metastatic disease. 1535

Improved MRI imaging with dynamic contrast enhancement (DCE) or MR spectroscopy will 1536

define sites of local recurrence and improve salvage radiation therapy targeting and the need to 1537


46


add adjuvant therapies such as androgen deprivation in patients with bulky recurrences not 1538

expected to be eradicated with conventional doses of radiation therapy. 1539

1540

1541

Biomarkers of prognosis. A significant need in the arena of adjuvant therapies of 1542

prostate cancer are biomarkers of prognosis. To illustrate this point simply requires an 1543

examination of SWOG 8794, the only clinical trial finding a survival benefit to adjuvant radiation 1544

(Thompson 2009). With a median followup of 12.6 years and up to 20 years of followup overall, 1545

metastases (the primary outcome) were reported in only 37 of 211 patients in the RP only 1546

group and in 20 of 214 patients in the ART group. Although a high-risk population, most men 1547

did not develop metastases nor die from their cancer; nonetheless, the number needed to treat 1548

with radiation to prevent 1 case of metastatic disease at a median followup of 12.6 years was 1549

12.2. 1550

1551

Ideally, adjuvant or salvage radiation should be given only to the patient who will 1552

ultimately develop an adverse outcome (e.g., metastases or death from cancer) and in whom 1553

treatment will prevent that outcome. The advantage of patients undergoing prostatectomy is 1554

that both blood-based biomarkers as well as tissue biomarkers from the entire prostate are 1555

available for analysis. A host of new markers have been identified which may be linked with 1556

disease prognosis. It is possible to embed these biomarkers within trials such as RADICALS as 1557

secondary objectives to validate their utility in discriminating the patient who is most likely to 1558

benefit from adjuvant or salvage therapy. 1559

1560

Quality of life. A major challenge with all prostate cancer therapies is the impact of 1561

therapy on Quality of Life (QOL) including sexual, urinary, and GI systems. The generally 1562

unanswered question in high-risk patients who are candidates for adjuvant or salvage therapy is 1563

how QOL is modulated by such therapies and how this compares and balances with the impact 1564

of therapy on survival outcomes. A major problem in most prostate cancer clinical trials (and 1565

clinical trials in general) is that QOL studies are underresourced and often undervalued with the 1566

primary focus on disease control. Clinical trials of salvage or adjuvant therapy should be 1567

designed in such a fashion so as to monitor disease and therapy-related QOL outcomes and to 1568

have a pre-planned analysis that integrates both survival and QOL outcomes to allow future 1569

patients and physicians to weigh the outcomes to reach a treatment decision for an individual 1570

patient. 1571

1572

Clinical trials are being conducted to evaluate the postoperative rehabilitation of men 1573

undergoing radical prostatectomy. Biofeedback, physical nerve stimulation and pharmaceutical 1574

intervention with phosphodiesterase inhibitors may lessen the impact of surgery on urinary and 1575

sexual dysfunction. Improved radiation therapy targeting may also lessen the adverse 1576

consequences of treatment for men receiving either adjuvant or salvage radiation therapy. 1577

1578


47


Combination or alternative therapies. For some patients who undergo adjuvant or 1579

salvage radiation, such treatment is not sufficient to control the disease. In SWOG 8794, 20 of 1580

214 patients developed metastatic disease despite early adjuvant RT (Thompson 2009). In 1581

these men, either alternative systemic therapy or combination therapy may have prevented 1582

this outcome. The major questions for these highest-risk men are (a) can early identification of 1583

men most likely to exhibit disease progression be accomplished (i.e., with prognostic markers), 1584

and (b) what are optimal therapies for these men (e.g., other therapies such as hormone 1585

therapies in combination with radiotherapy or alternate therapies that replace radiotherapy)? 1586

1587

Some evidence to suggest that combination/alternative therapy may be beneficial 1588

comes from early results of SWOG 9921. This trial randomized high-risk patients post-1589

prostatectomy to two years of adjuvant androgen deprivation therapy with or without 1590

chemotherapy (Dorff 2011). In this study, the surgery plus hormonal therapy arm included 1591

some patients who had received radiation due to pT3 disease and, with early followup, higher-1592

than-expected disease-free survival results were encountered. Prospective clinical trials are 1593

needed to examine prospectively the utility of systemic therapies in combination with radiation 1594

and other local therapies for such high risk disease. 1595

1596

Comorbidities. An issue that pervades the management of prostate cancer is how 1597

patient comorbidities affect treatment decision-making. Most patients are older and, in many, 1598

death due to other causes is far more frequent than death or complications from disease 1599

progression. Methods to better predict the chronology of disease relapse and progression as 1600

well as life expectancy will enhance the selection of patients most likely to benefit from 1601

adjuvant or salvage therapy. Additionally, as radiation does have side effects, the prediction of 1602

men more likely to have these complications would help better select patients for treatment. 1603

Some comorbidities such as diabetes, hypertension, and vascular disease may increase the risk 1604

of radiation-related toxicity. Predictors for such outcomes could be based on functional (e.g., 1605

validated measures of erectile, urinary, or GI function) or biologic (e.g., DNA repair mutations) 1606

measures. 1607 1608


48


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RADIOTHERAPY AFTER PROSTATECTOMY: AUA/ASTRO ......NOT TO BE COPIED, DISSEMINATED, OR REFERENCED 3 Radiotherapy After Prostatectomy: AUA/ASTRO Guideline – DRAFT 2-5-13 50 INTRODUCTION