American Journal of Clinical Oncology:
ACR Appropriateness Criteria® Postradical Prostatectomy Irradiation in Prostate Cancer
Rossi, Carl J. Jr. MD*; Joe Hsu, I-Chow MD†; Abdel-Wahab, May MD, PhD‡; Arterbery, V. Elayne MD§; Ciezki, Jay P. MD¶; Frank, Steven J. MD∥; Hahn, Noah M. MD**; Moran, Brian J. MD††; Rosenthal, Seth A. MD‡‡; Merrick, Gregory MD§§¶¶
From the *Department of Radiation Medicine, Loma Linda University Medical Center, Loma Linda, CA; †Department of Radiation Oncology, University of California San Francisco, San Francisco, CA; ‡Department of Radiation Oncology, University of Miami, Miami, FL; §Crittenton DMC, Rochester Hills, MI; ¶Cleveland Clinic Foundation, Cleveland, OH; ∥MD Anderson Cancer Center, Houston, TX; **Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN and American Society of Clinical Oncology; ††Chicago Prostate Cancer Center, Westmont, IL; ‡‡Radiological Associates of Sacramento, Medical Group Inc, Sacramento, CA; §§Schiffler Cancer Center, Wheeling, WV; and ¶¶Schiffler Oncology Center, Wheeling Jesuit University, Wheeling, WV.
The American College of Radiology seeks and encourages collaboration with other organizations on the development of the ACR Appropriateness Criteria through society representation on expert panels. Participation by representatives from collaborating societies on the expert panel does not necessarily imply society endorsement of the final document.
Reprints: Carl J. Rossi, Jr., MD, Department of Radiation Medicine, Loma Linda University Medical Center B121, 11234 Anderson St, Loma Linda, CA 92354–2871. E-mail: email@example.com.
The role of postradical prostatectomy radiation therapy continues to evolve under the influence of new clinical data. In particular, 2 recently published or updated randomized trials have prompted a reevaluation of its utility in the adjuvant and salvage setting. The Southwest Oncology Group 8794 trial randomized 473 patients with stage T3a–T3b disease to adjuvant radiotherapy versus observation. With a median follow-up of 12.7 years, this trial demonstrates an improvement in metastasis-free (93/214 vs. 114/211, P = 0.016) and overall survival (88 vs. 110 deaths, P = 0.023) favoring adjuvant radiotherapy. The European Organization for Research and Treatment of Cancer 22911 study of 972 patients with at least 1 “high risk” feature at surgery (extracapsular extension, positive surgical margins, seminal vesicle involvement) randomized to immediate adjuvant radiotherapy (60 Gy) versus observation. The freedom from biochemical failure at 5 years was 53% in the observation alone group versus 74% in the adjuvant radiotherapy group (P < 0.0001). This review summarizes the current evidence-based literature supporting the use of postradical prostatectomy radiation therapy in various common clinical settings and will serve to illustrate the appropriateness of postoperative radiotherapy by reviewing its implementation in a variety of commonly occurring clinical scenarios. It is intended to serve both as a guideline for the practicing radiation oncologist and a resource for further learning.
Radical prostatectomy (RP) and radiation therapy (RT) are the primary treatment options for organ-confined prostate cancer (T1–T2, stages I or II). Eventually, about 50% to 70% of postprostatectomy patients with high-risk pathologic features such as a positive margin, extracapsular extension (ECE), or seminal vesicle involvement (SVI) will develop biochemical failure (BF).1 Thus, RT may play a role either immediately following prostatectomy (based on various known high-risk pathologic features) or at the time of BF.
There are 3 main situations in which RT is given after RP: (1) adjuvant radiotherapy (ART) for men with an undetectable or barely detectable Prostate-Specific Antigen (PSA) (<0.2 ng/mL) who have high-risk pathologic features; (2) salvage radiotherapy (SRT) for men who had an undetectable or barely detectable PSA (<0.2 ng/mL) immediately postoperatively, but whose PSA rises at some later date—a delayed rise in PSA (DR-PSA); and (3) SRT for men whose PSA remains at 0.2 ng/mL or above postoperatively—a persistently detectable PSA (PD-PSA).
The purpose of distinguishing between ART and SRT is rooted in the observation that there are significant differences between the 2 groups in prognosis after RT, in dose of RT administered, and in prognostic factors. The further subdivision of salvage patients into 2 groups, those with a DR-PSA and those with a PD-PSA, is useful because their outcomes after RT appear to be different,2–6 with a worse prognosis for those having a PD-PSA. In general, the earlier the rise in PSA after RP, the worse the outcome because of a higher risk of metastatic disease; the PD-PSA group represents the extreme of patients being considered for SRT in this respect.
The rationale for administering ART after RP is predicated on the assumption that microscopic local disease remains. Local therapy would reduce recurrence in the prostate bed and prevent the residual nidus from disseminating distantly. The decision to administer ART is based on the presence of high-risk pathologic findings in the prostatectomy specimen. The primary high-risk features are ECE, positive margins (prostate cancer at the margin of resection), SVI, and lymph node involvement (LNI). The frequencies of occurrence are approximately 40% for ECE, 25% for margin positivity, 10% for SVI, and 5% for LNI.7–17 Another indication for ART is the presence of residual normal prostate at the inked specimen margin (a cut-through of the prostate), even without conclusive evidence that tumor remains and with an undetectable PSA. The assumption is that a cut-through of the prostate is representative of inadequate surgery and that microscopic disease could be left behind.
The prevalence of persistent local disease following RP is significant and generally under recognized. Residual disease has been documented in approximately 50% of prostatectomy cases at autopsy18 and in biopsy specimens of the prostatic fossa and urethrovesical anastomosis.19–21 Long-term follow-up has revealed that the risk of BF following prostatectomy is substantial. Various surgical series have reported that this risk continues to be present between 5 and 10 years postprostatectomy, with an average relative risk of about 2% to 3% per year without reaching a plateau.9,22–24 Late BFs are not insignificant, eventually leading to the development of painful bony metastases in 50% of patients in 7 to 8 years.25,26 ART has the potential to reduce failure and ultimately improve quality of life. Patients with a life expectancy of >10 years should benefit from ART.
A powerful predictor of biochemical and local failure after prostatectomy is margin positivity. It is estimated that approximately 40% of men with a positive surgical margin will experience a rise in PSA to detectable levels within 5 to 10 years.8,27–33 Other pathologic features that predict for BF include extraprostatic extension, Gleason score ≥7, and SVI.8,29,30,32–36 The balance of data from the available series indicates that margin status is an important determinant of outcome, along with Gleason score and PSA. The extent of margin positivity is another factor shown to influence BF,30,37,38 which has only been examined in retrospective series. ART may have less effect in the case of a small focal positive margin in the absence of other unfavorable pathologic features.39 In this setting, other factors, such as the degree of extraprostatic extension40 and/or Gleason score ≥7 disease, appear to contribute to a greater risk of BF and provide a stronger rationale for ART. Similarly, a focal area of ECE alone is associated with a lower risk of biochemical progression, as compared with more extensive ECE; but the risk will be higher when the ECE is accompanied by Gleason score ≥7 disease.
In the setting of negative margins and a rising PSA, a complete biochemical response to SRT is still achieved in the majority of cases, suggesting local disease persistence in the prostatic fossa. A rising PSA after a negative margin has been associated with a worse prognosis in some prostatectomy series41,42; however, one must consider that not every micron of tissue in the prostatectomy specimen is pathologically assessed. The RT response data suggest that tumor cells were left behind (a focal positive margin) but were not identified on pathologic evaluation. The risk of local disease persistence when there is obvious ECE in addition to Gleason ≥7 disease,40 even with negative margins, is likely high enough that ART should be considered.
Many retrospective studies have examined the role of ART.43–48 More recently, 3 prospective randomized trials comparing prostatectomy alone to prostatectomy plus ART have been described.48,49 All 3 have shown an improvement in biochemical control of about 20% with ART, with 1 trial demonstrating an improvement in both metastasis-free and overall survival. The European Organization for Research and Treatment of Cancer 22911 study included 972 patients with pT2–3 prostate cancer with at least one high-risk feature (ECE, positive margins, or SVI). Freedom from biochemical failure (FFBF) at 5 years was 53% in the RP alone group versus 74% in the RP + RT (60 Gy) group (P < 0.0001).49
A similar study was conducted by the Southwest Oncology Group and presented at the 2005 meetings of the American Urological Association and the American Society of Therapeutic Radiology and Oncology.50 There were 473 patients with pathologically determined ECE, positive margins, and/or SVI randomized to RT (60–64 Gy) versus observation. FFBF was significantly improved by the addition of radiation from 38% to 61% at 5 years and from 23% to 47% at 10 years. This benefit was shared by each of the 3 pathologic risk groups. ART also prevented the need for androgen deprivation therapy (ADT) in some patients and delayed its use significantly (by 2.5 years) in others. Perhaps most convincingly, this study is now demonstrating an improvement in metastasis-free and overall survival. With a median follow-up of 12.7 years, out of 425 evaluable patients, metastasis have developed in 114 of 211 patients on the observation arm versus 93 of 214 patients who received early adjuvant therapy (P = 0.016). In addition, there have been 110 deaths on the observation arm versus 88 deaths in the irradiated patients (P = 0.023). Although ART initially resulted in some adverse impact on quality of life, this difference disappeared by 2 years post-treatment, and the irradiated patients actually fared better beyond 3 years postradiotherapy.51
A third study (ARO, 96–02) randomized 388 men with pT3 disease after prostatectomy and an undetectable postoperative PSA to either RT (60 Gy) or observation.52 The 5-year FFBF rate was 54% in the RP-alone group versus 72% in the RP plus RT group (P = 0.0015). ART was very well tolerated, with the rate of grade 3 to 4 late adverse events being 0.3% (Tables 1, 2).
Radiotherapy is given for salvage after RP in 3 settings: (1) for a DR-PSA after the PSA has dropped to an undetectable level immediately postprostatectomy, (2) for a persistently detectable PSA after surgery, and (3) for treatment of a palpable recurrence within the prostatic fossa. This division may be important because the initial considerations in evaluation may be different, and there are reports of a distinction in prognosis. However, many retrospective series were based on small patient numbers and did not separate these patients, making conclusions difficult.
The time to a rising PSA after prostatectomy, the prostatectomy Gleason score, and the PSA doubling time (PSADT) are independent predictors of distant metastasis and mortality.25,26 When the time to BF is <3 years (the PD-PSA patients would be included in this group), Gleason score is ≥8, and PSADT is <9 months, the risk of death due to prostate cancer at 5 years is ≥19%.26 This risk increases to ≥74% at 10 years. PSADT has taken on much more importance over the last 5 years.42,53,54 If the above parameters included a postoperative PSADT of <3 months, nearly 50% will die within 5 years. Even the PSA kinetics prior to prostatectomy may be an independent determinant of mortality.55–57 A rapidly rising PSA prior to RP or prior to RT connotes a poor prognosis, suggestive of occult metastatic disease even if the metastatic workup is negative. Although our ability to predict progression after SRT has improved, we are a long way from making conclusive judgments on whether SRT would benefit most men. There is a need to optimize treatment selection with the goal of prolonging survival without unnecessary toxicity, particularly in the setting of rapid PSA kinetics.
Factors indicating that postprostatectomy RT for a PD-PSA might be beneficial include extensive extraprostatic extension (particularly in those with high-grade disease) or positive margins. Other indicators that there may be disease in the prostatic fossa are SVI, a cut-through of the prostate (a partial prostatectomy when there is palpable, biopsy, or imaging evidence of prostate remaining), or incomplete removal of the seminal vesicles in the setting of T3 disease (especially with ECE at the base or with SVI). In the absence of these features and with a PSA that is rising quickly (doubling time <6 months), the probability of distant metastasis is high,25,53,58–60 and SRT is discouraged.
The results of SRT have been relatively poor, with 5-year FFBF rates in most series ranging from 10% to 66%.3–6,41,59,61–66 The following factors have been correlated with worse FFBF rates: Gleason score >7, SVI, high pre-RT PSA (>1 to >2.5 ng/mL), short PSADT, negative prostatectomy margins, treatment for a PD-PSA (vs. a DR-PSA), a palpable prostatic fossa mass, and RT dose <65 Gy.
In general, when the PSA remains detectable after RP, the risk of distant metastasis is greater than when the PSA goes to undetectable and then rises later. Thus, outcomes of SRT in most series have been worse for patients with a PD-PSA compared with a DR-PSA.3,4,6,63 However, some series have not found a significant difference in FFBF rates between the 2 groups.5,42,65,67 While distinguishing between the groups seems to be the most objective way of evaluating the utility of SRT, most of the studies reporting SRT outcomes do not separately analyze the DR-PSA and the PD-PSA patients. In addition, all of these studies are retrospective, and most include small numbers of patients.
As described earlier in the text, the PSADT is an important predictor of SRT outcome. The shorter it is, the greater the risk of death due to prostate cancer. A doubling time of ≤10 months in the setting of a DR-PSA or a PD-PSA indicates a higher likelihood of occult metastatic disease,25,42,53,58–60 thus rendering postoperative RT much less effective. Another study showed that a PSADT of ≥5 months predicted a response to SRT (a response was defined as a PSA nadir of ≤0.1 ng/mL).68 One caveat concerning the PSADT as a reliable predictor of distant metastasis is that when the PSA is below 1 ng/mL, the estimates may be inaccurate.60,69,70 In reports of postoperative RT, few have identified PSADT as a predictor of FFBF. In a preliminary recursive partitioning analysis of about 1200 men in a pooled multi-institutional database, PSADT was not independently related to outcome, while pre-RT PSA, Gleason score, and margin status were.71 Standards are needed for when the PSADT calculation begins (from the PSA just prior to when an accelerated rise occurs or from the time of the first detectable PSA) and the minimum number of PSA values required to accurately calculate a PSADT.
The pre-RT PSA has been found to be the most consistent predictor of FFBF in both univariate and multivariate analyses of SRT.72–75 While a clear pre-RT PSA cutpoint has not yet been defined, evidence suggests that lower pre-RT PSAs are associated with higher FFBF rates. The best results have been seen when the pre-RT PSA is ≤1 ng/mL. A significant decline in FFBF is seen when the pre-RT PSA increases from ≤1 ng/mL to 2, and then to >2 ng/mL.
Other important prognostic factors include the Gleason score, margin status, and seminal vesicle invasion. Gleason scores of ≤7 predict for a better prognosis compared with scores of 8 to 10. A positive margin often indicates residual disease in the prostate bed, for which SRT is effective, and FFBF rates are higher when this is the case. Seminal vesicle invasion has been found to be a determinant of outcome in multivariate analysis in many series as well, with worse FFBF rates when the seminal vesicles were involved, due to these patients being at a higher risk of developing subsequent metastatic failure (Table 3).3,41,42
ANDROGEN DEPRIVATION THERAPY
The use of concurrent ADT with ART and SRT could impact the course of the disease hypothetically by 3 principal mechanisms: (1) better disease eradication locally (recurrence in a hypoxic scar may be radioresistant), (2) improved disease control distantly (cells in microscopic metastatic deposits might retain sensitivity to ADT), and (3) the combination of ADT and RT may alter the PSA kinetics in patients who eventually relapse.76,77 The mechanism of the effect on the kinetics of BF and the delayed appearance of distant metastasis is unknown. However, any improvement upon the current results of ART and SRT is potentially worthwhile. In some reports,4,6,41,78–83 ADT had positive results in patients at high risk of experiencing a rising PSA after SRT (eg, a pre-RT PSA >1 ng/mL). Randomized trials are needed and are in progress (Table 4).
ADJUVANT VERSUS SRT
The optimal timing of ART versus SRT for patients with high-risk pathologic features remains controversial. Some have supported watchful waiting before administering SRT.84 This rationale is based on 3 points. First, half of men will be treated unnecessarily. Second, salvage rates are fairly good when the pre-RT PSA is low (≤1.0 ng/mL).61,78,85–87 Third, the progression to distant metastasis after BF may be long.25,26 It is beyond the scope of this article to compare ART to SRT in depth; however, it should be noted that the addition of SRT to patients who were originally in the observation arm of the Southwest Oncology Group randomized trial still resulted in a higher rate of metastatic failure in these patients compared with early adjuvant therapy.51 Without a randomized trial to eliminate selection bias, it is impossible to ascribe an advantage to 1 strategy over the other based on FFBF outcomes. At least ART has a proven benefit in randomized prospective studies, supporting first principles that RT treatment should be used if the risk of local failure is >20% and the side effect profile is reasonable. Local persistence leads to distant metastasis in most malignancies, and there is evidence that this is the case for prostate cancer.88–91 In younger men with a long life expectancy, ART should be considered.
IRRADIATION IN PATIENTS WITH POSITIVE LYMPH NODES
LNI portends a very poor prognosis, with a high rate of distant failure. Although there are emerging data indicating that RP or RT should be used along with ADT when LNI is identified,92 there is no well-established benefit from this approach as yet. ART might be of some value when there is evidence of an appreciable locoregional tumor burden, such as extensive positive margins. There are insufficient data on the subject of pelvic nodal irradiation to make any recommendations, even when LNI has been documented (Table 5).93
* A high percentage of radical prostatectomy patients with high-risk pathologic features (positive surgical margins, extraprostatic extension of cancer, SVI) will experience a subsequent BF, with failure often due to the progression of residual disease within the surgical bed.
* The addition of adjuvant radiation therapy directed at the prostate fossa to these patients has been shown in 3 prospective randomized trials to improve the biochemical freedom from failure rate among the irradiated patients and, in 1 trial, to provide an improvement in metastasis-free and overall survival.
* Salvage radiation therapy, in which patients with biochemically detectable disease undergo radiotherapy to the prostate bed, has also been shown to improve freedom from BF, although the impact on overall survival remains uncertain.
* The appropriate radiation dose to the prostate fossa in the adjuvant or salvage setting is 66 to 70.2 Gy. Higher doses may be appropriate if there is an evidence of gross recurrence within the prostate bed.
* The addition of pelvic radiotherapy to prostate fossa radiation is generally discouraged, although it may be appropriate in certain clinical situations (absence of lymph node dissection, evidence of nodal involvement at prostatectomy or on imaging studies, etc).
* The benefit of neoadjuvant/adjuvant ADT is the subject of ongoing clinical trials, and its use is discouraged outside of the protocol setting.
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appropriateness criteria; adjuvant radiotherapy; salvage radiotherapy; radical prostatectomy; prostate cancer
© 2011 by Lippincott Williams & Wilkins, Inc
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