Monday, November 3, 2014

Radiation Therapy after Prostate Surgery: The Guidelines Say Yes, My Doctor Says No


Some men prostate cancer are faced with the realization that treatment of their prostate cancer may require multimodal treatment including some combination of surgery, radiation therapy and/or hormone therapy. The combined ASTRO/AUA (American Society for Therapeutic Radiology and Oncology/American Urological Association) Guideline for "Adjuvant and Salvage Radiotherapy after Radical Prostatectomy" makes a number of statements regarding the use of radiation therapy after surgery that can be confusing to patients and practitioners.

In this blog we review the statements from the ASTRO/AUA Guideline regarding adjuvant radiation therapy and the data supporting them.

 

THE STUDIES

The Guidelines are supported, mostly, by the data from three randomized trials of adjuvant radiation therapy (ART) versus observation for patients after radical prostatectomy (RP). The SWOG trial began first in 1988 followed by the EORTC and most recently the ARO trial. However, the EORTC trial had more than double the sample size compared to the other two trials. All three trials enrolled patients with pathologic stage, pT3, disease and/or positive surgical margins. However, they differed in that the ARO trial excluded men with a persistently elevated PSA after RP, whereas these patients were included in the other two trials.
All three trials used a relatively low radiation dose of 60 Gray (most radiation oncologist argue that adequate, contemporary treatment of prostate cancer requires 80 Gray), and only the more recent ARO trial used modern 3-dimensional treatment planning. Central pathology review was available for the majority, but not all, patients in the 3 trials. The primary endpoint was metastasis-free survival in the SWOG study, versus progression-free survival in the other 2 trials. Finally, because it began earlier, the initial SWOG publication and a more recent update had longer follow-up than in the other trials.


 

Vital Statistics:

SWOG 8794

Thompson et al. JAMA 2006; 296: 2329.
Thompson et al. JUrol 2009; 181: 956.
Initiated: 1988
Sample Size: 425
Inclusion Criteria: pT3* and/or SM+ (Positive Surgical Margin); 15.7% pT2*
Patients with Persistent PSA Elevation following Surgery: Approximately 1/3rd
Radiation Therapy Dose: 60-64 Gray
Primary Endpoint: Metastases-Free Survival
Median Follow-up: 12.6 years


EORTC 22911

Bolla et al. Lancet 2005; 366: 572.
Van der Kwast et al. JCO 2006; 26: 4178.
Bolla et al. Lancet. 2012 Dec 8;380(9858):2018-27
Initiated: 1992
Sample Size: 1,005
Inclusion Criteria: pT3* and/or SM+ (>1/3rd pT2*)
Patients with Persistent PSA Elevation following Surgery: 11%
Radiation Therapy Dose: 60 Gray
Primary Endpoint: clinical or biochemical Progression-Free Survival (PFS)
Median Follow-up: 10.6 years

ARO 96-02/ AUO 09/95
Wiegel et al. JCO 2009; 27: 2898.
Initiated: 1997
Sample Size: 388
Inclusion Criteria: pT3* with or without SM+ (No Lymph Node Metastases)
Patients with Persistent PSA Elevation following Surgery: 20%, were excluded
Radiation Therapy Dose: 60 Gray (using modern 3-D conformal techniques)
Primary Endpoint: biochemical Progression-Free Survival (PFS)
Median Follow-up: 4.5 years


**DEFINITIONS 
pT2: organ-confined prostate cancer at RP
pT3: non-organ confined disease at RP (includes pT3a: extraprostatic extension and pT3b: seminal vesicle invasion)
SM+: positive surgical margins


 

THE GUIDELINE STATEMENTS

Guideline Statement 1.

  • Patients who are being considered for management of localized prostate cancer with radical prostatectomy should be informed of the potential for adverse pathologic findings that portend a higher risk of cancer recurrence and that these findings may suggest a potential benefit of additional therapy after surgery. (Clinical Principle)

Guideline Statement 2.

  • Patients with adverse pathologic findings including seminal vesicle invasion, positive surgical margins, and extraprostatic extension should be informed that adjuvant radiotherapy, compared to radical prostatectomy only, reduces the risk of biochemical (PSA) recurrence, local recurrence, and clinical progression of cancer.
  • They should also be informed that the impact of adjuvant radiotherapy on subsequent metastases and overall survival is less clear; one of two randomized controlled trials that addressed these outcomes indicated a benefit but the other trial did not demonstrate a benefit. However, the other trial was not powered to test the benefit regarding metastases and overall survival. (Clinical Principle)

Guideline Statement 3.

  • Physicians should offer adjuvant radiotherapy to patients with adverse pathologic findings at prostatectomy including seminal vesicle invasion, positive surgical margins, or extraprostatic extension because of demonstrated reductions in biochemical recurrence, local recurrence, and clinical progression. (Standard; Evidence Strength: Grade A)

 

THE DATA SUPPORTING EACH STATEMENT

Biochemical Recurrence or Progression Free Survival

All three studies demonstrate a higher proportion of men experiencing a biochemical (PSA) recurrence after RP and ART. The risk of recurrence was decreased approximately 50% in meta-analysis data from all three trials including in the guideline indicating that ART reduces the risk of biochemical (PSA) recurrence in men with high-risk of recurrence after radical prostatectomy.


Biochemical Progression-Free Survival
Follow-up
RP+ART
RP alone
Hazard Ratio
SWOG8794
10 years
53.0%
26.0%
0.43, P<0.01
EORTC22911
10 years
60.6%
41.1%
0.49, P<0.01
ARO96-02
5 years
72%
54%
0.53, P=0.002




Locoregional and Metastatic Recurrence or Recurrence-Free Survival

This statistic refers to the proportion of patients who develop nodal metastasis or evidence of prostate cancer in the pelvis that can be treated with curative radiation. These numbers are expectedly low, even for patients with advanced disease. The ARO96-02 trial did not report locoregional recurrence, but both the SWOG and EORTC studies demonstrated a benefit for ART with regard to locoregional relapse.


Local Relapse-Free Survival
Follow-up
RP+ART
RP alone
Hazard Ratio
SWOG8794
10 years
8%
22%
NR, P<0.01
EORTC22911
10 years
8.4%
17.3%
0.45, p<0.01
ARO96-02
5 years
Not Reported

 

Metastatic recurrence refers to the proportion of patients who develop recurrent prostate cancer outside of the pelvis, are therefore not curable by local treatments like radiation and require systemic treatment like androgen deprivation and/or chemotherapy. The results for metastatic recurrence (and metastasis-free survival, MFS) are less clear with conflicting results among the studies. The SWOG study demonstrated a benefit to ART, while the EORTC did not and ARO96-02 has too few events at current follow-up. In the SWOG study, MFS was defined as the presence of metastases or death from any cause. In the SWOG study, 72% of the deaths occurred in men without metastases and there were only 5 more cancer deaths in the observation group – perhaps leading to the significant finding in this study.[1]



Metastases and Metastases-Free Survival (MFS)
Follow-up
RP+ART
RP alone
Hazard Ratio
SWOG8794
10 years
9.3%
17.5%
MFS:0.71, P=0.016
EORTC22911
10 years
10.1%
11%
MFS: 0.99, P=0.94
ARO96-02
4.5 years
2.7%
3.1%
NR

 

Overall Survival

Overall Survival (OS) was improved for patients receiving ART in the SWOG study, but not the EORTC or ARO96-02 studies. Mirroring the MFS data, there are conflicting results for OS among the studies.


Deaths and Overall Survival (OS)
Follow-up
RP+ART
RP alone
Hazard Ratio
SWOG8794
10 years
OS: 74%
66%
0.72, P=0.023
EORTC22911
10 years
OS: 76.9%
80.7%
1.18, P=0.2
ARO96-02
4.5 years
Deaths: 3.4%
5.0%
NR


SUBGROUP ANALYSES

All three studies consisted of a heterogeneous group of patients including patients with low-, intermediate- and high-risk features and variation in Gleason score, SM+ and pathological stage. When looking at these subgroups, ART appears to have the most benefit for patients with:
  • Positive Surgical Margins (SM+)
  • Gleason Sum ≥ 7


Other than biochemical (PSA) recurrence-free survival, the benefit to ART is unclear in patients with:
  • Gleason 6
  • Extraprostatic extension in the absence of SM+
  • Seminal vesicle invasion (pT3)


A future blog will discuss the subgroup analyses in greater detail.


SUMMARY


  • Adjuvant radiation therapy (ART) is an option for men with advanced prostate cancer and adverse features after radical prostatectomy.
  • The ASTRO/AUA Guidelines are based on the data from three large, randomized clinical trials:
    • SWOG 8794
    • EORTC 22911
    • ARO 96-02/ AUO 09/95
  • Patients who undergo ART will have an improvement in biochemical (PSA) and locoregional recurrence.
    • The impact of ART on distant metastases and overall survival is less clear.
  • Subgroup analyses indicate that patients with positive surgical margins and Gleason Score ≥ 7 are most likely to benefit from ART.
    • The benefit of ART is unclear in patients with Gleason 6, extraprostatic extension or seminal vesicle invasion.

 

This blog was written by Mark W. Ball, MD. This blog is the first of a series on "Radiation Therapy after Prostate Surgery."  Dr. Ball is a 5th year urology resident at the Brady Urological Institute at Johns Hopkins and looking forward to a career in urologic oncology.


 


 


 



[1] Cheng et al J Urol 182: 2531, 2009

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