Radiation Therapy after Prostate Surgery, Part III: Salvage Therapy

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 the third part in this blog series, we review the statements from the ASTRO/AUA Guideline regarding salvage radiation therapy and the data supporting them.
To read Part I: Adjuvant Radiation following Surgery for Prostate Cancer click here.
To read Part II: Subgroup Analyses of Adjuvant Radiation for Prostate Cancer click here.
The Guideline Statements regarding adjuvant radiation therapy and three randomized studies (SWOG 8794, EORTC 22911, and ARO 96-02/AUO 09/95) that support their conclusions are detailed in Part I. To summarize, Part I: Adjuvant radiation therapy (ART), or radiation therapy given without evidence of cancer in men at high-risk for recurrence, is an option for men with advanced prostate cancer and adverse features after radical prostatectomy. Patients who undergo ART can expect an improvement in biochemical (PSA) and locoregional recurrence, although the benefits on distant metastases and overall survival is less clear. Part II reviews the subgroups of patients who may benefit from ART. Based on these subgroup analyses, ART appears to have the most benefit for patients with positive surgical margins and Gleason score 7-10. The benefit of ART in patients with Gleason 6, extraprostatic extension (in the absence of a positive surgical margin) and seminal vesicle invasion is less clear.

Salvage radiotherapy (RT) is defined as RT with clinical evidence of prostate cancer recurrence. Clinical evidence of prostate cancer recurrence can include any combination of:

• Elevated PSA level
• Recurrent mass or lymph node on imaging (CT scan usually)
• Biopsy-proven cancer in a recurrent mass

The guideline statements regarding salvage RT are detailed below. There are no randomized studies regarding the use of salvage RT, however several well-designed retrospective studies provide evidence for the use of this treatment.

The Guideline Statements

Guideline Statement 4.

• Patients should be informed that the development of a PSA recurrence after surgery is associated with a higher risk of development of metastatic prostate cancer or death from the disease. Congruent with this clinical principle, physicians should regularly monitor PSA after radical prostatectomy to enable early administration of salvage therapies if appropriate. (Clinical Principle)

Guideline Statement 5.

• Clinicians should define biochemical recurrence as a detectable or rising PSA value after surgery that is ≥ 0.2 ng/ml with a second confirmatory level ≥ 0.2 ng/ml. (Recommendation; Evidence Strength: Grade C)

Guideline Statement 6.

• A restaging evaluation in the patient with a PSA recurrence may be considered. (Option; Evidence Strength: Grade C)

Guideline Statement 7.

• Physicians should offer salvage radiotherapy to patients with PSA or local recurrence after radical prostatectomy in whom there is no evidence of distant metastatic disease. (Recommendation; Evidence Strength: Grade C)

Guideline Statement 8.

• Patients should be informed that the effectiveness of radiotherapy for PSA recurrence is greatest when given at lower levels of PSA. (Clinical Principle)
  

The Evidence

Based on a number of studies, including a study from Johns Hopkins, prostate cancer specific survival is significantly worse in men with a biochemical (PSA) recurrence after radical prostatectomy. In this study of over 600 men, the 5- and 10-year prostate-cancer survival for men receiving no salvage RT were 88% and 62%. For men receiving salvage RT, the prostate-cancer survival rates were 96% and 82-86% at 5- and 10-years respectively. This translates into a 3-fold increase in prostate-cancer survival for men receiving salvage RT.[1]

Importantly, these men only had a PSA recurrence and no evidence of distant metastatic disease. Men with distant metastatic disease are best treated by systemic therapy, either hormones and/or chemotherapy, and do not benefit from salvage radiation therapy. In addition, the benefit was only seen in men with a PSA doubling time of six months or less who underwent salvage RT within 2 years of biochemical recurrence. Another study of 500 men over 11 years demonstrated that salvage RT benefits men with both a PSA doubling time less than and greater to 6 months; however the benefit may be greater for men with PSA doubling time less than 6 months.[2]

Two additional studies provide evidence for the benefits of salvage RT in men with a rising PSA after surgery. A study of 500 patients from five centers demonstrated that more than two thirds of patients receiving salvage RT had a complete response (PSA became undetectable). In this study, patients with a PSA <0.6 had the best response to RT and patients with a PSA >2.0 had the highest risk of failure of salvage RT.[2] A follow-up study of over 1,500 patients confirmed the importance of pre-RT PSA value on prognosis. Patients treated with salvage RT alone at PSA levels of 0.5 ng/mL or lower had a 6-year progression-free survival rate of 48% compared with 26% for those treated at higher PSA levels.[3]

These data do not necessarily indicate that there is a causal relationship between PSA value and response to salvage RT. Likely, the PSA phenomenon reflect the biology of the recurrent prostate cancer and indicate groups of men most likely to have a meaningful benefit to RT.

 

Summary

Salvage RT should be offered to men with a biochemical (PSA) recurrence after radical prostatectomy. The benefits of RT are greatest in men with a low PSA level and low PSA doubling time.

This blog was written by Mark W. Ball, MD.  Mark is a 5^th year urology resident at the Brady Urological Institute at Johns Hopkins and looking forward to a career in urologic oncology.

 





[1] Trock BJ, Han M, Freedland SJ, Humphreys EB, DeWeese TL, Partin AW, Walsh PC. Prostate cancer-specific survival following salvage radiotherapy vs observation in men with biochemical recurrence after radical prostatectomy. JAMA. 2008 Jun 18;299(23):2760-9. doi: 10.1001/jama.299.23.2760.
[2] Cotter SE, Chen MH, Moul JW, Lee WR, Koontz BF, Anscher MS, Robertson CN, Walther PJ, Polascik TJ, D'Amico AV. Salvage radiation in men after prostate-specific antigen failure and the risk of death. Cancer. 2011 Sep 1;117(17):3925-32. doi: 10.1002/cncr.25993. Epub 2011 Mar 22.
[3] Stephenson AJ, Shariat SF, Zelefsky MJ, et al . Salvage radiotherapy for recurrent prostate cancer after radical prostatectomy. JAMA 2004;291:1325–1332.
[4] Stephenson AJ, Scardino PT, Kattan MW, et al . Predicting the outcome of salvage radiation therapy for recurrent prostate cancer after radical prostatectomy. J Clin Oncol 2007;25:2035–2041. Erratum in: J Clin Oncol 2007;25:4153.