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Article of the Week: Does timing matter in postoperative RT for patients at high-risk of recurrence after RP?

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Every Week the Editor-in-Chief selects an Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

Finally, the third post under the Article of the Week heading on the homepage will consist of additional material or media. This week we feature a video from Dr. Peter Carroll, discussing his paper. 

If you only have time to read one article this week, it should be this one.

Postoperative radiation therapy for patients at high-risk of recurrence after radical prostatectomy: does timing matter?

Charles C. Hsu*†, Alan T. Paciorek‡, Matthew R. Cooperberg‡, Mack Roach III*, I-Chow J. Hsu* and Peter R. Carroll‡

 

*Department of Radiation Oncology, Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, †Department of Radiation Oncology, College of Medicine, University of Arizona, Tucson, AZ, and ‡Department of Urology, Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, CA, USA

 

Read the full article
OBJECTIVE

To evaluate among radical prostatectomy (RP) patients at high-risk of recurrence whether the timing of postoperative radiation therapy (RT) (adjuvant, early salvage with detectable post-RP prostate-specific antigen [PSA], or ‘late’ salvage with a PSA level of >1.0 ng/mL) is significantly associated with overall survival (OS), prostate-cancer specific survival or metastasis-free survival, in a longitudinal cohort.

PATIENTS AND METHODS

Of 6 176 RP patients in the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE), 305 patients with high-risk pathological features (margin positivity, Gleason score 8–10, or pT3–4) who underwent postoperative RT were examined, either in the adjuvant (≤6 months after RP with undetectable PSA levels, 76 patients) or salvage setting (>6 months after RP or pre-RT PSA level of >0.1 ng/mL, 229 patients). Early (PSA level of ≤1.0 ng/mL, 180 patients) or late salvage RT (PSA level >1.0 ng/mL, 49 patients) was based on post-RP, pre-RT PSA level. Multivariable Cox regression examined associations with all-cause mortality and prostate cancer-specific mortality and/or metastases (PCSMM).

RESULTS

After a median of 74 months after RP, 65 men had died (with 37 events of PCSMM). Adjuvant and salvage RT patients had comparable high-risk features. Compared with adjuvant, salvage RT (early or late) had an increased association with all-cause mortality (hazard ratio [HR] 2.7, P = 0.018) and with PCSMM (HR 4.0, P = 0.015). PCSMM-free survival differed by further stratification of timing, with 10-year estimates of 88%, 84%, and 71% for adjuvant, early salvage, and late salvage RT, respectively (P = 0.026). For PCSMM-free survival and OS, compared with adjuvant RT, late salvage RT had statistically significantly increased risk; however, early salvage RT did not.

CONCLUSION

This analysis suggests that patients who underwent early salvage RT with PSA levels of <1.0 ng/mL may have comparable metastasis-free survival and OS compared with adjuvant RT; however, late salvage RT with a PSA level of >1.0 ng/mL is associated with worse clinical outcomes.

Read more articles of the week

Editorial: Does a positive margin always mandate adjuvant radiotherapy?

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The appropriate treatment for clinically localized prostate cancer continues to generate controversy. For men with low grade disease it is unclear whether surgery or radiation therapy provides a survival advantage over active surveillance, and among men with high grade disease it is unclear how many derive a substantial benefit from either intervention. No trial has yet to compare surgery and radiation with observation, but the recent update of the Scandinavian Prostate Cancer Group 4 study suggests that radical prostatectomy provides a significant survival advantage for younger men with intermediate grade disease [1].

Unfortunately, many men undergoing radical prostatectomy are not cured of their disease. The Scandinavian Prostate Cancer Group 4 study has shown that as many as 26% of men undergoing surgery developed distant metastases and 18% died from their disease after a median follow-up of 13 years. For this reason many clinicians recommend additional radiation therapy for those men undergoing surgery who are at high risk of disease recurrence. Three randomized trials now support the use of radiation therapy in this setting. Two have shown lower rates of biochemical progression and one has shown improved distant metastases-free survival and overall survival [2-4]. These trials compared the use of adjuvant radiation therapy with observation. Some clinicians, however, are reluctant to refer patients for radiation therapy because of concerns about its potential impact on quality of life. This is especially true for those patients who have yet to show any evidence of biochemical recurrence.

In a manuscript published in this month’s BJUI, Hsu et al. [5] have turned to a large national prostate cancer registry that has accrued men with newly diagnosed prostate cancer since 1995. They evaluated the long-term outcomes of these men to gain insights into whether a delay in the initiation of radiation therapy compromises survival. Their findings suggest that delaying the initiation of radiation therapy until there is evidence of biochemical recurrence does not seriously compromise long-term outcomes and avoids radiation in some men who are never destined to have disease progression.

The authors are appropriately cautious with their conclusions and clearly recognize the limitations of a non-randomized study. In a registry study it is impossible to control adequately for selection biases. Men receiving adjuvant therapy had no evidence of biochemical recurrence at the time radiation was started. This group of men included both men who were destined to have disease progression and men who were destined to maintain an undetectable PSA. This differs from the men receiving salvage radiation therapy. All men receiving salvage radiation had evidence of disease progression and therefore their tumour burden and their long-term prognosis was probably worse when compared with men receiving adjuvant therapy. Despite this selection bias, men initiating salvage radiation when their postoperative PSA level was still <1.0 ng/mL had similar long-term outcomes when compared with the men receiving adjuvant radiation. Men with postoperative PSA levels >1.0 ng/mL had a much higher risk of aggressive disease and a worse outcome.

Ideally, the question about the timing of postoperative radiation would be subjected to a randomized trial. Until then, the information provided by Hsu et al. provides strong clinical support for a practical approach to the question of who should receive postoperative radiation. Men who are clearly at high risk of disease progression, which includes men with Gleason 8–10 disease and those with extensive margin positive disease and seminal vesicle invasion, should probably receive adjuvant radiation therapy as soon as they have recovered from surgery. For men with Gleason 7 disease or those men who have focal margin-positive disease it may make sense to monitor postoperative PSA levels closely and refer men for postoperative radiation when there is evidence of biochemical progression and before the PSA level reaches 1.0 ng/mL. This approach would spare some men the need for additional treatment and would defer treatment for many years in others. Men who are eventually found to have biochemical recurrence should feel reasonably comfortable that the delay in initiating radiation therapy is unlikely to have caused any significant compromise of their long-term outcome and probably improved their quality of life.

Large case series analyses frequently have selection biases that confound conclusions. In this instance the authors have cautiously interpreted a large community-based registry to gain a valuable insight into the management of localized prostate cancer. Their analysis provides appropriate support for their conclusions.

Read the full article
Peter C. Albertsen
University of Connecticut Health Center, Farmington, CT, USA

 

References

 

1 Bill-Axelson A, Holmberg L, Garmo H et al. Radical prostatectomy or watchful waiting in early prostate cancer. N Engl J Med 2014; 370: 932–42

 

2 Thompson IM, Tangen CM, Paradelo J et al. Adjuvant radiotherapy for pathological T3N0M0 prostate cancer significantly reduces the risk of metastases and improves survival: long-term followup of a randomized trial. J Urol 2009; 181: 956–62

 

3 Bolla M, van Poppel H, Collette L et al. Postoperative radiotherapy after radical prostatectomy: a randomized control trial (EORTC trial 22911). Lancet 2005; 366: 572–8

 

4 Wiegel T, Bottke D, Steiner U et al. Phase III postoperative adjuvant radiotherapy after radical prostatectomy compared with radical prostatectomy alone in pT3 prostate cancer with postoperative undetectable prostate-specific antigen. ARO 96-02/AUO AP 09/95. J Clin Oncol 2009; 27: 2924–30

 

5 Hsu D, Paciorek A, Cooperberg M et al. Postoperative radiation therapy for patients at high risk of recurrence after radical prostatectomy: does timing matter? BJU Int 2015; 116: 713–20

 

Video: Postoperative RT for patients at high-risk of recurrence after RP: does timing matter?

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Postoperative radiation therapy for patients at high-risk of recurrence after radical prostatectomy: does timing matter?

Charles C. Hsu*†, Alan T. Paciorek‡, Matthew R. Cooperberg‡, Mack Roach III*, I-Chow J. Hsu* and Peter R. Carroll‡

 

*Department of Radiation Oncology, Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, †Department of Radiation Oncology, College of Medicine, University of Arizona, Tucson, AZ, and ‡Department of Urology, Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, CA, USA

 

Read the full article
OBJECTIVE

To evaluate among radical prostatectomy (RP) patients at high-risk of recurrence whether the timing of postoperative radiation therapy (RT) (adjuvant, early salvage with detectable post-RP prostate-specific antigen [PSA], or ‘late’ salvage with a PSA level of >1.0 ng/mL) is significantly associated with overall survival (OS), prostate-cancer specific survival or metastasis-free survival, in a longitudinal cohort.

PATIENTS AND METHODS

Of 6 176 RP patients in the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE), 305 patients with high-risk pathological features (margin positivity, Gleason score 8–10, or pT3–4) who underwent postoperative RT were examined, either in the adjuvant (≤6 months after RP with undetectable PSA levels, 76 patients) or salvage setting (>6 months after RP or pre-RT PSA level of >0.1 ng/mL, 229 patients). Early (PSA level of ≤1.0 ng/mL, 180 patients) or late salvage RT (PSA level >1.0 ng/mL, 49 patients) was based on post-RP, pre-RT PSA level. Multivariable Cox regression examined associations with all-cause mortality and prostate cancer-specific mortality and/or metastases (PCSMM).

RESULTS

After a median of 74 months after RP, 65 men had died (with 37 events of PCSMM). Adjuvant and salvage RT patients had comparable high-risk features. Compared with adjuvant, salvage RT (early or late) had an increased association with all-cause mortality (hazard ratio [HR] 2.7, P = 0.018) and with PCSMM (HR 4.0, P = 0.015). PCSMM-free survival differed by further stratification of timing, with 10-year estimates of 88%, 84%, and 71% for adjuvant, early salvage, and late salvage RT, respectively (P = 0.026). For PCSMM-free survival and OS, compared with adjuvant RT, late salvage RT had statistically significantly increased risk; however, early salvage RT did not.

CONCLUSION

This analysis suggests that patients who underwent early salvage RT with PSA levels of <1.0 ng/mL may have comparable metastasis-free survival and OS compared with adjuvant RT; however, late salvage RT with a PSA level of >1.0 ng/mL is associated with worse clinical outcomes.

Read more articles of the week

Article of the week: Salvage focal or total cryoablation after failed primary radiotherapy: which is better?

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Every week the Editor-in-Chief selects the Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

This week, we feature two Articles of the Week.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

The final post under the Article of the Week heading on the homepage will consist of additional material or media. This week we feature a video by Dr. de Castro Abreu and colleagues.

Salvage focal and salvage total cryoablation for locally recurrent prostate cancer after primary radiation therapy

Andre Luis de Castro Abreu*, Duke Bahn*†, Scott Leslie*, Sunao Shoji*, Paul Silverman†, Mihir M. Desai*, Inderbir S. Gill* and Osamu Ukimura*

*USC Institute of Urology, Hillard and Roclyn Herzog Center for Prostate Cancer Focal Therapy, Keck School of Medicine, University of Southern California, Los Angeles, and †Prostate Institute of America, Community Memorial Hospital, Ventura, CA, USA

Read the full article
OBJECTIVES

• To present the oncological and functional outcomes of salvage focal (SFC) and salvage total (STC) cryoablation for recurrent prostate cancer (PCa) after failed primary radiotherapy.

PATIENTS AND METHODS

• From March 2003 to August 2010, 50 men with biopsy-proven unilateral (n = 25) or bilateral (n = 25) radio-recurrent PCa underwent SFC or STC, respectively.

• Patients were assessed after treatment by prostate-specific antigen (PSA) testing, transrectal ultrasonography, biopsy and questionnaires. Biochemical failure (BF) was defined using the Phoenix criteria (PSA nadir + 2 mg/mL).

• Data were prospectively collected and retrospectively analysed.

RESULTS

• The median pre-cryoablation PSA level and Gleason score were, respectively, 2.8 ng/mL and 7 for SFC, and 3.9 ng/mL and 7 for STC. The median follow-up was 31 and 53 months (P = 0.004) for SFC and STC, respectively.

• Oncological outcomes were as follows: no patient died; one patient who underwent STC developed bone metastases; eight patients who underwent SFC and three who underwent STC had BF and the 5-year BF-free survival rates were 54 and 86%, respectively. In those patients without BF, the mean PSA decreased by 86% for SFC and 90% for STC within the first year and remained stable.

• Functional outcomes were as follows: new onset urinary incontinence occurred in three (13%) patients in the STC group, whereas no patient in the SFC group developed incontinence (P = 0.10); Two of seven patients in the SFC group retained postoperative potency, but none of the four potent patients in the STC group recovered potency postoperatively (P = 0.48); one (4%) patient in the STC group developed a recto-urethral fistula, but none occurred in the SFC group (P = 0.48).

CONCLUSIONS

• SFC and STC are feasible and safe with acceptable mid-term oncological outcomes. For carefully selected patients, SFC is an option that could be associated with lower treatment-related morbidity compared with STC.

• Although longer follow-up and more patient numbers are needed, our initial oncological and functional outcomes of SFC and STC are encouraging.

 

Read Previous Articles of the Week

 

Editorial: Salvaging failed radiation therapy: does the tumour location permit a less toxic approach?

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In the introduction to their manuscript in this issue of the BJUI, Meeks et al. outline a significant challenge for physicians managing prostate cancer: from the estimated 240 000 diagnosed annually (USA) to the 120 000 choosing radiation, to the 40 000 estimated biochemical failures in the first 5 years who may benefit from additional local therapy to avoid local and/or systemic progression. The basis of these calculations was from conventional beam radiation, and although we expect dose-escalation strategies to perform better, the ideal management strategy remains to be identified. Indeed, Zelefsky et al. showed that there was a higher risk of metastatic disease with external beam radiation therapy than with surgery for high-risk prostate cancer, although there was some confounding of the results due to the differences in salvage treatment. This confounding may be the key point: more acceptable salvage options may promote optimal local control and fewer progressions.

Certainly, the concern with salvage therapy after failed radiation is the toxicity, and the concept of achieving less urinary incontinence with cryotherapy or even focal cyrotherapy is attractive, as outlined by de Castro Abreu et al. in this issue. In their parallel cohorts of total and focal salvage cryotherapy, urinary incontinence occurred in three (13%) of the 25 salvage total and zero of the 25 salvage focal therapies, and there was only one fistula in either series. However, the cancer control outcomes are different among these non-randomised and non-comparable cohorts: 87% disease-free survival for patients with bilateral disease treated with total cryotherapy and 54% disease-free survival for patients with unilateral disease treated with focal cryotherapy. These comparisons are limited, but one could hypothesise that salvage total therapy has improved disease control over salvage focal therapy.

Returning to the Meeks et al. study, a cohort of 198 patients with biopsy confirmed radiation recurrence underwent a salvage prostatectomy at a single institution. Pre-treatment biopsies showed 48% and 13% Gleason sums 7 and 8–10, respectively, and multifocal location in 61% (92/151 patients). Salvage prostatectomies showed 56% advanced pathological stage and 35% Gleason 8–10, and multifocal location in 57%. In comparing specific biopsy locations to radical prostatectomy mapping, undetected cancers from biopsy ranged from 12% to 26%, and 58% upgrading. In patients with unilaterally localised biopsies, final pathology was unilateral in only half – a statistic that matches the PSA failure rate from focal therapy in the de Castro Abreu et al.’s study. The authors point to a non-radiated biopsy-to-prostatectomy study and by comparison conclude that the accuracy of biopsy in radiated prostates is actually greater, perhaps due to the smaller radiated gland. But let’s be clear – both groups had significant rates of multifocal disease and inaccuracies between biopsy and radical prostatectomy.

These two BJUI studies provide a developing agenda of what we know and do not know about salvage therapy for failed radiation:

  • Local failure after radiation selects patients who probably have significant disease in terms of volume, stage, and grade, and should not be confused with the over-detection of low-volume, low-grade disease seen in primary treatments for PSA-screened disease.
  • Salvage focal therapy for unilateral disease by biopsy may be less morbid but may be only 50% effective.
  • The link between metastatic progression and PSA failure after failed salvage focal therapy is unknown, and completion treatment of the other side could be studied.
  • The additive accuracy of post-radiation biopsy plus imaging is not established.
  • We are basing most of our treatment recommendations on tumour morphology (histopathology, location, size) and surrogates (PSA failure definitions) rather than biology and survival.
  • The current management of post-radiation local failure should consider total gland treatments as the standard and focal therapies as experimental.

John W. Davis and Seungtaek Choi*
Departments of Urology and *Radiation Oncology, UT MD Anderson Cancer Center, Houston, TX, USA

Article by Meeks et al.
Article by de Castro Abreu et al.

Video: Cryoablation after failed primary radiotherapy: study finds encouraging results

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Salvage focal and salvage total cryoablation for locally recurrent prostate cancer after primary radiation therapy

Andre Luis de Castro Abreu*, Duke Bahn*†, Scott Leslie*, Sunao Shoji*, Paul Silverman†, Mihir M. Desai*, Inderbir S. Gill* and Osamu Ukimura*

*USC Institute of Urology, Hillard and Roclyn Herzog Center for Prostate Cancer Focal Therapy, Keck School of Medicine, University of Southern California, Los Angeles, and †Prostate Institute of America, Community Memorial Hospital, Ventura, CA, USA

Read the full article
OBJECTIVES

• To present the oncological and functional outcomes of salvage focal (SFC) and salvage total (STC) cryoablation for recurrent prostate cancer (PCa) after failed primary radiotherapy.

PATIENTS AND METHODS

• From March 2003 to August 2010, 50 men with biopsy-proven unilateral (n = 25) or bilateral (n = 25) radio-recurrent PCa underwent SFC or STC, respectively.

• Patients were assessed after treatment by prostate-specific antigen (PSA) testing, transrectal ultrasonography, biopsy and questionnaires. Biochemical failure (BF) was defined using the Phoenix criteria (PSA nadir + 2 mg/mL).

• Data were prospectively collected and retrospectively analysed.

RESULTS

• The median pre-cryoablation PSA level and Gleason score were, respectively, 2.8 ng/mL and 7 for SFC, and 3.9 ng/mL and 7 for STC. The median follow-up was 31 and 53 months (P = 0.004) for SFC and STC, respectively.

• Oncological outcomes were as follows: no patient died; one patient who underwent STC developed bone metastases; eight patients who underwent SFC and three who underwent STC had BF and the 5-year BF-free survival rates were 54 and 86%, respectively. In those patients without BF, the mean PSA decreased by 86% for SFC and 90% for STC within the first year and remained stable.

• Functional outcomes were as follows: new onset urinary incontinence occurred in three (13%) patients in the STC group, whereas no patient in the SFC group developed incontinence (P = 0.10); Two of seven patients in the SFC group retained postoperative potency, but none of the four potent patients in the STC group recovered potency postoperatively (P = 0.48); one (4%) patient in the STC group developed a recto-urethral fistula, but none occurred in the SFC group (P = 0.48).

CONCLUSIONS

• SFC and STC are feasible and safe with acceptable mid-term oncological outcomes. For carefully selected patients, SFC is an option that could be associated with lower treatment-related morbidity compared with STC.

• Although longer follow-up and more patient numbers are needed, our initial oncological and functional outcomes of SFC and STC are encouraging.

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