# Radiation Oncology/Prostate/Prostatectomy

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## Prostatectomy vs. Watchful waiting

Please see the Watchful waiting chapter

## Role of surgical staging

* Rate of lymphedema is 25-30% in pts undergoing limited dissection, 66% if complete (therapeutic) dissection in pts receiving XRT.
** Abstract Pilepich, from RTOG 75-06 and 77-06
* Abstract — "Impact of surgical staging in evaluating the radiotherapeutic outcome in RTOG #77-06, a phase III study for T1BN0M0 (A2) and T2N0M0 (B) prostate carcinoma." Asbell et al.
    Not randomized. 12-year OS 48% (staging laparotomy) vs 38% (lymphangiogram), DFS 38% vs 26%, decreased bone mets. Indicates that lymphangiogram group was understaged compared with surgical group.

## Natural history after RP

* Multi-Institutional; 2009 (1987-2005) PMID 19636023 -- "Prostate cancer-specific mortality after radical prostatectomy for patients treated in the prostate-specific antigen era." (Stephenson AJ, J Clin Oncol. 2009 Sep 10;27(26):4300-5. Epub 2009 Jul 27.)
** Retrospective; Memorial Sloan Kettering and Baylor patients to develop a nomogram, validation on Cleveland Clinic and University of Michigan data. 12,677 patients treated with RP. Primary outcome PCA-specific mortality. Median F/U 4 years
** Outcome: 15-year PCSM 12%, all-cause mortality 38%. Only 4% of contemporary patients had predicted 15-year PCSM >5%. Using D'Amico risk groups, 15-year PCSM good risk 2% vs. intermediate risk 10% vs. high risk 19% (good risk comprised 46% of patients)
** Conclusion: Few patients will die from prostate cancer within 15 years after radical prostatectomy, despite presence of adverse clinical features
Natural history of biochemical failure:
* Pound, 1999 - PMID 10235151 — "Natural history of progression after PSA elevation following radical prostatectomy." Pound CR et al. JAMA. 1999 May 5;281(17):1591-7.
** 315 of 1997 men developed biochemical failure. 34% developed mets in median time to mets 8 years after PSA elevation. Median time to death 5 years after mets. Predictive of mets: Gleason 8-10, PSA recurrence < 2 yrs after surgery, PSA doubling time < 10 months.
Factors predicting local recurrence:
    See section: Clinical and Pathologic Factors predicting recurrence at Adjuvant RT after Prostatectomy.
Factors predicting biochemical failure:
* Harvard 2005 (1989-2002) - PMID 16051949 — "Identifying patients at risk for significant versus clinically insignificant postoperative prostate-specific antigen failure." D'Amico AV et al. J Clin Oncol. 2005 Aug 1;23(22):4975-9.
** 1011 pts. Looked for factors identifying post-op PSA doubling time < 3 months ("clinically significant") or PSA DT > 12 months or no failure ("clinically insignificant")
** Predictive of clinically significant failure: 1) preoperative PSA velocity > 2 ng/mL/yr, and 2) Gleason 7 or above.
** Predictive of clinically insignificant or no failure: 1) PSA < 10, 2) nonpalpable cancer with Gleason 6 or less, and 3)preoperative PSA velocity < 2
Factors predicting metastatic disease:
* PSA doubling time < 10 months (from Pound)
* Extracapsular extension, SV invasion, Gleason 8-10, higher PSA at time of biochemical failure — (Dotan ZA et al - Abstract 162, 2005 Multidisciplinary Prostate Cancer Symposium) - nomogram
Factors predicting survival:
* Post-Prostatectomy PSA Velocity Linked to Increased Mortality
    Anthony D'Amico. NEJM, 8 July 2004, 351:125-135
* D'Amico - (Abstract) American Urological Association, 2005, Abstract 1678
** 1011 pts. Evaluated factors predictive of mortality - included 1-year PSA velocity prior to diagnosis, baseline PSA, Gleason score, clinical stage. Correlated with post-operative PSA doubling time, and correlated PSA doubling time with mortality.
** Short postoperative PSA doubling time (<3 months) predicted death due to cancer and overall deaths. Short PSA DT more likely in pts with preoperative PSA velocity > 2 per year and a Gleason of 7 or higher. Factors predictive of long PSA doubling time (>12 months) or no PSA failure were baseline PSA < 10, clinical stage T1c or less, Gleason 6 or less, and PSA velocity < 0.5 / yr.
** Conclusion: pts with protracted PSA after surgery may not need salvage treatment.
* Johns Hopkins (1982-2000)
** 379 pts with biochemical recurrences after RP. PSA-DT groups of <3 (6%), 3-9 (31%), 9-15 (21%), >15 (42%) months
** 2005 PMID 16046649 — "Risk of prostate cancer-specific mortality following biochemical recurrence after radical prostatectomy." Freedland SJ et al. JAMA. 2005 Jul 27;294(4):433-9. Median f/u 10 yrs after surgery.
*** Prostate-cancer specific survival is predicted by: PSA doubling time, Gleason score, and interval from surgery to biochemical failure.
** 2007 PMID 17470867 -- "Death in patients with recurrent prostate cancer after radical prostatectomy: prostate-specific antigen doubling time subgroups and their associated contributions to all-cause mortality." (Freedland SJ, J Clin Oncol. 2007 May 1;25(13):1765-71.) Median F/U 11.4 years
*** Outcome: PSA-DT <3 deaths account for only 13% due to low number; they die quickly, but with longer follow-up, slower PSA-DT patients start to die too. Intermediate PSA-DT 3-9 months account for 60% of PCA-related deaths
*** In PSA-DT <15 months, 90% will die *of* prostate cancer, not *with* prostate cancer at 15 years. Only if PSA-DT >15 months, competing-cause mortality greater
*** Conclusion: Even intermediate PSA-DT leads to prostate-cancer death

## Prostatectomy vs RT

    Also see: Radiation Oncology/Prostate/Localized Prostate Cancer (for comparisons of treatment modalities)
* Cleveland Clinic, 2002 (1990-98) - PMID 12177097 — "Comparison of the efficacy of local therapies for localized prostate cancer in the prostate-specific antigen era: a large single-institution experience with radical prostatectomy and external-beam radiotherapy." Kupelian PA et al. J Clin Oncol. 2002 Aug 15;20(16):3376-85.
** Retrospective, single-institution. 1682 pts with clinical stage T1-T2, treated during the PSA era. Treated with prostatectomy or RT to 68-78 Gy (median 70.2 Gy). Excluded pts with adjuvant androgen deprivation. Allowed neoadjuvant androgen deprivation if less than 6 months (19%). End-point was biochemical relapse free survival. Used ASTRO definition for PSA failure after RT. For RP failure was two consecutive PSA > 0.2; defined failure at time of first detectable level.
** bRFS increased for prostatectomy arm 80% vs 73% at 5-years and 72% vs 70% at 8-years. On multivariate analysis, treatment modality was not an independent predictor of relapse. For favorable tumors, no difference between RP and RT: 8-year bRFS 86% vs 90%. For unfavorable tumors, 8-year bRFS 62% vs 59% (N.S.). For unfavorable pts treated with RT to >= 72 Gy, there was an improved bRFS 82% vs 70% at 5 years compared to RP. For dose < 72 Gy, it was worse compared to RP: 50% vs 70%.
** Conclusion: "Eight-year biochemical failure rates were identical between RT and RP in any subgroup. Outcome is determined mainly by pretreatment PSA levels, bGS, clinical T stage, and, for RT patients, radiation dose."
* M. D. Anderson Cancer Center Orlando, 2004 (1990-98) - PMID 14697417 — "Radical prostatectomy, external beam radiotherapy <72 Gy, external beam radiotherapy > or =72 Gy, permanent seed implantation, or combined seeds/external beam radiotherapy for stage T1-T2 prostate cancer." Int J Radiat Oncol Biol Phys. 2004 Jan 1;58(1):25-33 Kupelian et al.
** Retrospective. Comparison of biochemical relapse-free survival (bRFS) for various methods.
** CONCLUSION: The biochemical failure rates were similar among PI, high-dose (> or =72 Gy) EBRT, COMB, and RP for localized prostate cancer. The outcomes were significantly worse for low-dose (<72 Gy) EBRT.
* Memorial Sloan Kettering Cancer Center at Mercy Medical Center, 2004 (1992-98) - PMID 15066293 — "Monotherapy for stage T1-T2 prostate cancer: radical prostatectomy, external beam radiotherapy, or permanent seed implantation" Radiother Oncol. 2004 Apr;71(1):29-33 Potters L et Al.
** Retrospective. 1819 pts, clinical stage T1-T2 (AJCC 1997). Compared freedom from biochemical recurrence (FBR) for various methods. EBRT dose was >= 70 Gy. All received monotherapy without adjuvant therapy.
** 7-year FBR for PPB vs EBRT vs RP were 74, 77, and 79%, respectively. Multivariate analysis identified iPSA and bGS as prognostic factors of relapse. Treatment modality, age, clinical T-stage, and race were not independent predictors of failure.
** CONCLUSIONS: Pretreatment PSA levels, and biopsy Gleason score determined outcome in this study cohort. Biochemical failure rates in this study cohort are similar between PPB, RT, and RP as monotherapy for clinically localized prostate cancer.

## Prostatectomy vs RT and Expected Patient survival

Although treatment outcomes after radical prostatectomy seem to be independent of the age of the patient, at least one study has found a higher PSA failure rate in patients younger than 60 years treated with conventional dose levels external-beam radiotherapy. Men with prostate cancer 60 years or younger treated with high dose conformal external beam radiotherapy seem to have an excellent biochemical outcome and to fare as well as older patients.
* PMID 12131302, 2002 - "Competing risk analysis after radical prostatectomy for clinically nonmetastatic prostate adenocarcinoma according to clinical Gleason score and patient age." Sweat et Al. J Urol 2002; 168: 525–29.
** Conclusions: This study shows that for any given Gleason score the prostate cancer death rate is similar in older and younger patients with few to no co-morbidities. Men with a score of 7 to 10 were at 29% to 43% risk of death from prostate cancer even when cancer was diagnosed as late as age 74 years and treated surgically.
* PMID 12131304 - "Biochemical disease-free survival in men younger than 60 years with prostate cancer treated with external beam radiation." Rosser CJ et al. J Urol. 2002 Aug;168(2):536-41
** 964 pts treated with RT alone. Biochemical failure defined per ASTRO consensus statement.
** Median f/u 48 months. Of the 98 men < 60 y.o. 46 (47%) had biochemical failure, whereas 261 (30%) of the 866 older men had biochemical failure. 5 and 7-year bDFS was 55% and 47% in younger men and 65% and 59% in older men (S.S.) In men > 60 yo, PSA, Gleason score, and lower radiation doses were predictive of biochemical failure.
** CONCLUSIONS: Men with prostate cancer who are 60 years or younger and treated with radiotherapy may be at significant risk for long-term biochemical failure.
* PMID 14532785 - "Improved biochemical disease-free survival of men younger than 60 years with prostate cancer treated with high dose conformal external beam radiotherapy." Zelefsky MJ et Al. J Urol. 2003 Nov;170(5):1828-32.
** Retrospective. 740 pts treated with 3D-CRT or IMRT to median dose of 75.6 Gy. Biochemical failure per ASTRo consensus statement.
** Median f/u 88 months. Biochemical failure in 21%-22%; 5 and 7 year bDFS in 79-82% and 78-79%. No difference between young men (< age 60) and older men. For young men who received >= 81 Gy, 7-year relapse free survival 96%, 87% and 50^ for favorable, intermediate, and unfavorable risk pts. For young pts, most important predictor of biochemical relapse was dose < 75.6 Gy followed by Gleason score > 7.
** Conclusions: Men < 60 yrs old treated with high dose XRT have excellent outcome and do as well as older pts. Treating younger pts with conventional RT doses led to 8-fold increase in relapse rate.

## Prostatectomy after neoadjuvant hormones

Hormones decrease the incidence of extracapsular extension and positive surgical margins. However, this does not lead to improved freedom from biochemical failure or survival (unlike hormones combined with RT).
* PMID 11743286 (Soloway), PMID 12230618 (Aus)
* SWOG 9109 - PMID 12394698 — "Neoadjuvant therapy before radical prostatectomy for clinical T3/T4 carcinoma of the prostate: 5-year followup, Phase II Southwest Oncology Group Study 9109." Powell IJ et al.
** 61 pts. Phase II. T3-4N0
** PFS 70%. OS 90%.

## Adjuvant Chemotherapy

    For adjuvant hormonal therapy after RP, See also: Radiation_Oncology/Prostate/Hormones/Adjuvant_ADT#Adjuvant_androgen_deprivation
* SWOG 9921 / Intergroup (2000-2007) -- ADT vs. ADT + mitoxantrone
** Randomized. Closed prematurely after AML toxicity. 983 patients, radical prostatectomy, high risk features (GS >=8, or pT3b-T4, or N1, or GS 7 and SM+, or PSA >15 ng/ml. Had to have undetectable post-op PSA). Arm 1) ADT x2 years (bicalutamide 50mg QD + goserelin 10.8 mg SC q3 months) vs. Arm 2) ADT x2 years + mitoxantrone 12 mg/m2 q3W x6 cycles
** 2008 PMID 18349405 -- "Randomization reveals unexpected acute leukemias in Southwest Oncology Group prostate cancer trial." (Flaig TW, J Clin Oncol. 2008 Mar 20;26(9):1532-6.)
*** Outcome: 3 cases of AML reported in 487 patients in mitoxantrone arm. Time-to-detection 13, 48, and 72 months. Trial stopped
*** Conclusion: Highlights importantce of controlled trials to define safety and efficacy
** 2011 PMID 21502546 -- "Adjuvant Androgen Deprivation for High-Risk Prostate Cancer After Radical Prostatectomy: SWOG S9921 Study." (Dorff TB, J Clin Oncol. 2011 May 20;29(15):2040-5.)
*** Final endpoints not yet available. In the ADT-alone control arm, 5-yr bFFS 92.5% and OS 95.9%.
*** Conclusion: consider use of adjuvant ADT in men with high risk prostate cancer