# Radiation Oncology/Prostate/Node Positive

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## Long-term outcomes

* RTOG 75-06 - PMID 9531359 — Ten-year outcomes for pathologic node-positive patients treated in RTOG 75-06. (Hanks GE, IJRBOP 1998).
** Conclusion: A small fraction of node-positive patients are cured at 10-year follow-up by radiation therapy (2 of 90 with PSA +3 of 90 by clinical endpoints). Innovative treatment programs should be directed at node-positive patients in an effort to improve the fraction cured.

## Local Therapy vs No Local Therapy

* SEER/U. Colorado PMID 24661660 - "The Impact of Definitive Local Therapy for Lymph Node–Positive Prostate Cancer: A Population-Based Study " (Rusthoven CG, Int J Radiat Oncol Biol Phys 2014; 88 (5); 1064-1073. )
** 1995-2005, 796 clinically node positive (cN+), 2991 pathologically node positive (pN+), analyzed as separate cohorts.
*** For cN+ patients, 43% had EBRT vs 57% had No Local Therapy (NLT). 10-yr OS 45% vs 29% (P<.001) (median OS 9.6 vs 5.9 yr)
*** For pN+ patients, 78% had local therapy (radical prostatectomy (RP) 57%, EBRT 10%, or both 11%) vs 22% had NLT. 10-yr OS 65% vs 42% (P<.001) (median OS 13.6 vs 8.3 years)
*** Local therapy beneficial across subgroups, including age >=70 years and multiple +lymph nodes
** Secondary comparisons of RP vs EBRT and RP +/- Adjuvant EBRT: no significant differences between modalities. +Trend toward improved OS with RP + Adjuvant EBRT over RP alone (p=.08).
** Conclusion: "RP and EBRT were associated with substantial improvements in OS and PCSS. The best available evidence suggests that patients with N1M0 PCa can achieve improved long-term survival outcomes with definitive local therapy and these strategies should be considered in appropriate candidates."
** "Mixed Population Model" PMID 25680608 - authors propose a model to account for potential "under-ascertainment" of radiation data (ie, coding "no radiation" in observational databases [SEER, etc] when radiation was actually delivered to the patient [Jagsi Cancer 2012;118:333-341, Walker IJROBP 2013;86:686-693, Jagsi IJROBP 2014;90(1):11-24]):

## Prostatectomy vs Radiotherapy

* Ulm, Germany / U. Michigan PMID 15356680 -- Comparison of external radiation therapy vs radical prostatectomy in lymph node positive prostate cancer patients. (2004 Kuefer, Prostate Cancer Prostatic Dis. 2004;7(4):343-9.)
** Retrospective. 102 pts RPX, 44 pts ERT. Adjuvant androgen ablation was given in 76 of 102 RPX, 21 of 44 ERT.
** Conclusion: "In case of positive lymph nodes, RPX and ERT might be considered and need to be explained to the patient. For future treatment decisions, the presented findings and a potential survival benefit need to be evaluated in a larger prospective setting."

## Radiotherapy alone

Dose for positive nodes:
* From Fletcher, Texbook of Radiotherapy, 3rd ed. (1980) - For lymphangiogram positive pelvic nodes, extend field to L4-L5 interspace, 45 Gy to pelvis + boost positive nodes to a total of 55-60 Gy.

## After prostatectomy
### Hormonal therapy after prostatectomy

Randomized data:
* Messing / ECOG EST-3886 (1988 - 93)
** 7 years, 1999 PMID 10588962 Full text — "Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer." (Messing EM, N Engl J Med. 1999 Dec 9;341(24):1781-8.)
*** 98 pts. Pts were found to have node-positive disease after radical prostatectomy + pelvic lymphadenectomy. Randomized to adjuvant goserelin (or bilateral orchiectomy) vs observation until disease progression (based on local or distant disease progression, not PSA).
*** Median 7.1 yrs f/u. 77% (antiandrogen) vs 18% (obs) were alive with no evidence of recurrent disease and undetectable PSA. Death from any cause in 7 of 47 men (antiandrogen) vs 18 of 51 (obs), S.S.
*** Conclusion: survival benefit for immediate hormonal therapy. RT not used.
** 12 years, 2006 PMID 16750497 -- "Immediate versus deferred androgen deprivation treatment in patients with node-positive prostate cancer after radical prostatectomy and pelvic lymphadenectomy." (Messing EM, Lancet Oncol. 2006 Jun;7(6):472-9.)
*** Median f/u 11.9 yr. Improved OS (HR=1.84), PCSS (HR=4.09) , and PFS (HR=3.42).
Retrospective:
* SEER/Medicare; 2009 (1991-1999) PMID 19047295 -- "Role of androgen deprivation therapy for node-positive prostate cancer." (Wong YN, J Clin Oncol. 2009 Jan 1;27(1):100-5.)
** 731 pts treated with RP with positive regional LNs. 209 men received ADT within 120 days of RP. Compared men receiving adjuvant ADT vs those without adjuvant ADT.
** OS: no sig difference between adjuvant ADT and non-ADT groups (HR 0.97).
** CONCLUSION: "Deferring immediate ADT in men with positive lymph nodes after RP may not significantly compromise survival."

### Adjuvant hormonal therapy plus RT

See also: Radiation Oncology/Prostate/Adjuvant RT page
* Multicenter; 2014 (1988-2010) - Retrospective
** PMID 25245445 -- "Impact of adjuvant radiotherapy on survival of patients with node-positive prostate cancer." (Abdollah F, J Clin Oncol. 2014 Dec 10;32(35):3939-47.)
** 1107 pts, all N+ after radical prostatectomy with extended LN dissection (obturator, ext iliac, and hypogastric); median 15 nodes removed. Treated at Mayo Clinic or San Raffaele (Milan). All received lifelong adjuvant hormonal therapy; adjuvant RT in 34.9%. RT median dose to prostate bed: 66.6 - 70.2 Gy; whole pelvis treated in 70-85% to median dose 45-50.4 Gy.
*** Developed stratification into 5 risk groups based on 4 parameters (number of positive nodes, pathologic Gleason score, tumor stage, surgical margin status). Validated using SEER database.
*** Adjuvant RT associated with more favorable CSM (HR 0.37). Only 2 risk groups benefitted from RT: intermediate risk (1-2 LN, G 7-10, pT3b/pT4 or +SM) and high risk (3-4 LN).
*** Conclusion: "The beneficial impact of aRT on survival in patients with pN1 prostate cancer is highly influenced by tumor characteristics. Men with low-volume nodal disease (≤ two PLNs) in the presence of intermediate- to high-grade, non-specimen-confined disease and those with intermediate-volume nodal disease (three to four PLNs) represent the ideal candidates for aRT after surgery."
*** Comment: PMID 25847937 -- "External Validation of the Benefit of Adjuvant Radiotherapy for Pathologic N1M0 Prostate Cancer" (Rusthoven, Carlson, Kavanagh. J Clin Oncol. 2015 Jun 10;33(17):1987-8). Authors report a re-analysis of Abdollah et al's SEER external validation cohort using identical RPA risk stratification groups to the primary analysis by Abdollah et al. The re-analysis with identical risk stratifications validates an OS benefit in 'intermediate-risk' patients (1-2 +LNs , G 7-10, pT3b/pT4 or +SM) (multivariate HR 0.63, p=0.048), but unable to validate benefit in 'high-risk' patients (3-4 +LNs) (multivariate HR 1.17, p=0.729).
| Risk Group | Criteria | Criteria | Criteria | 8-yr CSM-Free Survival (%) | 8-yr CSM-Free Survival (%) | 8-yr CSM-Free Survival (%) |
| Risk Group | Criteria | Criteria | Criteria | Entire Cohort | aHT alone | aHT + aRT |
| Very low risk | 1-2 LN | G 2-6 | - | 98.6 | 98.4 | 100 (p=0.7) |
| Low risk | 1-2 LN | G 7-10 | pT2/pT3a and SM- | 96.6 | 96.8 | 96.3 (p=0.4) |
| Int risk | 1-2 LN | G 7-10 | pT3b/pT4 or SM+ | 86.7 | 84.2 | 93.1 (p=0.03 *) |
| High risk | 3-4 LN | - | - | 85.3 | 78.8 | 96.5 (p=0.02 *) |
| Very high risk | >4 LN | - | - | 72.2 | 72.0 | 74.7 (p=0.9) |
| * denotes statistically significant difference Abdollah, J Clin Oncol 2014. |||||||
* Italy, 2011 (1986-2002) - Retrospective, multi-center
** 364 pts (of a series of 703 pts), pLN+ treated with RP. Matched analysis comparing 117 pts treated with HT + RT vs 247 pts treated with HT alone.
** 2011 PMID 21354694 -- "Combination of adjuvant hormonal and radiation therapy significantly prolongs survival of patients with pT2-4 pN+ prostate cancer: results of a matched analysis." (Briganti A, Eur Urol. 2011 May;59(5):832-40.)
*** Median f/u 95 mo. (7.9 yr). 5/8-year CSS 90%/82%, OS 85%/70%. Pts treated with RT+HT had higher CSS and OS rates (5/8-year CSS: 95%/91% vs 88%/78%, OS: 90%/84% vs 82%/65%).
*** Conclusion: "Adjuvant RT plus HT significantly improved CSS and OS of pT2-4 pN1 patients, regardless of the extent of nodal invasion. These results reinforce the need for a multimodal approach in the treatment of node-positive prostate cancer."
* Italy, 2009 (1988-2002) - Retrospective
** Retrospective review of 250 consecutive pLN+ patients treated with RP, followed by HT alone (48%) or HT and RT (52%). Seventy-four percent of patients received pelvic and prostate bed RT. Median dose 66.6 Gy.
** 2009 PMID 19211184 -- "Long-term follow-up of patients with prostate cancer and nodal metastases treated by pelvic lymphadenectomy and radical prostatectomy: the positive impact of adjuvant radiotherapy." (Da Pozzo LF, Eur Urol. 2009 May;55(5):1003-11.)
*** 5/8-year bRFS 72/61%, CSS 89/83%. In multivariate analysis, adjuvant RT and # of positive LN predicted bRFS and CSS. Patients treated with aHT alone had 2.6× risk of prostate cancer mortality vs. HT and RT after accounting for other predictors.

## Hormonal therapy and radiotherapy

* MD Anderson, 2001 (1984-1998) PMID 11489709 — "Addition of radiation therapy to androgen ablation improves outcome for subclinically node-positive prostate cancer." Zagars GK, Pollack A, von Eschenbach AC. Urology. 2001 Aug;58(2):233-9.
** Retrospective. 255 pts N+ found on lymphadenectomy treated with early androgen ablation alone (n=188) or with 70 Gy EBRT (n=72). Median F/U 9.4 years for ablation alone, 6.2 years for ablation + RT
** 10 year outcome: Adding EBRT improved OS from 46 to 67%. Freedom from relapse improved from 25% to 80%
** Conclusion: Early androgen ablation alone not helpful. Addition of RT offers substantial and significant improvement
* RTOG 85-31: Subset Analysis, PMID 15681524 — "Androgen suppression plus radiation versus radiation alone for patients with stage D1/pathologic node-positive adenocarcinoma of the prostate: updated results based on national prospective randomized trial Radiation Therapy Oncology Group 85-31." Lawton CA et al. J Clin Oncol. 2005 Feb 1;23(4):800-7.
** Updated analysis of pN+ pts (median f/u on all pts (6.5 yrs) and all living pts (9.5 yrs))
** 98 pts XRT + immediate adjuvant goserelin, 75 pts XRT alone w/ delayed goserelin @ time of failure.
** Conclusion: Multivariant analysis shows XRT + immediate adj goserelin have SS benefit in all four end points analyzed-- biochem control, met failure, DSF, absolute survival. Need prospective randomized trial to confirm, but until then, pN+ pts should be considered for XRT + immediate hormonal manipulation rather than XRT alone with hormone manipulation at the time of relapse.
* (closed due to poor accrual ) RTOG 96-08 (1997-98)
** Randomized node-positive pts to indefinite total androgen ablation vs total androgen ablation plus RT to the pelvis + prostate. 50.4 Gy to the pelvis (to L4/5 interspace) with boost to 68.4 - 70.2 Gy.

## Hormonal Therapy Alone

* EORTC 30846 - Randomized to immediate ADT vs delayed ADT; no treatment of the primary tumor
** 234 pts with prostate cancer and nodal metastases. No treatment to the primary tumor was given. Pts randomized to early ADT vs delayed ADT. Non-inferiority trial
** 2009 PMID 18823693 -- "Early versus delayed endocrine treatment of T2-T3 pN1-3 M0 prostate cancer without local treatment of the primary tumour: final results of European Organisation for the Research and Treatment of Cancer protocol 30846 after 13 years of follow-up (a randomised controlled trial)." (Schröder FH, Eur Urol. 2009 Jan;55(1):14-22.)
*** Median f/u 13 yr. Median duration of protocol ADT 2.7 yr (delayed) vs 3.2 yr (immediate).
*** 59.4% of pts died from PCa; 82.5% died overall. Median OS 6.1 yr (delayed) vs 7.6 yr (immediate) (HR 1.22), not signficant (non-inferiority not proven).
*** Conclusion: "After 13 years of follow-up, survival or PCa-specific survival between immediate and delayed ET appear similar, but the trial is underpowered to reach its goal of showing non-inferiority."