Treatments for Patients with Prostate Cancer

EFFECTIVE TREATMENT FOR PATIENTS WITH PROSTATE CANCER TO ACHIEVE A BIOCHEMICAL RECURRENCE FREE SURVIVAL

Mariam O. Akinwale

MEDICAL UNIVERSITY OF THE AMERICAS

Mentor:

Dr. Akintola Odutola

Manuscript word count

: 4205

HYPOTHESIS

: In the treatment of aggressive and metastatic prostate cancer, patients who undergo radical prostatectomy with additional radiation therapy and/or hormonal therapy have less recurrence rate in comparison to those who receive radical prostatectomy alone due to its additive curative effect.

ABSTRACT

(word count: 275)

Hypothesis


: In the treatment of aggressive and metastatic prostate cancer, patients who undergo radical prostatectomy with additional radiation therapy and/or hormonal therapy have less recurrence rate in comparison to those who receive radical prostatectomy alone due to its additive curative effect.

Method


: The articles reviewed in this studies were obtained from PubMed. The database search combined terms from three themes: men above the age of 50, radical prostatectomy, radiation therapy or hormonal therapy and prostate cancer remission. This search yielded 72 articles after inclusion criteria were considered. A total of 32 articles were used for final review after excluding 40 articles that did not compare management options for treatment of prostate cancer.

Result



:

Better life-expectancy have been indicated in patient treated with radiotherapy with hormonal therapy compared to patient treated with radical prostatectomy only. However, radical prostatectomy and radiotherapy with hormonal therapy are far more efficient compared to radiotherapy with hormonal therapy. The use of hormonal therapy for treatment of prostate cancer has always been frowned at because of it’s life-threating side effects but it’s patient-survival rate supersedes that of radical prostatectomy as a monotherapy.

Conclusion:


Combination therapy of radical prostatectomy with radiotherapy and hormonal therapy for treatment of patients with either benign or metastatic prostate cancer have a longer life-expectancy than radiotherapy with hormonal therapy, while patients treated with radiotherapy and hormonal therapy have a longer life-expectancy than those with radical prostatectomy with radiotherapy even after considering the side effects of hormonal therapy. Screening tests may help with early detection of biochemical recurrence and also prevent overtreatment with radiotherapy and/or hormonal therapy after radical prostatectomy.

Keywords



:

radical prostatectomy, adjuvant radiation therapy, hormonal therapy, biochemical recurrence, prostates cancer

INTRODUCTION

Prostate cancer (PCa) is the second commonest cancer in males above age 60. African- Americans have the highest prevalence in the US. Risk factors include diets high in beef and milk.

Two hundred and thirty-three thousand new cases are diagnosed yearly with 29,480 mortality reported in 2014. (American Cancer Society, 2014) Given these statistics, it is very important to diagnose and treat PC early in order to reduce the risk of high mortality.

Several treatments options are available in the management of PCa. Low- risk prostate cancer is managed by active surveillance in order to prevent unnecessary exposure to radiation or surgery. Intermediate or high- risk non-metastatic prostate cancer is treated with prostatectomy or radiation therapy (Zietman

et al.,

2010). Aggressive and metastatic prostate cancers are treated with variable combinations of radical prostatectomy (RP), radiation therapy (RT), chemotherapy, cryosurgery, hormonal therapy (HT) and bisphosphates. These combination therapeutic options address the tendency of aggressive PCa to metastasize to neighbouring structures/organs.

This study is designed to evaluate a specific combination of treatment option in the management of aggressive and metastatic PCa. It is hypothesized that patients with aggressive PCa who undergo radical prostatectomy and adjuvant radiotherapy have less recurrence rate compared to those who receive radical prostatectomy alone due to its additive curative effect (Thompson

et al.,

2013).

This study is significant because evidence suggests that different combination treatments of aggressive PCa are associated with different recurrence rate. The identification of the combination therapy with the lowest recurrence rate and longer life-expectancy is essential in this study.

I chose this topic because it is important for family practice physicians to have accurate information to give to their patients regarding best treatment options for aggressive metastatic PCa.

METHOD

The articles reviewed in this studies were obtained from PubMed. The database search combined terms from four themes: specific population (older men OR men above 50 OR prostate cancer patient OR post prostatectomy patient OR recurrent prostate cancer patient), intervention (prostate cancer adjuvant therapy OR prostate cancer adjuvant radiotherapy OR prostate cancer adjuvant chemotherapy), comparison (radical prostatectomy) and possible outcomes (prostate cancer recurrence OR prostate cancer remission OR prostate cancer curative OR prostate cancer life span OR prostate cancer prognosis OR prostate cancer quality of life).

Boolean operators used were OR and AND. OR was used to capture each term within a theme and AND was used to link each theme within parentheses. Filters used were: article types (randomized controlled trial), text availability (free full text), publication dates (5 years), and limited to human.

Inclusion criteria

Articles that were included in the systematic review of this study had to meet the following criteria: used randomised clinical trials, cohort studies and meta-analysis; prostate cancer population; radical prostatectomy with adjuvant radiotherapy and hormonal therapy as intervention; radical prostatectomy only as comparison; and prostate cancer recurrence, prostate cancer remission, prostate cancer curative, prostate cancer life span, prostate cancer prognosis, prostate cancer quality of life as outcome. Localized and high risk prostate cancer management were included in the study.

Exclusion criteria

Population of women and men below the age of 50 were excluded. Articles published prior to 2011 and were not written in English language were excluded. Articles that were not free full text were excluded. Articles that did not compare RP+RT+HT with radical prostatectomy only were excluded.

RESULTS

This search yielded 72 articles after inclusion criteria were considered. A total of 27 articles were used for final review after excluding articles that did not compare management options for treatment of prostate cancer.

Treatment of Prostate Cancer with Radical Retropubic Prostatectomy (RRP) And Pelvic Lymph Node Dissection (PLND)

Before we can lay emphasises on other possible treatments to prevent biochemical recurrence (BCR) after RP, we have to talk about RRP and PLND. According to one of the studies cited in this systematic review, ten of 11 patients with histologically confirmed lymph node metastasis (LNM) showed a PSA response (Winter

et al

., 2015). Three of 10 patients with single LNM had a complete biochemical remission (median follow-up 72months, range 31.0-83) (Winter

et al

., 2015). In five cases with single LNM PSA decreased <0.02ng/ml, histologically confirmed 13 of 16 metastasis suspicious LN, no LNM were detected in 2 patients (Winter

et al

., 2015). All of the additionally removed 30 LNs were completely negative (Winter

et al

., 2015).

Treatment of Prostate Cancer with Radical Prostatectomy (RP), PLND and Hormonal Therapy (HT)

The above combination therapies have been reported to be commonly used for the treatment of metastatic PCa to lymph nodes and other neighboring tissues than localized PCa due to it’s higher efficacy and potency for the treatment of metastatic PCa. The first article I will be talking about under this subtopic had a mean follow-up of 5.3 years and LNM occurred in 140 patients. An average of 10.9 lymph nodes was dissected from patient with pN1 through a method known as extended sentinel lymph node dissection (eSLND) (Muck

et al

., 2015). After the surgery, 121 patients with pN1 patients received adjuvant ADT for a sort period of time (Muck

et al

., 2015). Average survival year for; recurrence-free survival (RFS), RFS after secondary treatment, case-specific survival (CSS), and overall survival (OS) were 4.7, 7.0, 8.8, and 8.1 years, respectively (Muck

et al

., 2015). RFS, CSS, and OS were significantly correlated with tumor staging (Muck

et al

., 2015).

The second article focuses on the 67 Chinese patients with lymph node metastasis (LNM) after RP and extended PLND, and these patients received continuous adjuvant ADT. The median follow-up of this study was 46.7 months and two patients were lost to follow-up. BCR-free survival was recorded annually indicating 52%, 40%, 22% for the first 3 years respectively and a more significant survival was observed in patients with 5-year BCR free-survival which shows a 93% free-local recurrence, 83% free-systemic metastasis and 96% cancer death-free (Qin

et al

,2015). Postoperative BCR-free survival was 27.5 months (Qin

et al

.,2015).

Even though a lot of articles support the positive effect of HT as a treatment for PCa, we also have to consider the adverse effect of HT including depression. According to Lee

et al

, 2015, patients who are treated with ADT have shown to a significant prolonged depressive state (p< 0.05) (Lee

et al

.,2016). The depressive state in correlation to ADT is confirmed when compared to a control by indicating a p value less than 0.001 (Lee

et al

.,2016)

Apart from the adverse effect associated with HT, metastasis have been reported after adjuvant ADT has been used for treatment of both localized and high-risk PCAa (Taguchi

et al

., 2014). Taguchi et al. reported 9 (4.6%) patients developed metastasis and 6 (3.0%) died from PCa. Eight of nine metastatic patients had a GS greater than 9 and developed a metastasis to the bone, while the remaining one had a GS greater than 7 and developed lymphatic spread (Taguchi

et al

.,2014).

Based on the findings above, optimal timing of salvage ADT for BCR after RP is crucial. According to a study by Taguchi

et al.

, biochemical recurrence was seen in one patients (2.0%) in the ultra-early group and seen in 12 patients (17.1%) in the early salvage ADT group (Taguchi et al.,2014). Only one patient in the early salvage ADT group developed metastasis to a left supraclavicular lymph node, and no patient died from PCa during follow-up (Taguchi

et al

.,2014).

Treatment of prostate cancer with Radical Prostatectomy (RP) and Radiation Therapy (RT)

In order to examine the effect of RT after RP, an article which compared outcome of patients treated with radiotherapy after radical prostatectomy and patients who were under active surveillance after radical prostatectomy (Petruzzeillo

et al

., 2014). Patients who were under surveillance had a longer follow-up but higher recurrence rate and short life-expectancy (Petruzzeillo et al.,2014). Another article was able to back-up this finding, indicating significant longer life-expectancy and lower risk of recurrence (Gandaglia et al.,2014). However, the earlier administration of radiotherapy after RP is very essential. Studies had if indicated that patients who had ultra-early radiotherapy after RP had lower recurrence and longer life-expectancy (Azelie

et al.

,2012).

A number of reports have associated early RT after RP to decrease risk of BCR and longer overall survival (OS). According to Gandaglia

et al

, patients with high risk score benefitted more from early radiotherapy compared to patients with lower risk scores (Gandaglia

et al

.,2014). The risk scores were determined based on its association to increasing 5- to 10- year prostates cancer mortality rates with a p value less than 0.001 (Gandaglia

et al

.,2014). the risk score was associated with increasing 5- and 10-year cancer-specific mortality rates (P < 0.001). This was confirmed in multivariable analyses, where early radiotherapy decreased the risk of cancer-specific mortality only in patients with a risk score ≥ 2(P ≤ 0.02) (Gandaglia

et al

., 2014).

However, adjuvant RT after RP have shown to present with gastrointestinal and genitourinary toxicities. A study indicating the use of real-time tumor-tracking intensity-modulate radiation therapy (RT-IMRT) as a much preferable RT for treatment of PCa with less adverse effects (Shinohara

et al

.,2013). In patient treated with RT-IMRT have shown to have better quality of life with little or no risk of urinary and sexual dysfunction (Shinohara et al., 2013). No patients treated with RT-IMRT after RP have gastrointestinal discomfort (Azelie et al.,2012). An article has indicated that earlier RT can lower the risk of adverse effect such as gastrointestinal and urinary dysfunction (Hegarty

et al

.,2015).

Another concern is excessive treatment of PCa with RP+RT using standardized guideline. Patients who underwent RT after RP using this standard guideline 27 patients out of 163 patients had recurrence and 3 out 87 with PSA< 6.35ng/ml and Gleason score<7 had recurrence (Kang

et al

.,2014). Hence the other patients were over treated and therefore exposing them to preventable adverse effects.

Treatment of Prostate Cancer with Radical Prostatectomy(RP), Radiation Therapy(RT) and Hormonal Therapy (HT)

For the treatment of high-risk prostate cancer (PCa) different evidence-based therapies exist such as (RT+HT), (RP+RT), and (RP+RT+HT). RT + HT resulted in a longer life-expectancy which is always greater than 1 compared to RP+RT (Parikh et al.,2012). However, RP+RT+HT combination have a greater than 0.5 longer life-expectancy compared to RT+HT after considering their side effects (Parikh et al.,2012).

Treatment of Prostate Cancer with Radical Prostatectomy (RP), Radiation Therapy (RT), Hormonal Therapy (HT) and Neoadjuvant Chemotherapy (NCHT)

.

Patients with local and metastatic PCa are prone to recurrence after RP. Hence adjuvant therapies are required to reduce biochemical failure and also prolong life-expectancy. Therefore, it is important to study the adverse effect of these combination therapies (RP+RT+HT+NCHT). The major adverse effect associated with these combinations are gastrointestinal and urinary dysfunction while leucopenia and neutropenia mainly for NCHT (Guttilla

et al

.,2014) and (Thalgotti et al.,2014). Gastrointestinal and urinary dysfunction are seen in low grade pathologically (Guttilla

et al

.,2014). Thalgotti et al.,2014 reviewed the percentile of blood toxicity after patients have been administered the combination therapies; 90% had neutropenia and 53.8% leucopenia in the studied patients (Thalgotti et al.,2014).

Effective Screening Test to Aid Prevention of Biochemical Recurrence (BCR)

1. Eighty-eight miRNAs were identified to be significantly (p<0.05) associated with recurrence after RP by multi-analysis and they were categorized into two groups based on early recurrence (<36months) and late recurrence (>36months) (Bell
   
   et al
   
   .,2015). Nine miRNAs were identified to be significantly (p<0.05) associated with recurrence after RT by multi-analysis (Bell
   
   et al
   
   .,2015). Based on the efficacy of the above result a new prognostic stick has been created, composed of miRNA-4516 and miRNA-601, Gleason score and lymph node status (Bell
   
   et al
   
   .,2015).
2. A study was done to assess which patients would benefit the most from RT after RP using 11C-choline PET/CT. In order to identify which patients would benefit the most from restaging 11C-choline PET/CT before RT, 11C-choline PET/CT was positive in 28.4% of patients (172/605) (Castellucci
   
   et al
   
   , 2016). Castellucci et al.,2016 categorized these patients based on staging: Eighty-three of 605 patients were positive locally, 72 of 605 patients had systemic metastasis, and 17 of 605 patients had both local recurrence and systemic metastasis (Catellucci et al., 2016). At multi-analysis; PSA, PSA doubling time (PSAdt), and ADT were significant predictors for positive scan results, whereas PSA and PSAdt were significantly related to distant recurrence detection (P<0.05) (Castellucci
   
   et al
   
   .,2016).
3. Genomic classifier (GC) used to predict biochemical recurrence and distant metastasis in men receiving radiotherapy (RT) after radical prostatectomy (RP). Illustrating Den
   
   et al
   
   .,2015, the measurement of GC was used to predict recurrence of PCA at 5 years after receiving RT (Den et al.,2015). A multi-analysis was done which no correlation between GC and PSA before RP. However, patients with low GC had no significance recurrence at 5 years after RT while patients with high GC had recurrence at 5 years after RT (Den et al.,2015).

DISCUSSION

This reviews attempted to answer the question: Can adjuvant therapy be used in patients that have undergone radical prostatectomy to prevent local recurrences? The general collective consensus of articles included in this review supported the hypothesis that in the treatment of aggressive and metastatic prostate cancer, patients who undergo radical prostatectomy and adjuvant radiotherapy with hormonal therapy have less recurrence rate in comparison to those who receive radical prostatectomy alone due to its additive curative effect (Parikh et al.,2012; Kyrdalen et al.,2012; Hayachi et al., 2012; Shinohara et al.,2013; Kaplan et al.,2013; Linder et al.,2013; Azelie et al.,2012; Miyake et al.,2014; Taguchi et al.,2014; Muck et al.,2014; Gandaglia et al,2015; Den et al.,2014; Castellucci et al.,2014; Lee M. et al., 2015; Kang et al.,2014; Thalgotti et al.,2014; Sato et al.,2014; Gutilla et al.,2014; Kim et al.,2016; Rosenkrantz et al.,2015; Petruzzeillo et al.,2014;Den et al.,2014; Lee J. et al.,2015; Qin et al.,2015; Mizowaki et al,2015; Winter et al.,2015; Bell et al,2015; Hegarty et al.,2015; Den et al., 2015; Taguchi et al.,2014). Only one article concluded that patient with High Gleason score (GS) carry a risk of bone metastasis and cancer specific-death after RP with ADT (Taguchi

et al

.,2014). Seven articles laid more emphasise on the combination therapy’s adverse effects such as gastrointestinal, genitourinary toxicities and sexual dysfunction (Shinohara

et al

.,2013) and specifically; diabetes mellitus, heart disease, osteoporosis (Parikh et al.,2012) and depression for HT (Lee M.

et al

.,2015). However, few articles addressed these adverse effects by recommending ultra-early RT after RP (Azelia

et al.,

2012 and Hegarty

et al.

,2015) and early HT after RP (Taguchi

et al

.,2014 and Sato

et al

., 2014).

However, early RT after RP does not only reduce gastrointestinal and gastrourinary toxicities but it also prolongs quality-adjusted life expectancy (QALE) and lowers biochemical recurrence (BCR) (Azelie

et al

.,2012, Sato

et al

.,2014 and Gandgalia

et al

.,2014). Radiotherapy such as Real-time tumor-tracking intensity-modulated RT (RT-IMRT) may be a better treatment for localized PCa even though it has a similar effect as RP because of the adverse effects associated with RP such as urinary incontinence and erectile dysfunction (Azelie

et al

.,2012). Hence, better quality of life with RT compared to RP (Shinohara et al.,2013).

An article compared RT after RP with observation alone (OA) after RP which reviewed 87.1% to 30% biochemical progression-free survival, respectively (Petruzzeillo

et al

.,2014). This result lays further emphasises on the efficacy of RT after RP.

Despite all the articles emphasizing the efficacy of adjuvant RT and androgen deprivation therapy (ADT) after RP, there is concern for excessive treatment of PCa using AUA/ASTRO guideline on adjuvant RT. A particular article stretched on the concern by concluding that patients treated with RT who met the AUA/ASTRO guideline should be carefully considered to prevent excessive treatment (Kang

et al

., 2014). This is because in the article, among 163 patients with high risk BCR according to AUA/ASTRO guideline, only 27 patients developed BCR and treated with RT (Kang

et al

., 2014). In addition, in 87 patients with pre-operative PSA<6.35ng/ml and Gleason score of <8, only three reoccurred (3.4%) (Kang

et al

., 2014).

Some articles (Gutilla et al,2014; Gutilla et al,2014 and Thalgott et al.,2014) considered the effectiveness of screening test on predicting biochemical failure in order to prevent BCR after RP.

Several screening test were considered and tested. Specific miRNA (miR-4516 and miR-601), 11C-Choline PET/CT, Genomic Classifier (GC) and whole-lesion histogram apparent diffusion coefficient (ADC) metric have sensitivity and specificity for BCR after RP (Bell

et al.,

2015; Castellucci

et al

.,2015; Den

et al

.,2015; Den

et al

.,2014 and Rosenkrantz

et al

.,2015). These screenings can help to identify specific treatment for BCR, for example, patients with low GC scores are best treated with RT only, whereas those with high GC scores benefit from additional therapies (Den

et al.

, 2014).

Some studies verified that the trimodality therapy (RP+RT+HT) has shown an increase in quality of life expectancy (QALE) (Parikh

et al

.,2012; Guttilla

et al

.,2014; Kyradalen

et al

.,2012 and Den

et al

.,2014).

Limitations of the search strategy include searching only one database (PubMed), only one source of information is used (database), only published data is included, only data from the last 5 years is included, only articles published in the English language are included, and only one reviewer is reviewing the abstracts. The major limitation of this systematic review is use of more retrospective cohort than clinical trials and use of only free-full articles and also broad question covering several treatment options such as different types of adjuvant radiation therapies, hormonal therapies and inclusion of some chemotherapies.

Future research may consider comparing multiple interventions in a single randomized clinical trial with several approaches to allow for better comparison across clinical outcome measures. Further research may consider more screening test to prevent overtreatment.

APPENDICES

First Author	Date of Publication	Study Design	Level of Evidence	Study Population	Therapy	Outcome
Azelie C.	2012	Randomized Clinical trial	1b	178 patients were referred for daily exclusive image guided IMRT (IG-IMRT) and 69 patients were the control group	IG-IMRT vs RP+IMRT	Patients with low risk PCa treated with IG-IMRT had a more significant outcome compared to the control group (patient treated with RP + IMRT)
Bell E.	March, 2015	Prospective Cohort Study without controls	4	43 patients who undergone RT after RP	miRNAs	miRNA signatures (Notably, two novel miRNAs: miR-4516 and miR-601) can be used as a diagnostic tool to determine patients who will benefit from additional therapy after RP.
Castellucci P.	Nov., 2015	Case series	4	605 patients treated with RT after RP.	RT+RP vs ADT at the time of 11C-choline PET/CT	At the early stage of BCr after RP 11C-choline PET/CT should be suggested before ADT is administered.
Den R.	March, 2015	Randomized Clinical Trials	1b	188 patients with positive margin of PCa at Thomas Jefferson University and Mayo Clinic between 1990 and 2009 were considered.	Neoadjuvant HT, IMRT, salvage RT, ART	In patients treated with RT after RP,genomic classifier (GC) was a good prognostic tool for determining metastasis.
Den R.	August, 2014	Randomized Clinical trial	1b	139 patients who underwent RT after RP that were identified with pT3 or positive prostate margin.	Using genetic classifier to predict biochemical failure after RP+RT	The genetic classifier (GC) predicted biochemical failure and metastasis after RP +RT. Patients with lower GC may benefit from delayed RT, as opposed to those with higher GC.
Gandaglia G.	August, 2014	Randomized Clinical trial	1b	7616 prostate cancer patients treated with RP.	Early treatment with RT after RP vs not receiving early RT after RP	Patients with two or more adverse pathological characteristics at RP might benefit the most from adjuvant RT in terms of reduced cancer specific mortality.
Guttilla A.	2014	Randomized Clinical Trial	1b	35 patients with newly diagnosed high-risk localized prostate cancer	IMRT, RP, ADT, docetaxel-based chemotherapy	This treatment phase for high-risk PCa indicated an acceptable oncological outcome.
Hayashi S.	July, 2012	Retrospective Cohort Study without controls	4	41 patients were treated with external beam RT as salvage RT because of increasing PSA levels following RP.	RT after radical prostatectomy	Lymphatic invasion is reported after RT+RP Vascular invasion is not associated with biochemical failure in PCa treatment.
Hegarty S.	February, 2015	Prospective Cohort Study without controls	4	Using the Surveillance, Epidemiology, and End Results-Medicare linked database, we identified 6,137 prostate cancer patients diagnosed during 1995-2007 who had one or more adverse pathological features after prostatectomy.	RT after RP	RT after RP is associated with adverse effects such as gastrointestinal and genitourinary toxicities while early treatment with RT is not associated with these adverse effects.
Kaplan J.	2013	Retrospective Cohort Study without controls	4	577 men with LN metastases discovered during RP and 177 men underwent ART with no distant metastases	Adjuvant RT, RP	ART after RP in men with LN-positive prostate cancer was associated recurrence free-survival.
Kang J.	2014	Retrospective Cohort Study without controls	3b	163 men who had pT2-3 with undetectable PSA level after RP who had metastasis.	Adjuvant RT (ART) after RP	ART in patient who met the ASTRO/AUA criteria should be applied more selectively to avoid overtreatment.
Kyrdalen A.	2012	Randomized Clinical Trial	1b	771 compliers were divided into four groups (i) no treatment, (ii) RP, (iii)RT without HT and (iv) RT+HT	No treatment vs RP vs RT vs RT+HT	No treatment group: had the highest level of moderate/severe bladder outlet-obstruction. RP group: reported more urinary incontinent compared to other treatment groups and also the highest prevalence of poor erectile functions. RT group: reported highest gastrointestinal dysfunction and fecal leakage compared to RP and no treatment group. Bladder outlet obstruction and poor sexual drive were significantly associated with low quality of life.
Lee J.	July, 2015	Prospective Cohort Study without controls	4	307 patients who underwent RP at Seoul National University Hospital between January,2006 and July,2007.	RP	According to this finding, SHBG may be useful in selection of candidate for adjuvant treatment following RP.
Lee. M	2015	Observational studies with controls	3b	61 men with prostate cancer and their match control group (n=61) without cancer	ADT	This article indicates an association with PCa patient developing depression after receiving ADT.
Linder B.	2013	Retrospective Cohort Study without controls	4	419 patients who received additional HT	Adjuvant HT after RP	Adjuvant HT after RP with high-risk PCa does not increase non-prostate cancer (such as cardiovascular disease) mortality, even in patient with multiple comorbidities.
Mizowaki T.	April, 2015	Observational Study with controls	3b	Patients with localized PCa from the Japanese Radiation Oncology Study (JROSG) who were treated with RP before 2005 and those who received RT in 2007..	HT, RT	Hormonal therapy was combined with radiotherapy which resulted in a longer life- expectancy.
Muck A.	March, 2014	Retrospective Cohort Study without controls	4	819 patients with localized prostate cancer (PCa)	Extended sentinel lymph node dissection (eSLND) and RP.	The use of ESLND and RP in patients with low risk can serve serve as complete cure for BCR.
Parikh R.	Jan., 2012

EFFECTIVE TREATMENT FOR PATIENTS WITH PROSTATE CANCER TO ACHIEVE A BIOCHEMICAL RECURRENCE FREE SURVIVAL

Mariam O. Akinwale

MEDICAL UNIVERSITY OF THE AMERICAS

Mentor:

Dr. Akintola Odutola

Manuscript word count

: 4205

HYPOTHESIS

: In the treatment of aggressive and metastatic prostate cancer, patients who undergo radical prostatectomy with additional radiation therapy and/or hormonal therapy have less recurrence rate in comparison to those who receive radical prostatectomy alone due to its additive curative effect.

ABSTRACT

(word count: 275)

Hypothesis


: In the treatment of aggressive and metastatic prostate cancer, patients who undergo radical prostatectomy with additional radiation therapy and/or hormonal therapy have less recurrence rate in comparison to those who receive radical prostatectomy alone due to its additive curative effect.

Method


: The articles reviewed in this studies were obtained from PubMed. The database search combined terms from three themes: men above the age of 50, radical prostatectomy, radiation therapy or hormonal therapy and prostate cancer remission. This search yielded 72 articles after inclusion criteria were considered. A total of 32 articles were used for final review after excluding 40 articles that did not compare management options for treatment of prostate cancer.

Result



:

Better life-expectancy have been indicated in patient treated with radiotherapy with hormonal therapy compared to patient treated with radical prostatectomy only. However, radical prostatectomy and radiotherapy with hormonal therapy are far more efficient compared to radiotherapy with hormonal therapy. The use of hormonal therapy for treatment of prostate cancer has always been frowned at because of it’s life-threating side effects but it’s patient-survival rate supersedes that of radical prostatectomy as a monotherapy.

Conclusion:


Combination therapy of radical prostatectomy with radiotherapy and hormonal therapy for treatment of patients with either benign or metastatic prostate cancer have a longer life-expectancy than radiotherapy with hormonal therapy, while patients treated with radiotherapy and hormonal therapy have a longer life-expectancy than those with radical prostatectomy with radiotherapy even after considering the side effects of hormonal therapy. Screening tests may help with early detection of biochemical recurrence and also prevent overtreatment with radiotherapy and/or hormonal therapy after radical prostatectomy.

Keywords



:

radical prostatectomy, adjuvant radiation therapy, hormonal therapy, biochemical recurrence, prostates cancer

INTRODUCTION

Prostate cancer (PCa) is the second commonest cancer in males above age 60. African- Americans have the highest prevalence in the US. Risk factors include diets high in beef and milk.

Two hundred and thirty-three thousand new cases are diagnosed yearly with 29,480 mortality reported in 2014. (American Cancer Society, 2014) Given these statistics, it is very important to diagnose and treat PC early in order to reduce the risk of high mortality.

Several treatments options are available in the management of PCa. Low- risk prostate cancer is managed by active surveillance in order to prevent unnecessary exposure to radiation or surgery. Intermediate or high- risk non-metastatic prostate cancer is treated with prostatectomy or radiation therapy (Zietman

et al.,

2010). Aggressive and metastatic prostate cancers are treated with variable combinations of radical prostatectomy (RP), radiation therapy (RT), chemotherapy, cryosurgery, hormonal therapy (HT) and bisphosphates. These combination therapeutic options address the tendency of aggressive PCa to metastasize to neighbouring structures/organs.

This study is designed to evaluate a specific combination of treatment option in the management of aggressive and metastatic PCa. It is hypothesized that patients with aggressive PCa who undergo radical prostatectomy and adjuvant radiotherapy have less recurrence rate compared to those who receive radical prostatectomy alone due to its additive curative effect (Thompson

et al.,

2013).

This study is significant because evidence suggests that different combination treatments of aggressive PCa are associated with different recurrence rate. The identification of the combination therapy with the lowest recurrence rate and longer life-expectancy is essential in this study.

I chose this topic because it is important for family practice physicians to have accurate information to give to their patients regarding best treatment options for aggressive metastatic PCa.

METHOD

The articles reviewed in this studies were obtained from PubMed. The database search combined terms from four themes: specific population (older men OR men above 50 OR prostate cancer patient OR post prostatectomy patient OR recurrent prostate cancer patient), intervention (prostate cancer adjuvant therapy OR prostate cancer adjuvant radiotherapy OR prostate cancer adjuvant chemotherapy), comparison (radical prostatectomy) and possible outcomes (prostate cancer recurrence OR prostate cancer remission OR prostate cancer curative OR prostate cancer life span OR prostate cancer prognosis OR prostate cancer quality of life).

Boolean operators used were OR and AND. OR was used to capture each term within a theme and AND was used to link each theme within parentheses. Filters used were: article types (randomized controlled trial), text availability (free full text), publication dates (5 years), and limited to human.

Inclusion criteria

Articles that were included in the systematic review of this study had to meet the following criteria: used randomised clinical trials, cohort studies and meta-analysis; prostate cancer population; radical prostatectomy with adjuvant radiotherapy and hormonal therapy as intervention; radical prostatectomy only as comparison; and prostate cancer recurrence, prostate cancer remission, prostate cancer curative, prostate cancer life span, prostate cancer prognosis, prostate cancer quality of life as outcome. Localized and high risk prostate cancer management were included in the study.

Exclusion criteria

Population of women and men below the age of 50 were excluded. Articles published prior to 2011 and were not written in English language were excluded. Articles that were not free full text were excluded. Articles that did not compare RP+RT+HT with radical prostatectomy only were excluded.

RESULTS

This search yielded 72 articles after inclusion criteria were considered. A total of 27 articles were used for final review after excluding articles that did not compare management options for treatment of prostate cancer.

Treatment of Prostate Cancer with Radical Retropubic Prostatectomy (RRP) And Pelvic Lymph Node Dissection (PLND)

Before we can lay emphasises on other possible treatments to prevent biochemical recurrence (BCR) after RP, we have to talk about RRP and PLND. According to one of the studies cited in this systematic review, ten of 11 patients with histologically confirmed lymph node metastasis (LNM) showed a PSA response (Winter

et al

., 2015). Three of 10 patients with single LNM had a complete biochemical remission (median follow-up 72months, range 31.0-83) (Winter

et al

., 2015). In five cases with single LNM PSA decreased <0.02ng/ml, histologically confirmed 13 of 16 metastasis suspicious LN, no LNM were detected in 2 patients (Winter

et al

., 2015). All of the additionally removed 30 LNs were completely negative (Winter

et al

., 2015).

Treatment of Prostate Cancer with Radical Prostatectomy (RP), PLND and Hormonal Therapy (HT)

The above combination therapies have been reported to be commonly used for the treatment of metastatic PCa to lymph nodes and other neighboring tissues than localized PCa due to it’s higher efficacy and potency for the treatment of metastatic PCa. The first article I will be talking about under this subtopic had a mean follow-up of 5.3 years and LNM occurred in 140 patients. An average of 10.9 lymph nodes was dissected from patient with pN1 through a method known as extended sentinel lymph node dissection (eSLND) (Muck

et al

., 2015). After the surgery, 121 patients with pN1 patients received adjuvant ADT for a sort period of time (Muck

et al

., 2015). Average survival year for; recurrence-free survival (RFS), RFS after secondary treatment, case-specific survival (CSS), and overall survival (OS) were 4.7, 7.0, 8.8, and 8.1 years, respectively (Muck

et al

., 2015). RFS, CSS, and OS were significantly correlated with tumor staging (Muck

et al

., 2015).

The second article focuses on the 67 Chinese patients with lymph node metastasis (LNM) after RP and extended PLND, and these patients received continuous adjuvant ADT. The median follow-up of this study was 46.7 months and two patients were lost to follow-up. BCR-free survival was recorded annually indicating 52%, 40%, 22% for the first 3 years respectively and a more significant survival was observed in patients with 5-year BCR free-survival which shows a 93% free-local recurrence, 83% free-systemic metastasis and 96% cancer death-free (Qin

et al

,2015). Postoperative BCR-free survival was 27.5 months (Qin

et al

.,2015).

Even though a lot of articles support the positive effect of HT as a treatment for PCa, we also have to consider the adverse effect of HT including depression. According to Lee

et al

, 2015, patients who are treated with ADT have shown to a significant prolonged depressive state (p< 0.05) (Lee

et al

.,2016). The depressive state in correlation to ADT is confirmed when compared to a control by indicating a p value less than 0.001 (Lee

et al

.,2016)

Apart from the adverse effect associated with HT, metastasis have been reported after adjuvant ADT has been used for treatment of both localized and high-risk PCAa (Taguchi

et al

., 2014). Taguchi et al. reported 9 (4.6%) patients developed metastasis and 6 (3.0%) died from PCa. Eight of nine metastatic patients had a GS greater than 9 and developed a metastasis to the bone, while the remaining one had a GS greater than 7 and developed lymphatic spread (Taguchi

et al

.,2014).

Based on the findings above, optimal timing of salvage ADT for BCR after RP is crucial. According to a study by Taguchi

et al.

, biochemical recurrence was seen in one patients (2.0%) in the ultra-early group and seen in 12 patients (17.1%) in the early salvage ADT group (Taguchi et al.,2014). Only one patient in the early salvage ADT group developed metastasis to a left supraclavicular lymph node, and no patient died from PCa during follow-up (Taguchi

et al

.,2014).

Treatment of prostate cancer with Radical Prostatectomy (RP) and Radiation Therapy (RT)

In order to examine the effect of RT after RP, an article which compared outcome of patients treated with radiotherapy after radical prostatectomy and patients who were under active surveillance after radical prostatectomy (Petruzzeillo

et al

., 2014). Patients who were under surveillance had a longer follow-up but higher recurrence rate and short life-expectancy (Petruzzeillo et al.,2014). Another article was able to back-up this finding, indicating significant longer life-expectancy and lower risk of recurrence (Gandaglia et al.,2014). However, the earlier administration of radiotherapy after RP is very essential. Studies had if indicated that patients who had ultra-early radiotherapy after RP had lower recurrence and longer life-expectancy (Azelie

et al.

,2012).

A number of reports have associated early RT after RP to decrease risk of BCR and longer overall survival (OS). According to Gandaglia

et al

, patients with high risk score benefitted more from early radiotherapy compared to patients with lower risk scores (Gandaglia

et al

.,2014). The risk scores were determined based on its association to increasing 5- to 10- year prostates cancer mortality rates with a p value less than 0.001 (Gandaglia

et al

.,2014). the risk score was associated with increasing 5- and 10-year cancer-specific mortality rates (P < 0.001). This was confirmed in multivariable analyses, where early radiotherapy decreased the risk of cancer-specific mortality only in patients with a risk score ≥ 2(P ≤ 0.02) (Gandaglia

et al

., 2014).

However, adjuvant RT after RP have shown to present with gastrointestinal and genitourinary toxicities. A study indicating the use of real-time tumor-tracking intensity-modulate radiation therapy (RT-IMRT) as a much preferable RT for treatment of PCa with less adverse effects (Shinohara

et al

.,2013). In patient treated with RT-IMRT have shown to have better quality of life with little or no risk of urinary and sexual dysfunction (Shinohara et al., 2013). No patients treated with RT-IMRT after RP have gastrointestinal discomfort (Azelie et al.,2012). An article has indicated that earlier RT can lower the risk of adverse effect such as gastrointestinal and urinary dysfunction (Hegarty

et al

.,2015).

Another concern is excessive treatment of PCa with RP+RT using standardized guideline. Patients who underwent RT after RP using this standard guideline 27 patients out of 163 patients had recurrence and 3 out 87 with PSA< 6.35ng/ml and Gleason score<7 had recurrence (Kang

et al

.,2014). Hence the other patients were over treated and therefore exposing them to preventable adverse effects.

Treatment of Prostate Cancer with Radical Prostatectomy(RP), Radiation Therapy(RT) and Hormonal Therapy (HT)

For the treatment of high-risk prostate cancer (PCa) different evidence-based therapies exist such as (RT+HT), (RP+RT), and (RP+RT+HT). RT + HT resulted in a longer life-expectancy which is always greater than 1 compared to RP+RT (Parikh et al.,2012). However, RP+RT+HT combination have a greater than 0.5 longer life-expectancy compared to RT+HT after considering their side effects (Parikh et al.,2012).

Treatment of Prostate Cancer with Radical Prostatectomy (RP), Radiation Therapy (RT), Hormonal Therapy (HT) and Neoadjuvant Chemotherapy (NCHT)

.

Patients with local and metastatic PCa are prone to recurrence after RP. Hence adjuvant therapies are required to reduce biochemical failure and also prolong life-expectancy. Therefore, it is important to study the adverse effect of these combination therapies (RP+RT+HT+NCHT). The major adverse effect associated with these combinations are gastrointestinal and urinary dysfunction while leucopenia and neutropenia mainly for NCHT (Guttilla

et al

.,2014) and (Thalgotti et al.,2014). Gastrointestinal and urinary dysfunction are seen in low grade pathologically (Guttilla

et al

.,2014). Thalgotti et al.,2014 reviewed the percentile of blood toxicity after patients have been administered the combination therapies; 90% had neutropenia and 53.8% leucopenia in the studied patients (Thalgotti et al.,2014).

Effective Screening Test to Aid Prevention of Biochemical Recurrence (BCR)

1. Eighty-eight miRNAs were identified to be significantly (p<0.05) associated with recurrence after RP by multi-analysis and they were categorized into two groups based on early recurrence (<36months) and late recurrence (>36months) (Bell
   
   et al
   
   .,2015). Nine miRNAs were identified to be significantly (p<0.05) associated with recurrence after RT by multi-analysis (Bell
   
   et al
   
   .,2015). Based on the efficacy of the above result a new prognostic stick has been created, composed of miRNA-4516 and miRNA-601, Gleason score and lymph node status (Bell
   
   et al
   
   .,2015).
2. A study was done to assess which patients would benefit the most from RT after RP using 11C-choline PET/CT. In order to identify which patients would benefit the most from restaging 11C-choline PET/CT before RT, 11C-choline PET/CT was positive in 28.4% of patients (172/605) (Castellucci
   
   et al
   
   , 2016). Castellucci et al.,2016 categorized these patients based on staging: Eighty-three of 605 patients were positive locally, 72 of 605 patients had systemic metastasis, and 17 of 605 patients had both local recurrence and systemic metastasis (Catellucci et al., 2016). At multi-analysis; PSA, PSA doubling time (PSAdt), and ADT were significant predictors for positive scan results, whereas PSA and PSAdt were significantly related to distant recurrence detection (P<0.05) (Castellucci
   
   et al
   
   .,2016).
3. Genomic classifier (GC) used to predict biochemical recurrence and distant metastasis in men receiving radiotherapy (RT) after radical prostatectomy (RP). Illustrating Den
   
   et al
   
   .,2015, the measurement of GC was used to predict recurrence of PCA at 5 years after receiving RT (Den et al.,2015). A multi-analysis was done which no correlation between GC and PSA before RP. However, patients with low GC had no significance recurrence at 5 years after RT while patients with high GC had recurrence at 5 years after RT (Den et al.,2015).

DISCUSSION

This reviews attempted to answer the question: Can adjuvant therapy be used in patients that have undergone radical prostatectomy to prevent local recurrences? The general collective consensus of articles included in this review supported the hypothesis that in the treatment of aggressive and metastatic prostate cancer, patients who undergo radical prostatectomy and adjuvant radiotherapy with hormonal therapy have less recurrence rate in comparison to those who receive radical prostatectomy alone due to its additive curative effect (Parikh et al.,2012; Kyrdalen et al.,2012; Hayachi et al., 2012; Shinohara et al.,2013; Kaplan et al.,2013; Linder et al.,2013; Azelie et al.,2012; Miyake et al.,2014; Taguchi et al.,2014; Muck et al.,2014; Gandaglia et al,2015; Den et al.,2014; Castellucci et al.,2014; Lee M. et al., 2015; Kang et al.,2014; Thalgotti et al.,2014; Sato et al.,2014; Gutilla et al.,2014; Kim et al.,2016; Rosenkrantz et al.,2015; Petruzzeillo et al.,2014;Den et al.,2014; Lee J. et al.,2015; Qin et al.,2015; Mizowaki et al,2015; Winter et al.,2015; Bell et al,2015; Hegarty et al.,2015; Den et al., 2015; Taguchi et al.,2014). Only one article concluded that patient with High Gleason score (GS) carry a risk of bone metastasis and cancer specific-death after RP with ADT (Taguchi

et al

.,2014). Seven articles laid more emphasise on the combination therapy’s adverse effects such as gastrointestinal, genitourinary toxicities and sexual dysfunction (Shinohara

et al

.,2013) and specifically; diabetes mellitus, heart disease, osteoporosis (Parikh et al.,2012) and depression for HT (Lee M.

et al

.,2015). However, few articles addressed these adverse effects by recommending ultra-early RT after RP (Azelia

et al.,

2012 and Hegarty

et al.

,2015) and early HT after RP (Taguchi

et al

.,2014 and Sato

et al

., 2014).

However, early RT after RP does not only reduce gastrointestinal and gastrourinary toxicities but it also prolongs quality-adjusted life expectancy (QALE) and lowers biochemical recurrence (BCR) (Azelie

et al

.,2012, Sato

et al

.,2014 and Gandgalia

et al

.,2014). Radiotherapy such as Real-time tumor-tracking intensity-modulated RT (RT-IMRT) may be a better treatment for localized PCa even though it has a similar effect as RP because of the adverse effects associated with RP such as urinary incontinence and erectile dysfunction (Azelie

et al

.,2012). Hence, better quality of life with RT compared to RP (Shinohara et al.,2013).

An article compared RT after RP with observation alone (OA) after RP which reviewed 87.1% to 30% biochemical progression-free survival, respectively (Petruzzeillo

et al

.,2014). This result lays further emphasises on the efficacy of RT after RP.

Despite all the articles emphasizing the efficacy of adjuvant RT and androgen deprivation therapy (ADT) after RP, there is concern for excessive treatment of PCa using AUA/ASTRO guideline on adjuvant RT. A particular article stretched on the concern by concluding that patients treated with RT who met the AUA/ASTRO guideline should be carefully considered to prevent excessive treatment (Kang

et al

., 2014). This is because in the article, among 163 patients with high risk BCR according to AUA/ASTRO guideline, only 27 patients developed BCR and treated with RT (Kang

et al

., 2014). In addition, in 87 patients with pre-operative PSA<6.35ng/ml and Gleason score of <8, only three reoccurred (3.4%) (Kang

et al

., 2014).

Some articles (Gutilla et al,2014; Gutilla et al,2014 and Thalgott et al.,2014) considered the effectiveness of screening test on predicting biochemical failure in order to prevent BCR after RP.

Several screening test were considered and tested. Specific miRNA (miR-4516 and miR-601), 11C-Choline PET/CT, Genomic Classifier (GC) and whole-lesion histogram apparent diffusion coefficient (ADC) metric have sensitivity and specificity for BCR after RP (Bell

et al.,

2015; Castellucci

et al

.,2015; Den

et al

.,2015; Den

et al

.,2014 and Rosenkrantz

et al

.,2015). These screenings can help to identify specific treatment for BCR, for example, patients with low GC scores are best treated with RT only, whereas those with high GC scores benefit from additional therapies (Den

et al.

, 2014).

Some studies verified that the trimodality therapy (RP+RT+HT) has shown an increase in quality of life expectancy (QALE) (Parikh

et al

.,2012; Guttilla

et al

.,2014; Kyradalen

et al

.,2012 and Den

et al

.,2014).

Limitations of the search strategy include searching only one database (PubMed), only one source of information is used (database), only published data is included, only data from the last 5 years is included, only articles published in the English language are included, and only one reviewer is reviewing the abstracts. The major limitation of this systematic review is use of more retrospective cohort than clinical trials and use of only free-full articles and also broad question covering several treatment options such as different types of adjuvant radiation therapies, hormonal therapies and inclusion of some chemotherapies.

Future research may consider comparing multiple interventions in a single randomized clinical trial with several approaches to allow for better comparison across clinical outcome measures. Further research may consider more screening test to prevent overtreatment.

APPENDICES

First Author	Date of Publication	Study Design	Level of Evidence	Study Population	Therapy	Outcome
Azelie C.	2012	Randomized Clinical trial	1b	178 patients were referred for daily exclusive image guided IMRT (IG-IMRT) and 69 patients were the control group	IG-IMRT vs RP+IMRT	Patients with low risk PCa treated with IG-IMRT had a more significant outcome compared to the control group (patient treated with RP + IMRT)
Bell E.	March, 2015	Prospective Cohort Study without controls	4	43 patients who undergone RT after RP	miRNAs	miRNA signatures (Notably, two novel miRNAs: miR-4516 and miR-601) can be used as a diagnostic tool to determine patients who will benefit from additional therapy after RP.
Castellucci P.	Nov., 2015	Case series	4	605 patients treated with RT after RP.	RT+RP vs ADT at the time of 11C-choline PET/CT	At the early stage of BCr after RP 11C-choline PET/CT should be suggested before ADT is administered.
Den R.	March, 2015	Randomized Clinical Trials	1b	188 patients with positive margin of PCa at Thomas Jefferson University and Mayo Clinic between 1990 and 2009 were considered.	Neoadjuvant HT, IMRT, salvage RT, ART	In patients treated with RT after RP,genomic classifier (GC) was a good prognostic tool for determining metastasis.
Den R.	August, 2014	Randomized Clinical trial	1b	139 patients who underwent RT after RP that were identified with pT3 or positive prostate margin.	Using genetic classifier to predict biochemical failure after RP+RT	The genetic classifier (GC) predicted biochemical failure and metastasis after RP +RT. Patients with lower GC may benefit from delayed RT, as opposed to those with higher GC.
Gandaglia G.	August, 2014	Randomized Clinical trial	1b	7616 prostate cancer patients treated with RP.	Early treatment with RT after RP vs not receiving early RT after RP	Patients with two or more adverse pathological characteristics at RP might benefit the most from adjuvant RT in terms of reduced cancer specific mortality.
Guttilla A.	2014	Randomized Clinical Trial	1b	35 patients with newly diagnosed high-risk localized prostate cancer	IMRT, RP, ADT, docetaxel-based chemotherapy	This treatment phase for high-risk PCa indicated an acceptable oncological outcome.
Hayashi S.	July, 2012	Retrospective Cohort Study without controls	4	41 patients were treated with external beam RT as salvage RT because of increasing PSA levels following RP.	RT after radical prostatectomy	Lymphatic invasion is reported after RT+RP Vascular invasion is not associated with biochemical failure in PCa treatment.
Hegarty S.	February, 2015	Prospective Cohort Study without controls	4	Using the Surveillance, Epidemiology, and End Results-Medicare linked database, we identified 6,137 prostate cancer patients diagnosed during 1995-2007 who had one or more adverse pathological features after prostatectomy.	RT after RP	RT after RP is associated with adverse effects such as gastrointestinal and genitourinary toxicities while early treatment with RT is not associated with these adverse effects.
Kaplan J.	2013	Retrospective Cohort Study without controls	4	577 men with LN metastases discovered during RP and 177 men underwent ART with no distant metastases	Adjuvant RT, RP	ART after RP in men with LN-positive prostate cancer was associated recurrence free-survival.
Kang J.	2014	Retrospective Cohort Study without controls	3b	163 men who had pT2-3 with undetectable PSA level after RP who had metastasis.	Adjuvant RT (ART) after RP	ART in patient who met the ASTRO/AUA criteria should be applied more selectively to avoid overtreatment.
Kyrdalen A.	2012	Randomized Clinical Trial	1b	771 compliers were divided into four groups (i) no treatment, (ii) RP, (iii)RT without HT and (iv) RT+HT	No treatment vs RP vs RT vs RT+HT	No treatment group: had the highest level of moderate/severe bladder outlet-obstruction. RP group: reported more urinary incontinent compared to other treatment groups and also the highest prevalence of poor erectile functions. RT group: reported highest gastrointestinal dysfunction and fecal leakage compared to RP and no treatment group. Bladder outlet obstruction and poor sexual drive were significantly associated with low quality of life.
Lee J.	July, 2015	Prospective Cohort Study without controls	4	307 patients who underwent RP at Seoul National University Hospital between January,2006 and July,2007.	RP	According to this finding, SHBG may be useful in selection of candidate for adjuvant treatment following RP.
Lee. M	2015	Observational studies with controls	3b	61 men with prostate cancer and their match control group (n=61) without cancer	ADT	This article indicates an association with PCa patient developing depression after receiving ADT.
Linder B.	2013	Retrospective Cohort Study without controls	4	419 patients who received additional HT	Adjuvant HT after RP	Adjuvant HT after RP with high-risk PCa does not increase non-prostate cancer (such as cardiovascular disease) mortality, even in patient with multiple comorbidities.
Mizowaki T.	April, 2015	Observational Study with controls	3b	Patients with localized PCa from the Japanese Radiation Oncology Study (JROSG) who were treated with RP before 2005 and those who received RT in 2007..	HT, RT	Hormonal therapy was combined with radiotherapy which resulted in a longer life- expectancy.
Muck A.	March, 2014	Retrospective Cohort Study without controls	4	819 patients with localized prostate cancer (PCa)	Extended sentinel lymph node dissection (eSLND) and RP.	The use of ESLND and RP in patients with low risk can serve serve as complete cure for BCR.
Parikh R.	Jan., 2012