Management of Biochemical Recurrence of ADKP

Abstract
The second most common form of cancer in men in europe is prostate cancer. The main
primary treatement of these type of cancer is represented by radical prostatectomy (RP) which
has great oncologic result. RP has a high succes and low morbidity rates for patients with
localized prostate cancer. The life expentancy has to be more than 10 years. Studies shows that
approxiately 20-40% of patients with RP can present biochemical recurrance. The biochemical
recurrancy is represented by the value of the prostatic specific antigen (PSA). In some cases ( in
patients with high-risk prostate cancer) adjuvant therapy after radical prostatectomy, like
radiotherapy or androgen deprivation therapy can significantly reduce the risk of biochemical
recurrancy. The optimal management of recurrent disease remains uncertain.

The objectiv of this present article is to systematically review recent literature regarding
management of biochemical recurrence and to compare our clinical experience to literature
studies.

Introduction
According to the latest guidelines prostate cancer is the second most commonly
diagnosed cancer in men, with an estimated 1.1 million diagnoses worldwide in 2012, accounting
for 15% of all cancers diagnosed. The primary way of detecting prostate cancer is given by the
value of PSA, and the presence of a suspected nodule in rectal tact. The prevalence of prostate
cancer at age < 30 years is 5% and it’s increasing by an odds ratio of 1.7 (1.6-1.8) per decade, to
a prevalence of 59% (48-71%) by age > 79 years[1]. In the setting of organ confined disease,
PSA is supposed to reach undetectable value after radical prostatectomy. Despite primary
treatment(radical prostatectomy ) of localized prostate cancer, 20–30% of patients experience a
biochemical recurrence, typically detected by arise in serum prostate-specific antigen levels[2].
Usualy there is a mean time between 5 and 8 years from the radical prostatectomy to the
appearance of biochemical recurrency. Important prognostic parameter in the appearance of
biochemical recurrency after radical prostatectomy is represented by the Gleason score.

Because biochemical recurrency is known to determine distant metastasis and cancer

death, it is necessary for men with biochemical recurrency to undergo salvage therapy and to by
carefully monitored.
 Results
We performed a study between 2016 and 2017 on a lot of 82 patients with prostate cancer
in our clinic. 72 patients were diagnosed using congnitive transrectal echoguided biopsy, and 10
using fusion transrectal biopsy. The PSA levels were between 7 and 25. The pT stage was graded
according to the EAU guidelines. All of the patients underwent radical prostatectomy, 61 using
classical open retropubic surgery and 21 using laparoscopic approach. Preoperatively MRI was
performed on all patients for staging- on which they were divided in 2 grups: 48 preseded high
risk-with
invasion of the prostate capsule or invasion of seminal vesicles, and 34 were on low risk. 1 year
after the surgery only 8 patients presented biochemical recurrency with a PSA level between 0,8
and 1,2 ng/ml, and salvage treatement was required.

Many studies were preformed to examine the characteristics and management of earlier
and late biochemical recurrence after radical prostatectomy. Jean-Baptiste Beauval et al
performed a study on a lot of 517 patients who underwent radical prostatectomy with bilateral
ileo-obtratory lymph-node dissection for clinical high-risk prostate cancer in D’Amico risk
classification. The PSA value was >20 ng/ml, with clinical T2c or more stage, biopsy Gleason
between 8 and 10. The study was performed between 1990 and 2013 in two French clinical
centers. Open, laparoscopic or robotic assisted prostatectomy was performed. Lymph node
metastasis was noted in 12.4 % of patients. Only in 29 cases requested adjuvand therapy like
radiotherapy or androgen deprivation therapy. Biochemical recurrency-free survival was 56.4 %.
The rate of biochemical free recurrence was significantly improved with the number of risk
factors.[3]

Another study performed in Turkey by Cuneyt Ozden et al on a lot of 305 patients

observed the relationship between the effect of age on biochemical recurrance on patiens who
underwent radical prostatectomy. The patients were separated in three groups based on the age:
under 60, between 60 and 70, and above 70. The rates of positive surgical margin, lymph node
involvement, the invasion of seminal vesicle , patients Gleason score, and biochemical
recurrency were not significantly different among the three age groups. Biochemical recurrance
after 70 months of follow-up was 20% - similar to literature. Age above 70 years was not a factor
associated with biochemical recurrance.[4]

According to clinical studies and the literature, a biochemical reccurance after radical
prostatectomy it’s not equal to clinic failure and metastases. Almost 24% to 34% of men on
which the PSA serum was >0,2 after the surgery will develop metastatic disease up to 15 years
after the surgery.[5,6], There are severel indicators that can highlight the patients most of risk of
developing metastasis like: positive surgical margins is more likely to be a result of local recur-
rence, if the recurrence apeares in less than 6 months ofter surgery, there is a high probability of
methastasis. The patiens at most risk of developing metastases are those with a short PSA
doubling time, seminal vesical invasion, a high Gleason score between 8 and 10, and
biochemical recurrance under 3 years from the prostatectomy.

If biochemical recurrance is detected on a patient with radical prostatectomy, the logical

step to follow is to determine if the recurrance is represented by local recurrance or metastatic
disease, or in some cases, both, in order to determine the right treatment course. In order to do
so, a bone scan and abdominopelvic CT, must be performed. All these imagistic metodes rarely
detect metastases in asymptomatic patients. The probability of a positive bone scan in men with
biochemical relapse after RP is under 5% if the PSA level is under 7 ng/mL[7,8].

Salvage treatement for biochemical recurrence

There are severel therapies options that can be applied on patients with biochemica
recurrance after radical prostatectomy. One of them is radiotherapy on pelvic area. Radiotherapy
can be used in men with positive margins and/or pT3 disease that present a greater than 50%
risk of failure 10 years after radical prostatectomy.[9] In a Cochrane study on 3 randomised
controlled trials on a batch of 1,815 patients with high-risk features found at the time of surgery
like seminal vesicle invasion or capsular invasion, radiotherapy improved biochemical
progression-free survival compared with only the surgery itself alone at 5 and 10 years.[10]

Other type of salvage therapy after radical prostatectomy with biochemical recurrance is
androgen deprivation therapy (ADT) , although data supporting this use is generally obtained
from retrospective studies. [11] Not all patients with biochemical recurrance can benefit from
ADT, the best effect observed was on patients with high-risk, long life expectancy, and the
patient who refused the idea of radiotherapy. After multiple studies that researched if there is an
optimal timing regarding the beginning of ADT early in the detection of biochemical recurrance
vs late (>2 years), it turned out that there is no difference regarding the two moments of choice in
the beginning of the ADT.[12]

The use of brachytherapy in case of biochemical recurrence after prostatectomy and

salvage radiotherapy has limited indications and low results, as the total dose that can be used is
low. There are some selected cases with good results regarding using high doses of
brachytherapy within an acceptable toxicity range.

Discusions
The management of biochemical recurrance after radical prostatectomy is complicated
because of the many variables that must be taken into consideration. All the evidence regarding
the prognosis of patients with biochemical recurrance at more than 5 years after RP is
insufficient. A study performed by Loeb and Caire showed that patients that present biochemical
recurrance after 5 years from radical prostatectomy are less likely to present local or remote
metastasis, than patients with biochemical recurrance under 5 years.[13] Also, other studies
showed that there is no direct link between the time of appearance of biochemical recurrency
with the risk of systemic progression or cancer-specific mortality. It is known that a high value
of PSA prior to surgery, a positive surgical margin, pathological stage and other factors are
predictors of biochemical recurrency. In all the patients in whom biochemical recurrance
occurred under 5 years after radical prostatectomy, a positive surgical margin, a high Gleason
score or high pathological stage are good predictions factors of the recurrency, but the value of
preoperative PSA is not.[14]

Studies showed that in patients with a positive surgical margin, the tumor grade at the
site of the positive margin has prognostic value and that the Gleason score of the radical
prostatectomy specimen is associated with PSA velocity.

Prostate cancer is a disease that generaly affects older men, over 60 years old, and there
is an estimated increasing trend in its incidence in the upcoming years. How age affects the
apparition of prostate cancer is yet to be known, but androgen hormones are known factors in the
apparition of this desease. Age can also facilitate both carcinogenesis and the evolution and
progression of cancer cells by producing various inflammatory mediators, such as interleukin-6,
interleukin-10, and tumor necrosis factor.[15]

Conclusions
Radical prostatectomy is the definitive treatment option for clinically localized prostate
cancer. It is known that positive surgical margins, the presence of invaded lymph nodes, a high
value of the PSA and the Gleason score are risk factors regarding the appearance of biochemical
recurrence, and prostate cancer mortality. Even if there are many definitions of biochemical
recurrence after radical prostatectomy, the PSA value ≥0.2ng/dL is the most used one. There are
some salvage treatement options in patients who develop biochemical recurrace like radiotherapy
and androgen deprivation therapy with good results.
 REFERENCES

1. Bell, K.J., et al. Prevalence of incidental prostate cancer: A systematic review of

autopsy studies. Int J Cancer, 2015. 137: 1749

2. Rosenbaum E, Partin A, Eisenberger MA. Biochemical relapse after primary treatment

for prostate cancer: studies on natural history and therapeutic considerations. J Natl Compr Canc
Netw 2004;2:249–56.

3. Jean-Baptiste Beauval, Mathieu Roumiguié, Thomas Filleron, Thibaut Benoit,

Alexandre de la Taille, Bernard Malavaud, Laurent Salomon, Michel Soulié and Guillaume
Ploussard- Biochemical recurrence-free survival and pathological outcomes after radical
prostatectomy for high-risk prostate cancer Beauval et al. BMC Urology (2016) 16:26 DOI
10.1186/s12894-016-0146-6

4. Cuneyt Ozden, Binhan Kagan Aktas, Suleyman Bulut, Guven Erbay, Suleyman Tagci,
Cevdet S. Gokkaya, Mehmet M. Baykam, Ali Memis - Effect of age on biochemical recurrence
after radical prostatectomy Kaohsiung Journal of Medical Sciences (2017) 33, 91e95

5. Pound CR, Partin AW, Eisenberger MA, Chan DW, Pearson JD, Walsh PC: Natural
history of progression after PSA elevation following radical prostatectomy. JAMA 1999; 281:
1591–1597.

6. Boorjian SA, Thompson RH, Tollefson MK, Rangel LJ, Bergstralh EJ, Blute ML,
Karnes RJ: Long-term risk of clinical progression after biochemical recurrence following radical
prostatectomy: the impact of time from surgery to recurrence. Eur Urol 2011; 59: 893– 899.

7. Gomez P, Manoharan M, Kim SS, Soloway MS: Radionuclide bone scintigraphy in pa-
tients with biochemical recurrence after radical prostatectomy: when is it indicated? BJU Int
2004; 94: 299–302.

8. Beresford MJ, Gillatt D, Benson RJ, Ajithkumar T: A systematic review of the role of
imaging before salvage radiotherapy for post-prostatectomy biochemical recurrence. Clin Oncol
2010; 22: 46–55.

9. Karakiewicz PI, Eastham JA, Graefen M, Cagiannos I, Stricker PD, Klein E, Cangiano
T, Schroder FH, Scardino PT, Kattan MW: Prognostic impact of positive surgical margins in
surgically treated prostate cancer: multi-institutional assessment of 5831 patients. Urology 2005;
66: 1245–1250.
 10. Daly T, Hickey BE, Lehman M, Francis DP, See AM: Adjuvant radiotherapy
following radical prostatectomy for prostate cancer. Cochrane Database Syst Rev 2011;
12:CD007234.

11. Mottet N, Bellmunt J, Briers E, Bolla M, Cornford P, De Santis M, Henry A, Joniau

S, Lam T, Mason MD, Matveev V, Van der Poel H, Van der Kwast TH, Rouvière O, Wiegel T:
EAU – ESTRO – SIOG Guidelines on Prostate Cancer, EAU – ESTRO – SIOG, 2016

12. Garcia-Albeniz X, Chan JM, Paciorek A, Logan RW, Kenfield SA, Cooperberg MR,
Carroll PR, Hernán MA: Immediate versus deferred initiation of androgen deprivation therapy in
prostate cancer patients with PSA-only relapse. An observational follow-up study. Eur J Cancer
2015; 51: 817–824.

13. Loeb ,Feng Z Ross A, Trock BJ, Humphreys EB, Walsh PC- Can we stop prostate
specific atigen testing 10 years after radical prostatectomy. J Urol 2011; 186:500–5

14. Ahove DA, Hoffman K E, Hu JC, Choueiri TK, D'Amico AV, Nguyen PL- Which
patients with undetectable PSA levels 5 years after radical prostatectomy are still at risk of
recurrence? Implications for a risk-adapted follow-up strategy. Urology 2010; 76:1201–5.

15. Vasto S, Carruba G, Lio D, Colonna-Romano G, Di Bona D, Candore G, et al.

Inflammation, ageing and cancer. Mech Ageing Dev 2009;130:40e5