MANAGEMENT OF EARLY PROSTATE CANCER

1. MANAGEMENT OF EARLY PROSTATE CANCER BY: EHAB ESMAT FAWZY M.D. ONCOLOGY FACULTY OF MEDICINE CAIRO UNIVRSITY

2. INTRODUCTION • Prostate cancer represents 4.9% of all cancer incidences , and its average incidence all over the world is about 3.4 /100000 population. • It ranks 9th among all cancers all over the world. • The median age of patients with prostate cancer is 72 years . • North America and Europe represent the highest regions of prostate cancer incidence all over the world with almost 189,000 newly diagnosed cases and 30200 mortality for the year 2002 in USA (Cancer statistics 2002).

3. DIAGNOSIS • Early ( preclinical diagnosis) : This represented the basis of screening program for early detection of prostate cancer ; and it consists of 3 modalities: 1- Digital rectal examination (DRE) : it is subjected to personal clinical experience ,so it is less sensitive than other modalities (Thompson et al 1984); however , it is required as many cases of prostate cancer are not PSA ( prostate specific antigen) positive (Lodding et al 1998).

4. DIAGNOSIS 2- Serum level of PSA it is both sensitive and specific ( it has a positive predictive value [PPV] of 20% -30% for PSA 4-8 ng/ml and PPV of 42-71.4% for PSA > 10ng/ml) (Brawer et al 1999).So it had been used for screening of prostate cancer

5. DIAGNOSIS 3- Transrectal ultrasound (TRUS) +/- biopsy : *Indications for biopsy: • Palpable mass on DRE. • Elevated PSA. • Both high PSA & palpable mass.

6. DIAGNOSIS • Pathology : - Location : Majority (75%) in peripheral zone , 15% in the central zone , and 10-15 % in the periurethral zone.

7. DIAGNOSIS - Grade : the most commonly adopted system is the Gleason score (based on the fact that prostate cancer is a multifocal disease with heterogeneous glandular pattern ), patients with a score 2-4 represent well differentiated cancers , 5-7 moderately differentiated , and 8-10 poorly differentiated ( Gleason , 1992).

8. Diagnosis • Radiology : • TRUS : Is the earliest modality , and helps for doing biopsy from suspicious lesions , for screening purposes and target volume determination for prostate brachytherapy . Improvement in resolution power improved its sensitivity a lot ( like the use of contrast ultrasonography ( Sedelaar 1999) , and Gleason et al (2003). .

9. DIAGNOSIS • Bone scan is indicated if there is a high risk factors (PSA > 10ng/ml ; Gleason score > 8 ), or if the patient is symptomatic ( Scherr et al 2003). • Pelvic CT scan and MRI are essential for local staging and localization of prostate lesions and targeting for conformal external beam radiation therapy or brachytherapy ( Berthelet et al 2003).

10. DIAGNOSIS • Preoperative CT scan of the prostate is recommended to draw the planning target volume( PTV) if post operative radiation therapy is indicated as shown by Hocht et al ( 2002) who showed in their study that almost 93% of patients who had postoperative PTV without looking to their preoperative CT scans required an increase in their PTV to cover the tumor properly.

11. DIAGNOSIS • MRI had a great addition to CT scan for initial staging , and target localization for radiation therapy ( Mah et al 2002).

12. DIAGNOSIS • Radioisotopes can be used for imaging and staging of prostate carcinoma , as shown by Feneley et al (2000) , who used immunoscintigraphy with radiolabelled antibody to prostatic- specific membrane antigen (PSMA) ; the radioactive material was Indium-111. The high sensitivity was shown as they noted that 36 patients of the whole study group(49) who were classified before as having localized cancer , 7 of them (19%) had radiotracer uptake in regional and distant lymph nodes.

13. DIAGNOSIS • Risk group stratification: A lot of prognostic factors affect the biological behavior of prostate cancer and its response to different treatment modalities ; so depending on TNM staging system to treat those patients may lead to under treatment of some patients ( eg T1/ T2 lesions with PSA > 20 ng/ml or with a Gleason score of 8 or more) , so the National Comprehensive Cancer Network( NCCN) has recently adopted a reasonable risk stratification for prostate cancer( Scherr et al 2003)

14. NCCN RISK STRATIFICATION • Low risk: T1-T2a , and Gleason score 2-6 , and PSA < 10 ng/ml( allthe criteria should be present). • Intermediate risk: T2b-T2c,or Gleason score 7 or PSA 10-20 ng/ml. • High risk :T1/T2, Gleason score 8-10 , or , PSA > 20ng/ml.

15. Treatment options for prostate cancer • Observation alone. • Radical prostatectomy. • Radiation therapy. • Hormonal treatment.

16. OBSERVATION ALONE • Rationale: • Most cases will not die of their disease. • A life expectancy of every patient should be taken into consideration trying to avoid the treatment related complications for those with relatively limited expected survival. • Patients are not left for just observation ; but a close monitoring of disease progression is done. • Patient preference should be considered.

17. OBSERVATION ALONE • WHICH PATIENTS BENEFIT FROM OBSERVATION ALONE? - Choo et al (2001) suggested that those patients with T1-T2 , and age 70 years or more , and , Gleason score <6, and , PSA < 10 ng/ml , and PSA doubling time > 10years are more suitable for observation alone.

18. OBSERVATION ALONE • Follow up regimen : - Scherr et al (2003) recommended to have a six monthly assessment of : • PSA • DRE -Repeat prostate biopsy after the 1st year ( to detect transformation to higher grades.

19. OBSERVATION ALONE Signs of disease progression on observation modality: - Rise in PSA level. - Clinical symptoms of disease progression. -Increase in size as felt by DRE. -Biologic transformation to higher grades.

20. OBSERVATION ALONE • Survival figures : Aldolfssen et al (2000) reviewed the survival of 11, 500 cases of early prostate cancer treated with watchful waiting between 1965 – 1993 , had found that only 5 % of these patients died , and this happened during the years 11-20 of follow up.

21. RADIACAL PROSTATECTOMY • Indications: • Organ confined prostate cancer ie T1 or T2 , pelvic lymph node dissection is indicated for any one of these features : -Either : PSA >20 ng/ml. + Gleason score 5-6. Or- PSA 15 –20ng/ml + Gleason score >7. (Bishoff et al 1995).

22. RADIACAL PROSTATECTOMY • Types: • Radical retropubic prostatectomy(RRP). • Radical Perineal prostatectomy(RPP). • Radical Laparoscopic prostatectomy(RLP)

23. RADICAL PROSTATECTOMYPROS & CONS • RP had the same overall and disease free survival figures as the other local control modalities ( 3D-CRT , IMRT , and brachytherapy ) however the sequelae are more with surgery ( higher incidence of urinary incontinence , impotence ) .

24. EXTERNAL BEAM RTI-conventional external beam radiation therapy(CEBRT) • Main problem: dose limitation usually radiation dose does not exceed 70GY in CEBRT ( dose limiting structures ; rectum and urinary bladder) and for early T1 / T2 lesions , the results of CEBRT are much inferior than 3D-CRT as shown by Cattonet al (2002) .

25. 3D-CRT • Three dimensional conformal radiation therapy(3DCRT) has a better localization of the target volume and less radiation dose to critical organs,as compared to CEBRT Ghilezan et al (2001) .

28. ROLE OF PORT • Patients with high PSA , positive surgical margins , after RRP will benefit from adjuvant PORT in the form of better DFS and this is confirmed by Do LV etal (2002).

29. HYPOFRACTIONATION/EBRT • The use of higher radiation dose per fraction ( hypo fractionation) had been studied by many oncologists as Yeoh et al (2003) who found that , biochemical relapse-free survival rate was did not differ significantly between the CEBRT and hypofractionation schedule as well the toxicity profile.

30. Intensity modulated radiation therapy (IMRT): • A major advantage of IMRT in comparison to three-dimensional conformal radiotherapy is the higher capability in providing dose distributions that conform very tightly to the target even for very complex shapes so sparing a lot of adjacent normal tissues( Francescon et al 2003)

32. NEUTRON BEAM THERAPY • Lindsley et al (1996) in a prospective randomized study comparing the CEBRT and neutron beam therapy in localized prostate cancer , found a significant reduction in the number of 5 years local failures (11%) as compared to that of CEBRT ( 32%) ,, however the 5 years survival rate was not statistically different between the two study groups , and the toxicity profile of neutron beam therapy was acceptable .

33. STEREOTACTIC RADIOTHERAPY • There are no mature data on the results of stereotactic radiotherapy in prostate cancer ; however , methods for its optimization for treatment of early cases of prostate cancer are going on ; Herfarth(2000).

34. BRACHYTHERAPY • The basic principle of the use of interstitial brachytherapy in prostate carcinoma is the inverse square law which entails the fact that the deposition of radiation energy in tissues decreases exponentially as a square function of the distance from the radiation source , ( Blasko et al 1991)

39. A) 3D reconstruction of the implant with dose distribution, (B) 3D reconstruction, lateral view with dose distribution, and (C) 3D reconstruction, AP view with dose distribution.

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42. SEQUELAE OF DIFFERENT TREATMENT MODALITIES

43. CRYOTHERAPY • Mack ET AL(1997) had a study on the open perineal cryotherapy for 66 prostate cancer patients ( early stge ) .The mean survival was 7.2 years. The mean follow-up period of survivors (38 patients) is 8.5 years. Complications were: stress-incontinence in 10%, impotence in 10% and temporary rectoperineal fistula in 8% . Donnelly etal (2002) reported 89% 5 year overall survival rate , and 98% disease free survival rate after cryotherapy for early prostate cancer.

45. NEOADJUVANT HORMONAL TREATMENT • Wachter et al(2002) in a study on 164 patients with early prostate carcinoma were randomized to either a total dose of 66 Gy (n = 109) alone or in combination with a short-term hormonal treatment (n = 55) . The 4-year rates of no biochemical evidence of disease for all patients was 58%.

46. NEOADJUVANT HORMONAL TREATMENT • For the high-risk group the 4-year rates could be improved with borderline significance from 35% to 66% (p = 0.057) by additional neoadjuvant hormonal treatment. In contrast for the low-risk group no significant improvement was observed: 73% and 82%, respectively (p = 0.5).