Prostate cancer is becoming the most important male cancer in Europę. About
1 out of 11 males will develop a Clinically significant prostate canccer during his lifespan. A localized prostate cancer is perfectly curable and therefore screening for prostate cancer is probably the only way to detect these patients with prostate cancer in an early curable stage before symptoms occur.
With better screening and earlier detection programs more and more patients are
found in early stages although still an important number consults the urologist with localy adwanced disease. At our Institute we detected 251 new prostate cancers in 1993. In the entire Belgian population (10 million inhabitants) about 2,000 new prostate cancers are detected per year. While in the late seventies about 80% of the prostate cancers were in our department detected in locally advanced or metastatic stage, we actually detect 60% of the patients with localized disease (T1T2) in the 1993 population. Still 16% were Clinically T3 and 24% proved to have metastatic disease at the time of diagnosis.
Radical prostatectomy has become standard treatment for T1T2 tumors but the
optimal treatment for the clinical T3 prostate cancers has always been and is still controversial.
The problem of the treatment of the pathological T3 (pT3) prostate cancer
patient is even more controversial. The problem of pT3 is very relevant because in a recent series of 200 radical prostatectomy patients, Clinically T2 in 70% and T3 in 17% we found 51% being pT2 but 43% being pT3 (Table I). This means that nearly one half of the patients who underwent radical prostatectomy in our department were pathologically T3.
Although some Urologists felt that radical prostatectomy was unable to bring
cure in stage T3 prostate cancer and that its role was therefore limited to palliation (1), others found that radical prostatectomy remained a treatment option for T3 prostatic cancer when the poor prognosis patients were excluded (2). This means that the controversy remains complete.
Following the TNM classification of 1992 T3 prostate cancer means the
presence of a tumor which extends through the prostate capsule. This extracapsular octension is unilateral for T3a, is bilateral for T3b while seminal vesicle involvemant is designated as T3c (3).
Although this classification is very helpful in an attempt to compare treatment
results in different centers, difficulties arise when this TNM classification is used in pathological staging. It is well known that many prostate cancers are multifocal and it is therefore maybe not very relevant to make a distinction between uni- or bilateral tumors. In no way the TNM classification specifies whether the extracapsular extension is focal, minimal or extensive. It is also impossible to consider extracapsular extension in sites where the prostate capsule is known to be imcomplete, for instance at the level of the prostate apex, at the level of the bladder neck and at the anterior commissure. So tumor extension at this level can not be considered as extracapsular extension because at these sites the capsule is absent. Finally the TNM classification does not consider positive resection margins. The latter can occur because of extracapsular extension (which is then surely a pT3 prostate cancer) but positive margins can also occur in T2 tumors where the surgeon inadvertently performs an intracapsular dissection (tumor transection). It is clear that a positive margin in a pT2 tumor has not the same outcome as a positive margin in a pT3 tumor.
HOW TO TREAT A T3 PROSTATE CANCER?
The clinical staging of locally confined or locally advanced prostate cancer is not
reliable. Most obvious is the very fre±uent underestimation of clinical T2 tumors that proved to be pT3 when the specimen is pathologically examined. More than 70% of Clinically T2 tumors are pT3. On the other hand, one should not forget that Clinically T3 tumors are sometimes overestimated and about 20 % of the clinical T3 cancers were shown to be pT2 (4). The use of transrectal ultrasound, CT-scan and nuclear magnetic resonance imaging was shown not to be very helpful in improving the accuracy in identifying extracapsular extension. The sensitivity of transrectal ultrasound and MRI was only about 50% while the negative predictive value was shown to be between 40 and 50% for these different examinations (5).
Therefore, one could try to recognize extracapsular extension before treatment.
Staging biopsies of the seminal vesicles, the trapezoid area, the neurovascular bundles
as well as a biopsy taken tangentially to the lesion all can indicate that the patient has a pT3 tumor when these biopsies are positive. The implications of such an assisted clinical staging of prostate cancer are only obvious for those who should not offer the patient a curative treatment when the diagnosis of extracapsular extension is known on the beforehand. It doesn’t matter however to the urologist who operates preoperatively diagnosed pT3 prostate cancer. Therefore the only interest of an assisted clinical staging could be the assessment of the efficacy of hormonal treatment before radical prostatectomy where one could show that a real downstaging would occur i.e. that when extracapsular tumor was found before treatment, it disappeared on the definitive radical prostatectomy specimen after neo-adjuvant hormonal treatment.
Still a lot of centers will propose radiotherapy to patients with a clinical T3
prostate cancer. As for surgery, the ideał indications for radiotherapy are smali sized locally confined prostate cancers and also the radiotherapists are not enthusiastic to embark on irradiation for a bulky prostate tumor. One could also propose hormonotherapy alone. Nevertheless sometimes a clinical T3 tumor was shown to be pathologically T2. In these cases the overestimation and treatment by hormones alone would exclude a group of patients who could be cured by radical prostatectomy. Some authors proposed radical prostatectomy alone for clinical T3 prostate cancer, first because cure can be obtained in a smali percentage. Others will defend radical prostatectomy alone in these cases in order to prevent later local comp- lications.
Because of the problems with either radiotherapy, hormonotherapy or radical
prostatectomy alone it was obvious that Combination treatment came up. Androgen Suppression before and during radiation therapy showed a significant improvement of the disease-free survival (6). Another Combination is explored within the EORTC (protocol 22911) where after radical prostatectomy patients are randomized for no further treatment or for 60 Gy radiotherapy in case of extracapsular extension, positive margin or seminal vesicle involvement. Concerning the preoperatively diagnosed pT3 prostate cancer but also the clinical T2b and T3 prostate cancers neo-adjuvant hormonal treatment has recently gained renewed interest. Several presentations on international meetings suggested that there was not only a downsizing of the prostate gland but also a downstaging, even tumor disappearance, and downgrading. Others found that the radical prostatec- tomy became easier, there was less hemorrhage and the results as concerned to continence were better.
We have been studying the idea of neo-adjuvant hormonal treatment since 1990
and a first report was published in 1992. With respect to the difficulty of the surgery, the perioperative hemorrhage and complications we found no difference in patients who underwent neo-adjuvant hormonal treatment or who had radical prostatectomy alone (7). With respect to eventual downgrading we felt that this is very difficult to assess. The Gleason grade is very difficult to estimate in a prostate that was pretreated with hormones. It is moreover useless to compare the grade of a prostate puncrure biopsy and the definitive grade found on pathological examination of the specimen since the prostate puncture biopsy can be misleading due to a sanpling error. Concerning an eventual downstaging we believe that this can not be assessed by digjtal rectal examination or ultrasound. Indeed, digital rectal examination underes- timates 70% of the tumors in a non-pretreated prostate cancer population and it is obvious that this also occurs after hormonal treatment. Also assessment by ultrasound before and after hormonal treatment is not reliable: hormonal treatment indeed makes that die entire peripheral zone becomes hypo-echoic and this makes the recognition of the tumor.or extent mostly impossible. Therefore, we can hardly believc reports that mention that a Clinically T3 tumor becomes T2 after hormonal treatment because there is no reliable examination to assess this evolution. Also the tumor diasppearance that was described (8) should be confirmed by a pathologist who is aware of the fact that the pathological changes induced by hormonal treatment can be very confusing.
Lymphocytic infiltration and pycnosis are very difficult to distinguish and only
application of basal membrane stainings and the staining of cytokeratins can definitively show whether the tumor is still present or not.
Therefore the only way to assess the effect of neo-adjuvant hormonal treatment
could be done in I randomized trial where the results in the 2 groups of patients are compared concerning the number of pT3 tumors and the number of positive margins.
We performed such a multicenter randomized study within the Belgian Uro-
Oncological Study Group where 230 patients with T2b or c and T3 prostate cancers were randomized. The first 127 patients were analyzed as concerning pathological stage and margins, one arm receiving immediate radical prostatectomy and the other nm receiving 6 weeks of Estramustine Phosphate followed by radical prostatectomy. This study showed that clinical T2 tumors were much less pT3 when they received neo-adjuvant treatment and that significantly less positive margins were found. No benefit however of neo-adjuvant hormonotherapy was shown for clinical T3 tumors.
Finally, one should notę that also for the T2 tumors, where neo-adjuvant hormonal
Treatment could be useful this still has to be confirmend in the final parameters of the study being diseasefree survival (9).
Although the attitude towards a clinical T3 prostate cancer is very different in
die different leading centers, there is certainly a trend towards agressive treatment of these patients. This is induced by the very low morbidity of radical prostatectomy and we are now initiating a new study where clinical T3 prostate cancers will be treated by upfront hormonal treatment, radical prostatectomy and postoperative radiotherapy with continued hormonal treatment.
HOW TO TREAT PATHOLOGICAL pT3 PROSTATE CANCER AFTER RADICAL
As was shown earlier the urologist who operates locally advanced prostate cancer
will end up with a pT3 in about 70% of the cases either because the tumor shows extracapsular extension uni- or bilaterally or because of seminal vesicle involvement.
In this group of patients about 30% will also have nodal involvement and once this
occurs adjuyant local treatment seems illogical. Also when seminal vesicle invol- vement is present many authors believe that adjuyant local treatment is not very helpful since the disease is mostly metastatic. This makes that a pathological pT3 prostate cancer is not comparable to another pT3 prostate cancer and maybe different categories deserve different trearments.
The choice for the treatment is between no adjuyant treatment, adjuyant
hormonotherapy, adjuyant radiotherapy or a Combination. No randomized studies are actually ayailable enabling to delineate precisely what the best treatment is. Maybe the EORTC study number 22911 can give a partial answer to this ±uestion. Maybe stratification in different subcategories of pT3 is necessary in upcoming new trials in order to ever prove the advantage of one treatment modality over another. Indeed, extracapsular extension following the TNM classification can be pT3a or b meaning that this extracapsular extension is uni- or bilateral. This extracapsular extension however can be focal, minimal with just a few malignant glandular structures outside the prostate capsule or can be extensive with gross involvement of the neurovascular bundle. On the other hand, the pT3c prostate cancer, indicating the involvement of the seminal vesicle, is prognostically completely different when the seminal vesicle itself or the adipose tissue surrounding the seminal vesicle is invaded. Even when a tumor is pT3a, b or c the tumor can be specimen confined with negative resection margins or positive margins can be found. The distinction can optimally be made by all whole mount step sections of the prostate that was inked immediately after removal. An experienced pathologist will indicate whether the positive margins are dubious, focal, minimal or massive and whether this positive margin is due to the extracapsular extension itself or to inadvertent intracapsular dissection meaning the surgical transection of a pT2 tumor. Probably all those different subcategories are not comparable when an eventual adjuyant treatment has to be considered.
Also the postoperative PSA can make different subcategories in the pT3 patients.
Some of them will have their PSA undetectable while others have a low PSA and
some still a high PSA. The PSA level can be an indication of local tumor persistence (that should then be confirmed by the finding of positive margins) or of systemic disease.
Finally, probably the most important prognosticator, the Gleason score, can only
be properly evaluated on the definitive pathological examination of the resected specimen. Prostate tumors with a Gleason score of 8 or more will do very poorly whatever adjuyant treatment is chosen.
A clinical T3 and a pathological pT3 prostate cancer can mean so many different
tumors that not one single approach can actually be proposed. In daily urological practice therefore, the treatment should be individualized taking the different
Prognostic factors into account.
On the other hand, it is clear that the optimal treatment for T3 pT3 prostate
cancer is much more controversial than that for T1T2. Only well designed randomized studies performed in centers with sufficient surgical skill and radiation expertise, on properly selected patients, stratified following the mentioned risk factors for progression, will be able to elucidate the problem of the choice of an ideal treatment of T3pT3 prostate cancer.