1. GENERAL INFORMATION
1.1.1 Incidence and mortality
Carcinoma of the prostate is the most frequent cancer among men in Northern and Western Europe. About 190,000 new cases occur each year (15% of all cancers in men) (Ferlay 2001). In Europe, the annual incidence rates (ASW) in 2000 ranged between 19 (Eastern Europe) and 55 (Western Europe) per 100,000. In most European countries, the incidence has increased more than any other cancer over the past two decades (Hsing 2000); it has been increasing by about 10% every five years in Europe (more in Sweden and France), as in many developed countries. Mortality has not been increasing quite as quickly. In Europe, there are about 80,000 deaths a year from prostate cancer (Ferlay 2001). In the USA, following large increases in prostate cancer incidence due to the introduction of PSA screening in the late 1980s, the incidence has been stable from 1995 through 1998, while death rates have continued to decline. Much of the geographic variation in prostate cancer incidence rates reflects differences in PSA screening (Feuer 1999; Howe 2001), with regions of high PSA screening penetration having higher incidence rates, often because of the discovery of clinically insignificant tumours. About 81% of patients with prostate cancer are over 65 years of age. Prostate cancer is rare under the age of 45 (0.4 per 100,000/year). In the age group 45-54 the incidence has been reported as 6 per 100,000/year and thereafter it increases to much higher rates (60 per 100,000/year for men aged 55-64 and 270 per 100,000/year for those older than 65 years of age) (Ferlay 2001). Most of the invasive prostate cancers are adenocarcinomas. Epidermoid carcinoma (primarily transitional cell carcinomas) and sarcomas are infrequent. The histological types of sarcomas are primarily rhabdomyosarcomas and leiomyosarcomas. Cases occurring in males younger than age 30 are invariably sarcomas (Gilliland 1995).
In Europe during the early 1990s (Berrino 2003) the relative survival rate at 5 years after diagnosis of prostate cancer was 67%. Survival increased slightly with age from 59% in the youngest (<55 years) to 70% in the older age group of patients (65-74 years), then fell to 52% for the oldest group of 85 years old or more. During the period 1983-94 5-year survival significantly increased from 52% to 67%. Increased survival with time was observed in most countries (Sant 2003). There are major between-country differences in survival for European patients with prostate cancer: some countries such as Poland, Malta, Portugal and Denmark were characterised by low 5-year survival (less than 45%). In Austria, Germany, France and Ireland, 5-year survival was generally higher (more than 75%) (Berrino 2003). Comparison of prostate cancer survival in European populations should take account of the slow geographic and temporal spread of transurethral resection and PSA testing, which result in increases in the detection (incidence) of early good-prognosis prostate cancers (Sant 2003). European patients had significantly lower 5-year survival than U.S. patients for prostate cancer (56% vs. 81%). For this cancer the inclusion of small, or clinically silent, lesions identified by screening and preclinical diagnostic activity will boost overall survival in one area compared with an area where such activity is less widespread. The greater incidence of prostate cancer in the USA is likely to be influenced by such activity, with consequently higher survival rates in American patients (Gatta 2000). Five-year relative survival varies with stage at diagnosis, from 80% or more when malignancy is confined to the prostate to about 25% where bone metastases are present (Dickman 1999). An association between deprivation and survival has been found for cancer of the prostate (Coleman 1999). Survival has generally been 3-6% lower for men in deprived groups than for men in affluent groups. The survival data reported in this document are derived from information collected by population-based cancer registries. They provide the means by which we can measure progress against cancer.
In men, prostate cancer accounts for 12% of the total cancer prevalence (lung cancer is second) (Micheli 2002). The proportion of men with prostate cancer was 244 per 100,000. The 5-year prevalence, that is the number of living people with a diagnosis of prostate cancer made 5 or less years before the index date, was 153 per 100,000. The last figure demonstrates the need for clinical follow-up and treatment of recurrences. There were large differences between European countries in the prevalence of prostate cancer; estimates ranged from 44 in Poland to 575 per 100,000 in Sweden.
1.2 Aetiology and risk factors
The causes of prostate cancer are essentially unknown, although hormonal factors are involved, and diet may exert an indirect influence. The proportion of cases attributable to ionising radiation, occupational exposure to cadmium or possibly vasectomy, appears to be low. While prostate cancer is uncommon in Japanese in Japan, Japanese in Hawaii have prostate cancer rates intermediate between those in Japan and the high incidence seen among Hawaiian whites (Parkin 1997). These results, and other studies which show that the risk in migrant populations tends toward the prostate cancer risk pattern of their host country, strongly suggest that environmental factors contribute to the large differences in risk found between countries.
1.2.2. Risk factors
Epidemiological studies have suggested quite a lot of factors that could have a role in prostate cancer, but the evidence is fragmentary or inconsistent (e.g., history of benign prostatic hyperplasia, vasectomy, sexually transmitted infectious agents, sexual activity level, androgenic hormones, weight or obesity, cigarette smoking, alcohol and tea consumption, low intake of vitamin E, vitamin D, and selenium). One of the major environmental factors is diet. Among populations with higher overall meat intake, the majority of both cohort and case-controlled studies show an increased risk is associated with higher consumption. Diets high in vegetables are possibly protective, and regular consumption of fat, saturated/animal fat, red meat and milk and dairy products possibly increase risk. Current evidence suggests that the most effective dietary means of preventing prostate cancer, is consumption of a diet high in vegetables and low in fat, red meat, milk and diary products WCRF& AICR 1997). There seems to be a slightly increased risk of prostate cancer among farmers. It is plausible that certain pesticides or herbicides, acting as hormone modifiers, may influence prostate cancer risk, but this hypothesis remains speculative. Prostate cancer risks is increased among workers in metalworking operations and among workers exposed to polycyclic aromatic hydrocarbons (Parent 2001). A genetic contribution to the risk of prostate cancer is considered likely; for brothers of prostate cancer patients there is a two or three-fold increased risk of developing the disease (Monroe 1995; Whittemore 1995). Several genes involved in the metabolism of androgens in the prostate gland are polymorphic in humans (Coetzee 1994).
There are no conclusive data to confirm that early detection will decrease mortality for prostate cancer (Hsing 2000). Until randomised trials, now underway in the United States and Europe, can be completed, the efficacy of prostate-specific antigen (PSA) screening of asymptomatic men remains uncertain (Potosky 2001). Therefore, the benefits and risks of early detection of prostate cancer and the accompanying treatment methods should be thoroughly discussed with patients. The benefit is a more likely detection of early stage disease at diagnosis, when it is more likely to be curable. However, about 30% of men over the age of 50 have latent prostate cancers that are unlikely to produce symptoms or affect survival. Screening would preferentially identify these latent cancers (rather than aggressive disease). Consequently, these men would be subjected to unnecessary testing and treatment for prostate cancer. It has been estimated that two out of three men with abnormal results on routine PSA screening will not have a cancer. Before cancer can be excluded, one must undergo repeat PSA testing, ultrasonography, and biopsy with the attendant anxiety of waiting for results. Furthermore, a more serious concern is the potential complications of treatment (e.g., impotence, incontinence, urethral stricture, and death).
Referral of prostate cancer patients to specialized institutions is generally recommended. Inclusion in prospective trials can be discussed with those patients who meet the eligibility criteria, if the trials meet the following criteria: 1) population-based studies in order to augment knowledge about the natural history of this cancer or about screening; 2) trials investigating early treatment, and the benefits and costs. These studies should be developed and conducted on an international scale, under professional guidance and with the agreement of governmental ethical committees.
2. PATHOLOGY AND BIOLOGY
2.1 Biological data
About 70-75% of prostate cancers arise in the peripheral zone of the gland, mainly in a posterior location; of the remaining cases, 15% derive from the central zone and 10-15% from the transitional zone. A high-grade prostatic intraepithelial neoplasia (HGPIN) may be associated with or precede cancer in a high percentage of cases (Qian 1997).
2.1.2 Tumour Growth
Prostate adenocarcinoma may spread locally, by direct invasion of seminal vesicles, urinary bladder or surrounding tissues, or distantly. Distant metastases can derive from an initial lymphatic spread or from a direct haematogenous spreading, mainly to the bones (Cotran 1999).
2.1.3 Genetic Abnormalities
Some genes have been identified as potentially involved in hereditary prostate cancer (HPC). The first identified gene locus, named HPC-1 (hereditary prostate cancer locus-1), is located in the 1q 24-25 region, but other regions potentially involved in HPC have been identified (Smith 1996). Oncogenes, such as Myc, have been reported to be amplified and this is related to a worse prognosis (Sato 1999), while tumour suppressor genes such as p53, RB 1 or PTEN can be mutated or inactivated (McMenamin 1999). Modifications of tumour suppressor genes frequently correlate with higher Gleason grades and stages (Bookstein 2001). Other genetic changes can involve the apoptosis pathways, i.e. overexpression of FAS (fatty acid synthetase) and BCL-2, an antiapoptotic protein, and accumulation of p53 (Krajewska 1996).
2.2 Histological Types
2.2.1 Incidence of histological types
Almost all prostate cancers (95%) are adenocarcinomas. The remaining 5% of cases consist of squamous cell carcinoma, signet-ring carcinoma, transitional carcinoma, neuroendocrine carcinoma, or sarcoma (Cotran 1999).
2.2.2 ICD-O Classification ICD-O 2000)
Squamous cell carcinoma (8070/3)
Signet-ring carcinoma (8490/3)
Transitional cell carcinoma (8120/3)
Neuroendocrine carcinoma (8246/3)
Adenocarcinomas account for about 95% of prostate cancers. The tumour is characteristically multifocal and heterogeneous with small glands infiltrating larger, benign glands possibly with nuclear anaplasia, perineural and vascular-lymphatic invasion on the basis of the differentiation level (Mostofi 1992).
2.2.4 Squamous cell carcinoma
Squamous cell carcinomas (SCC) account for 0.5-1.0% of cases of prostate cancer. This tumour has to be distinguished from similar cases arising in the urethra. Histological and immunohistochemical characteristics (no glands, PSA negativity) differentiate prostate SCC from adenocarcinomas which initially show a similar clinical presentation.
2.2.5 Signet-ring carcinoma
Signet-ring carcinoma is a rare and very aggressive variety of prostate carcinoma. Typicallly, its histological appearance resembles the homonym tumour of the gastrointestinal tract.
2.2.6 Transitional Cell Carcinoma
Primary transitional cell carcinoma (TCC) of the prostate is rare and has to be distinguished from the more frequent condition of invasion of the prostate by primary bladder cancers. The prognosis and treatment are similar to those for bladder tumours.
2.2.7 Other different histological tumours
Other different tumours which are only rarely found in the prostate gland are neuroendocrine and endometriod carcinoma and sarcomas.
2.2.8 Tumour Grading
The Gleason system is the most widely used grading system for prostate cancer (adenocarcinoma only). Prostate cancers are stratified into 5 grades (1-5) on the basis of the glandular pattern and degree of differentiation. The Gleason Score is derived from the sum of the most represented grade (primary grade) with the second most represented grade (secondary grade) (e.g. 3+4=7); this correlates better with prognosis than the single Gleason grade. The Gleason system can be applied to biopsy and surgical specimens, but not to FNB (fine needle biopsy) which lack architectural data (Mostofi 1992).
2.3 Accuracy and reliability of pathological diagnosis
2.3.1 The pathology report on needle biopsy
The pathology report of a needle biopsy should include the number and site of positive cores and the measurement of the proportion of each biopsy core containing cancer; primary, secondary Gleason grades and Gleason score; eventual perineural invasion; eventual presence of PIN (prostate intraepithelial neoplasia). All these data relate to pathological stage, tumour volume, risk of positive margins and risk of relapse after eventual radical prostatectomy (Peller 1995; Bastacky 1993; Bostwick 1996).
2.3.2 The pathology report on radical prostatectomy
The pathology report following radical prostatectomy should include the extent of tumour involvement (one lobe or more), presence and site of eventual positive margins, presence of eventual extension through the capsule and/or involvement of seminal vesicles; presence of perineural invasion; number and site of resected lymph nodes with or without eventual metastases; primary, secondary Gleason grades and definitive Gleason score; expression of pathological stage (pTNM) (Epstein 2001).
3.1 Signs and symptoms
LUTS (low urinary tract symptoms) can be present in organ-confined tumors but are usually due to concomitant benign prostatic hyperplasia (BPH). Locally advanced disease, however, is more likely to have an increase in LUTS due both to BPH and carcinoma. In the case of metastatic prostate cancer patients may present with lumbar or pelvic pain as the predominant symptom.
3.1.2 Physical signs
A diagnosis of prostate cancer may be suspected from symptoms, a suspicious digital rectal examination (DRE) finding and/or an elevated serum prostate-specific antigen (PSA) value. A definitive diagnosis, however, demands the presence of a positive prostate biopsy. DRE can be utilized to detect (or eliminate) suspected tumors since the majority of cancers are located in the peripheral (posterior) zone. A minimal volume of 0.2 ml is requested for a possible diagnosis (15-40% of suspected cases at DRE) depending on the clinical experience of the examiner. If DRE is used to detect unsuspected CaP in asymptomatic men it will identify carcinoma in only 0.1-4% of those examined (Chodak 1989; Pedersen 1990).
3.2 Diagnostic strategy
Serum PSA, DRE and transrectal ultrasonography (TRUS) constitute the three major diagnostic means for the detection of cancer.
3.2.1 Laboratory markers
Determination of serum PSA has a relevant role in the diagnosis of CaP (Oesterling 1991). and assure a more accurate detection of cancer than a suspicious finding on DRE or TRUS. Elevated PSA levels, however, may also be the sign of benign disorders, such as BPH or prostatitis because of the organ and not cancer specificity of this protein (Catalona 1994; Elgamal 1996); further studies are needed to better define the threshold level associated with the highest risk for cancer (Brawer 1992; Catalona 1991). PSA positive predictive value (PSA PPV) is 25-35% for levels in the interval 4-10 ng/ml (Haas 1993), as the consequence of most patients having a benign disease although recent studies demonstrated a large number of organ-confined malignancies, and 50-80% for levels higher than 10 ng/ml (Catalona 1994). In the case of elevated PSA levels as the only evidence of a possible cancer, a prostate random biopsy can be performed (suggested cut-off level: 4 or 10 ng/ml) to detect non-palpable cancers (T1c) which comprise significant and not-significant tumors (Elgamal 1997). A significant risk of detecting clinically insignificant cancers with this procedure in patients with low PSA levels has to be rememberd. Numerous modifications have been suggested to improve both PSA specificity and early detection, particularly in the range 4-10ng/ml: PSA velocity (Carter 1992) and PSA doubling time (Schmid 1993); Age-specific reference ranges (Oesterling 1993a; Partin 1996); PSA density (Benson 1992; Wolff 1995) and PSA density of the transition zone (Zlotta 1997); PSA molecular forms (Catalona 1995). Anyone of these parameters, however, can be actually considered for routine application.
3.2.2 TRUS and biopsy technique
Even if some authors reported an increased (> 50%) detection rate of TRUS in respect to DRE, in the routine practice only few cancers are detected by TRUS in the presence of normal PSA levels and/or DRE findings (Gustafsson 1992; Mettlin 1996; Ellis 1994; Jones 1990). The adjunct of a Color Doppler technology has not yet been shown to improve detection rate or staging procedures (Oyen 1996; Patel 1994). Histopatological material for diagnosis is routinely obtained by ultrasound-guided transrectal or transperineal 18G core biopsies. Antibiotic prophylaxis and local anesthesia are generally required (Aus 1996; Collins 1993). Multiple systematic ultrasound-guided biopsies have to be performed to increase the detection rate in respect to digital- or ultrasound-guided biopsies of hypoechoic zones alone (Hodge 1989). Sextant biopsies (but the actual trend is toward 8-12 cores) are recommended (Aus 1997). A laterally directed technique, as standard procedure, has been suggested to include the posterolateral area of the peripheral zone where early cancer is typically detected (Stamey 1995). Biopsy has to be repeated in men with persistently elevated serum PSA and a negative initial biopsy (detection rate of about 20%) (Keetch 1994; Roehrborn 1996). The presence of high grade prostatic intraepithelial neoplasia (HG PIN) strongly suggest the concomitant presence of a cancer. As a consequence an immediate second biopsy is suggested (Haggman 1997 ; Zlotta 1996).
3.2.3. Detection rates: Relationship between DRE, PSA and TRUS
The detection rate in a screened population depends by the results of three major diagnostic tools: PSA, DRE and TRUS. Positive Predicting Value (PPV) for biopsy could range from about 20 to 80% depending on the number of positive findings and operator experience (DRE, TRUS): 5-25% in the case of 1/3 positive findings, 15-60% for 2/3 and 55-70% for 3/3 (Gerber 1991; Gustafsson 1992; Mettlin 1996).
4.1 Stage classification
Two systems are usually employed in the staging of prostate cancer: the “Jewett System” (stages A through D) introduced in 1975 (Jewett 1975) and a revised TNM System proposed by the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (UICC), which includes some subcategories in the same T categories of the Jewett System. The TNM system is more precise in stratifying newly diagnosed patients (UICC 2002).
4.1.1 TNM definitions
Primary tumour (T)
Tx: Primary tumour cannot be assessed
T0: No evidence of primary tumour
T1: Clinically inapparent tumour, not palpable or visible by imaging
T1a: Tumour incidental histologic finding in 5% or less of tissue resected
T1b: Tumour incidental histologic finding in more than 5% of tissue resected
T1c: Tumour identified by needle biopsy (e.g., because of elevated PSA)
T2: Tumour confined within prostate*
T2a: Tumour involves one-half of one lobe or less
T2b: Tumour involves morethan one-half of one lobe but not both lobes
T2c: Tumour involves both lobes
T3: Tumour extends through the prostatic capsule**
T3a: Extracapsular extension (unilateral or bilateral)
T3b: Tumour invades seminal vesicle(s)
T4: Tumour is fixed or invades adjacent structures other than seminal vesicles: bladder neck, external sphincter, rectum, levator muscles, and/or pelvic wall
*Note: Tumour found in 1 or both lobes by needle biopsy, but not palpable or reliably visible by imaging, is classified as T1c.
**Note: Invasion into the prostatic apex or into (but not beyond) the prostatic capsule is not classified as T3, but as T2.
pT2* Organ confined
pT2a Unilateral, involving one-half of one lobe or less
pT2b Unilateral, involving more than one-half of one lobe but not both lobes
pT2c Bilateral disease
pT3 Extraprostatic extension
pT3a Extraprostatic extension**
pT3b Seminal vesicle invasion
pT4 Invasion of bladder, rectum
*Note: There is no pathologic T1 classification
**Note: Positive surgical margin should be indicated by an R1 (residual microscopic disease)
Regional lymph nodes (N)
Regional lymph nodes are the nodes of the true pelvis, which essentially are the pelvic nodes below the bifurcation of the common iliac arteries. Laterality does not affect the N classification. Distant lymph nodes are outside the confines of the true pelvis and their involvement constitutes distant metastasis.
Nx: Regional lymph nodes cannot be assessed
N0: No regional lymph node metastasis
N1: Metastasis in regional lymph node or nodes
pNx Regional nodes not sampled
pN0 No positive regional nodes
pN1 Metastases in regional node(s)
Distant metastasis*** (M)
Mx: Distant metastasis cannot be assessed
M0: No distant metastasis
M1: Distant metastasis
M1a: Nonregional lymph node(s)
M1c: Other site(s) with or without bone disease
***Note: When more than 1 site of metastasis is present, the most advanced category is used. pM1c is most advanced
Histologic Grade (G)
Gx Grade cannot be assessed
G1 Well differentiated (slight anaplasia) (Gleason 2-4)
G2 Moderately differentiated (moderate anaplasia) (Gleason 5-6)
G3-4 Poorly differentiated/undifferentiated (marked anaplasia) (Gleason 7-10)
|Stage II||T1a||N0||M0||G2, 3-4|
|Stage III||T3||N0||M0||Any G|
|Stage IV||T4||N0||M0||Any G|
|Any T||N1||M0||Any G|
|Any T||Any N||M1||Any G|
4.1.2 The Jewett staging system
Stage A is clinically undetectable tumour confined to the prostate gland and is an incidental finding at prostatic surgery.
Substage A1: well-differentiated with focal involvement, usually left untreated
Substage A2: moderately or poorly differentiated or involves multiple foci in the gland
Stage B is tumour confined to the prostate gland
Substage B0: nonpalpable, PSA-detected
Substage B1: single nodule in 1 lobe of the prostate
Substage B2: more extensive involvement of 1 lobe or involvement of both lobes
Stage C is a tumour clinically localized to the periprostatic area but extending through the prostatic capsule; seminal vesicles may be involved.
Substage C1: clinical extracapsular extension
Substage C2: extracapsular tumour producing bladder outlet or ureteral obstruction
Stage D is metastatic disease
Substage D0: clinically localized disease (prostate only) but persistently elevated enzymatic serum acid phosphatase titers
Substage D1: regional lymph nodes only
Substage D2: distant lymph nodes, metastases to bone or visceral organs
Substage D3: D2 prostate cancer patients who relapsed after adequate endocrine therapy.
4.2 Staging procedures
Staging procedures of prostate cancer derive partly from the same tools that have led to the bioptic diagnosis of the disease (i.e. transrectal ultrasound and PSA) and partly from traditional imaging techniques such as chest-x-ray, abdomen CT or MRI and radionuclide bone scan, currently the most sensitive method for detection of bone metastases (McGregor 1978; O’Donoghue 1978). In case of single or uncertain findings, or scintigraphic result in contrast with other staging procedure evaluation of the relevant bone segment can be completed with CT or MRI using specific bone algorithms. Coline PET scan or PET-CT scan are not actually considered as a part of standard staging procedures. For lymph-node staging, CT scan and MRI present a moderate sensitivity, that varies between 0 and 70%, and can be recommended in patients with high risk of lymph node involvement. The downward stage migration caused by the introduction of PSA testing has resulted in a majority of cases being diagnosed in the early stages of the disease, where diagnostic accuracy of imaging methods might not be sufficient. Nonetheless, it is of great importance to establish a risk factor stratification, based on clinical staging, in order to provide the most appropriate therapeutic indication for each patient, especially in non-metastatic disease. Clinical, serological and pathological tools such as ER, PSA, Gleason score, number of positive cores, to mention some of the most widely used tools, all appear useful in the attempt to give a clearer configuration of the disease. The predictive value of these factors has led, beginning with Alan Partin’s studies in 1997 (Partin 1997), to the diffusion of combined systems of analysis of the predictive factors, gathered from retrospective evaluation of a large number of case studies. These integrated systems (based on PSA, primary and secondary Gleason grades, and rectal examination), are commonly used for effective decision-making in nonmetastatic prostate cancer therapy. Nomograms yield a range of probability that a disease in a certain clinical stage may be, at definitive pathological diagnosis, organ-confined or extracapsular, with eventual seminal vesicle or lymph node involvement. The information we can glean from nomograms, providing a prediction of the pathological stage, can be used also to predict patient’s overall survival (disease-free survival, clinical and biochemical recurrence-free survival). The increase in the number of variables used in nomograms and the diffusion of simple software programs www.nomograms.org) should make these tools more widely used in the near future.
5.1 Natural history
5.1.1 General consideration
Prostate cancer is characterized by an extremely high histological prevalence, and a relatively low mortality. The five-year observed survival of men with prostate cancer has increased steadily from 45% for men newly diagnosed in 1973 to 70% for men newly diagnosed in 1990, whereas the ten-year observed survival has increased by about 0.9 per year from 22% for men newly diagnosed in 1973 to 32% for men newly diagnosed in 1985. These data, however, derive from a substantial stage migration caused from an increased early diagnosis and relate to an actual majority of cases diagnosed with localized or locally-advanced disease. Relative survival of men with advanced disease remains poor.
Prostate cancer is often a slow growing tumour and predictive factors are needed in order to correctly characterize prognosis and to provide a tailored therapeutic indication for each patient.
5.2.1 Prognosis of localized diasease
The most accepted predictive factors for localized diasease are PSA, Gleason score, and clinical stage. Several nomograms have been constructed to integrate these data starting from the Johns Hopkins model (the Partin tables) (Partin 1993). Other authors (Kattan 1999) have produced prognostic factors from preoperative data, such as serum PSA level, preoperative prostate biopsy and clinical stage (Graefen 1999; Stamey 2000; Lerner 1996). Integration of these factors has made possible to define 3 risk classes characterized by a 5-year risk of biochemical recurrence after standard treatment 20 ng/ml, Gleason 8-10, T3a) (D’Amico 1998). Prognosis does not change significantly with therapy choices (surgery, EBRT, brachytherapy or W-W) in patients of the low-risk classes, especially in the case of a life expectancy < 10 yrs, because of a cancer-specific mortality in this class of about 7% (D’Amico 1998). Albertsen clearly demonstrated the importance of age, co-morbidities and tumour histology: men with a low Gleason Score (2-4) had only a 4-7% risk of dying from prostate cancer within 15 years from diagnosis and those treated conservatively incurred no loss of life expectancy compared to the general population (Albertsen 1998). Watchful waiting and brachytherapy remain viable therapeutic options in patients belonging to the medium-risk group, characterized by a the ten-year cancer-specific mortality of 24%, only in cases with a life expectancy of less than 10 years (Albertsen 1995), while in high and very high risk patients only integrated therapeutic approaches, makes possible to obtain a rates of biochemical progression free survival of about 65% (Zelefsky 1998). In patients who undergo surgery, the possibility of a pathological staging can provide a considerable advantage in terms of prognostic precision, especially in locally advanced stages, where integrated approaches with adjuvant therapies can yield significant advantages.
5.2.2 Prognosis of metastatic disease
Patients with metastatic disease were considered at very high risk by the NCCN which added a fourth class for these cases www.nccn.org). Hormonal therapy is the mainstay of treatment for metastatic (stage D2) disease. Cure is rare, if ever possible, but striking subjective or objective responses to treatment occur in the majority of patients. Median time to clinical progression of patients with metastatic disease was about 1.5 years, with a median survival of 2.5-3 years (Robinson 1995). In patients who receive hormone therapy pre-treatment PSA levels and reduction of PSA to undetectable levels provide information regarding the duration of progression-free status (Matzkin 1992). Yet, because PSA expression itself is under hormonal control, androgen deprivation therapy can decrease the PSA serum level independently of tumour response. Therefore, clinicians cannot rely solely on serum PSA level to monitor a patient’s response to hormone therapy (Ruckle 1994).
6.1 Treatment Strategy
6.1.1 General Considerations
Treatment strategy is defined according to initial PSA, stage and grade of the disease and to the age and general conditions of the patient. Watchful Waiting (WW), surgery and radiotherapy (with or without hormone-therapy) could be appropriate choices for patients with localized disease, while hormone-therapy plus radiotherapy should be considered treatment of choice for locally advanced or bulky disease. In cases of advanced disease, ablative hormone-therapy remains the mainstay of treatment while chemotherapy has to be evaluated in patients with hormone-refractory prostate cancer (HRPC).
6.2 Localized disease T1-T2, Nx-0, M0
6.2.1 Watchful Waiting (WW)
Watchful Waiting is indicated as primary option for patients with well or moderately differentiated clinically localized tumours and a life expectancy of less than 10 years (15 years in patients with T1a tumours). Other possible indications for WW are locally advanced well or moderately differentiated disease and metastatic asymptomatic disease. A close follow up, with biochemical (PSA) and clinical examination, is strongly recommended to ensure the early beginning of an appropriate treatment when needed (Chodak 1994; Steinberg 1998; Holmberg 2002).
6.2.2 Surgical treatment
Radical prostatectomy (characterized by the removal of the entire prostate gland with seminal vesicles and lymph-node resection) is currently the most common tratment option in young patients with organ confined prostate cancer (Huland 1997). Until 25 years ago this procedure had unacceptable morbidity, with high urinary incontinence and erectile dysfunction rates. In the 70’s, however, Walsh and Reiner outlined the penile venus drainage in the area of the prostate gland and delineated the autonomic innervation to the corpora cevernosa developing and popularizing the nerve sparing technique. A further decrease in the incidence of urinary incontinence derived, more recently, from a better understanding of the male urethral sphincteric mechanism and the importance af apical dissection. Since the anatomy has been carefully outlined, radical prostatectomy allows for preservation of sexual function and continence. The retropubic approach is generally preferred to the perineal approach, as it enables simultaneous assessment of pelvic lymph node (Reiner 1979; Walsh 1982; Myers 1987).
126.96.36.199 Standard surgical approach according to the stage of disease
Selection of patients amenable to radical prostatectomy should be very accurate with a main indications in patients with a life expectancy >10 years and: stage T1a when the expected survival is > or = 15 years, or when high grade tumor, stages T1b, T1c and stage T2. Optional indication in stage T3 with a limited extracapsular extension and a Gleason score below 8 and a PSA level below 20 ng/ml (Loughlin 1999; Lowe 1996; Epstein 1994; Oesterling 1993b; Elgamal 1997; Gibbons 1988; Pound 1997). Patients with poorly differentiated tumours, apical tumour extension and intraoperatively palpable tumour should not undergo nerve-sparing radical prostatectomy. Laparoscopic radical prostatectomy has been introduced with the intention of minimizing perioperative and postoperative morbidity (Guillonneau 2000). However, even considering morbidity data, oncological and fuctional results of this approach are still preliminary and the retropubic approach remains the gold standard.
188.8.131.52 Node dissection: is it necessary? For staging or for cure?
Pretreatment PSA, clinical stage and biopsy Gleason score, can identify a subset of patients with low incidence of nodal metastases (3-5%). Therefore a standard pelvic limphadenectomy (including the internal, external iliac artery and the obturator fossa) is currently performed and justified (because of an increased morbidity) in cases with preoperative PSA level >10ng/ml, biopsy Gleason score > 6 and clinical stage ¡Ý T2 (Bishoff 1995; Bluestein 1994; Narayan 1994; Parra 1996; Partin 1997). A considerable controversy still remains on the appropriate therapy of patients with positive lymph nodes. Discussion about treatment addresses whether initial hormonal therapy alone or prostatectomy (with delay of hormonal treament until PSA begins to increase or clinical recurrence is documented) is preferable or whether androgen deprivation should be immediately started after radical surgery (this combined therapy, found to be effective for local and systemic control, becomes standard therapy in many institutions) (Schroeder 2003; Bader 2003; Zincke 1989; Seay 1998; Zincke 2001; Cheng 2001; Frazier 1994; Messing 1999; Zwergel 2004). Actually, however, any approach for the treatment of node positive patients has to be considered standard.
184.108.40.206 Preoperative medical treatment
Many cases of apparently localized prostate tumours resulted not disease-free (because of positive margins and/or extracapsular extension) after radical prostatectomy (Pound 1997). Neoadjuvant hormone-therapy was developed as an approach to reduce the incidence of this problem (clinical understaging). Published studies have shown a significant decrease in the positive margin rate after neoadjuvant androgen deprivation (probably due to an increased difficulty in determining e accurately the tumor at the inked margin) (Soloway 1995; Meyer 1999; Aus 1998; Schulman 2000). However this reduction not resulted in any benefit in terms of biochemical and clinical desease-free survival for patients treated with (Scolieri 2000; Schulman 2000) neoadjuvant androgen ablation plus prostatectomy (Soloway 2002). In conclusion currently there is no evidence to indicate that neoadjuvant androgen deprivation before radical prostatectomy improves progression-free survial in patients with stage CT1-T2 prostate cancer.
220.127.116.11 The role of palliative surgery
Occasional patients affected by a local recurrence following definitive radiation therapy can be salvaged with prostatectomy (Moul 1991). However, only about 10% of relapsing cases initially treated with radiation will have just a local relapse and in these patients a prolonged disease control is often possible with hormone therapy (median cancer-specific survival of 6 years after local failure) (Schellhammer 1993). Alternative approaches for treatment of local recurrencies after radiation therapy, such as cryosurgical ablation or Hi-FU (High Focused Ultrasound), are still under clinical evaluation. In summary, most relapsing patients will fail with disseminated disease and, probably, are best managed with hormonal therapy.
6.2.3 External-beam radiotherapy
Radical radiation therapy can be offered to patients with localized disease as a viable alternative to radical prostatectomy. Associate treatment with radiotherapy and hormone-therapy has to be evaluated in some subsets of patients as the consequence of an increased survival observed in patients with high Gleason Scores in studies 85-31 and 92-02. On the contrary patients with bulky disease and low Gleason score treated with short-course neoadjuvant hormonal manipulation fared better than those treated with RT only in RTOG study 86-10 . Even if no large phase III Trials comparing radical prostatectomy with radical radiotherapy have been published, many studies report comparable 10-15 year DFS (disease free survival) and overall survival outcomes with these two competing treatments, on a type 3 level of evidence. Moreover, in recent years, radiotherapy has witnessed major technological advances with the advent of 3D-conformal radiotherapy (3D-CRT). Conventional irradiation with the classic 4-field technique, in fact, could safely be carried out to a total target dose of 65-70 Gy. The frequent persistence of local residual tumour following conventional radiotherapy at these dose levels has been a matter of concern in the literature. This was likely due to failure to eradicate the disease from intrinsically resistant prostate tumour clonogens and from uncertainties in tumour delineation, organ motion, and patient positioning from day to day. 3D-CRT has therefore been developed with the aim of addressing some of these issues. 3D-treatment planning is based on the ability to define anatomically each pixel within the entire 3D space of irradiated tissues and to precisely calculate the dose delivered at each point. In the treatment of localized prostate cancer, by means of significant exclusion of adjacent normal tissues from the high-dose region, 3D-CRT has been shown to reduce the risk of rectal and bladder toxicities, thus enabling safe dose escalation to unprecedented dose levels (80 – 86 Gy) (Hanks 1998; Pollack 2000; Zelefsky 2001). Recently, further techological advancements have been conducted into the clinical implementation of intensity modulated radiotherapy (IMRT). This technique carries the potential of even greater normal tissue sparing in selected cases where the anatomical relationships of the prostate and seminal vesicles relative to the adjacent critical structures do not allow dose escalation with conventional 3D-CRT (Zelefsky 2000).
Early stage disease with favourable prognostic factors (PSA < 10, GPS < or = 6) may be effectively treated with permanent seed implants (iodine 125 or palladium 103 seeds) with similar biochemical-free survival rates to radical prostatectomy and external-beam RT, on a type 3 level of evidence (Blasko 2002; Sylvester 2003). Candidates for brachytherapy as a sole treatment modality should also be devoid of urinary symptoms to avoid the risk of urinary retention (Locke 2002). In the presence of risk of extracapsular extension, the combination of brachytherapy and external-beam radiotherapy has also been suggested as an alternative to exclusive high dose 3D-CRT with conficting results (Blasko 2000, Dattoli 1996).
6.3 Locally advanced disease T3-T4, Nx-1, M0
6.3.1 General considerations
Stage T3a cancer is defined as capsular perforation and stage T3b cancer as invasion of the seminal vesicles. The treatment for locally advanced T3 prostate cancer accounting nowadays for less than 40% of all clinically assessed tumours, remains a controversial issue. Although radiotherapy plus hormone-therapy could be considered the treatment of choice, some cases, could be effectively managed with radical prostatectomy plus eventual adjuvant hormone-therapy.
6.3.2 Radiation therapy plus hormone-therapy
Numerous randomized RTOG trials using various schedules of hormone therapy combined with radical radiotherapy have shown a significant increase in local control, disease free survival (DFS) and time to distant metastases in patients with bulky and not-bulky disease, on a type on a type 1 level of evidence (Pilepich 2001; Lawton 2001; Hanks 2000). An increased survival was shown in subsets of patients with high Gleason Scores in studies 85-31 and 92-02. Patients with low Gleason score treated with short-course neoadjuvant hormonal manipulation fared better than those treated with RT only in RTOG study 86-10. This result remains controversial and needs to be confirmed by further randomized studies. Only one trial, thus far, has reached a statistical significance in an improvement in overall survival (EORTC-22863, 5.5 year results, OS: 78 vs 62%, p=0.0002) with the combined approach using conventional radiotherapy (70 Gy) and concomitant and adjuvant LH-RH analogue for 3 years (Bollà 2002) on a type 2 level of evidence. Further randomized trials are clearly needed to confirm the role of hormonal manipulation and radiotherapy both in the setting of organ-confined disease and of locally-advanced high-risk disease.
6.3.3 Surgery plus hormone-therapy
The role of surgical treatment in T3 CaP remains questionable. Most studies have demonstrated that about 15% of all clinical stage T3 tumours were overstaged (cT3, pT2), while only 8% were understaged (cT3, pT4) (Lerner 1995; Morgan 1993), therefore patients who were overstaged obviously did very well. The selection before surgery of these patients with use of nomograms, is raccomended. Incomplete tumour excision in radical prostatectomy T3 series, is often associated with higher risk of local recurrence and higher risk of systemic progression. Radical prostatectomy for clinical T3 cancer requires sufficient surgical expertise in order to keep the morbidity level acceptable. Increased overall surgical experience has certainly favoured the decreased operative morbidity rate from radical prostatectomy for clinical T3 cancer patients (Lerner 1995). Reports on treatment outcomes in patients with clinical T3 cancer are currently available (Di Silverio 1996; Gerber 1997; Lerner 1995; Morgan 1993; Theiss 1997; van den Ouden 1994; van den Ouden 1998; van Poppel 2000). A recently published ECOG study in 98 node positive patients randomized to early vs deferred hormone-therapy reported an increased 5-year overall survival. All the patients underwent radical prostatectomy with pelvic lymph node dissection. The reported increase was significant (77 vs 18%, p<0.001) but these data have to be confirmed (Messing 1999).
6.3.4 Post-operative and salvage radiotherapy
Several retrospective studies report the impact of loco-regional radiotherapy on the local recurrence rate in patients with pathological pT3/T4 pN0/N1 tumours. The local recurrence incidence at 10 years is invariably statistically different in all series, favouring the combined modality approach on a type 3 level of evidence (Mayer 2002; Vicini 1999; Nudell 1999; Valicenti 2003; Petrovich 2002; Taylor 2003, Catton 2001). Overall survival, however, does not differ between the two treatment groups. Controversy still remains as to whether patients with high risk of local recurrence (i.e. pT3, positive surgical margins) but with undetectable post-operative PSA ought to be treated adjuvantly or may be treated just as effectively at the time of biochemical recurrence, provided RT is performed early on with PSA values in the order of about 1.0 ng/mL (Taylor 2003; Parker 2001).
6.4 Advanced disease Tx, Nx, M+
The The treatment of choice for advanced prostate cancer is androgen ablation, achieved via surgical (bilateral orchiectomy) or medical (LH-RH analogues) castration, which is effective, but not curative in 80-85% of cases. A recent meta-analysis published by the Prostate Cancer Trialist Group (PCTG) analyzed the 5- year results of 27 randomized trials involving 8275 men (metastatic cases: 88%). No significant advantage for overall survival was found for maximum androgen blockade (MAB) vs androgen suppression alone (25.4 vs 23.6%, +1.8%, p= 0.11). This results, however, changed to 27.6 vs 24.7% (+2.9%, p=0.005) by evaluating only trials with pure antiandrogens (bicalutamide, flutamide, nilutamide) and fell to 15.4 vs 18.0% (-2.8%, p=0.04) with steroidal antiandrogens. As a result, by adding a pure antiandrogen to LH-RH monotherapy a marginal advantage in overall survival of about 3% can be obtained; the same entity can be lost by adding steroidal antiandrogens (PCTCG 2000). Early hormone-therapy seems to be advantageous in respect to delayed treatment in asymptomatic metastatic patients (MRCPCWPIG 1997). Definitive data from phase III studies on intermittent androgen suppression are awaited.
6.4.2 Second line hormone-therapy
Patients progressing after hormone-therapy can be treated successfully with second-line hormone-therapy. In the case of patients submitted to MAB the antiandrogen has to be omitted with a probability of response to the withdrawal of the antiandrogen of about 25% (range: 15-50%) and a median duration of response of 3-4 month. On the contrary, patients who underwent androgen ablation alone (monotherapy) can be treated by adding an antiandrogen with a similar probability of response (Small 1995; Figg 1995; Gomella 1997). In androgen-independent patients another chance of treatment could derive from drugs such as ketoconazole or aminogluthetimide, which inhibit adrenal steroidogenesis. The probability of PSA response is about 25% (Mahler 1993).
6.4.4 Palliative radiotherapy
The relative role of radiotherapy in metastatic disease is to deal with isolated symptoms which may persist despite systemic treatment. Exceptions to this rule may be the patient presenting with a pathological fracture in an isolated site or the rare instances of brain metastases where radiotherapy would be the local treatment of choice. The role of external beam radiotherapy in the treatment of isolated bone pain is supported by a large body of literature. Areas of controversy, however, still exist, principally around the most appropriate dose fractionation schedule to be used. Single doses of between 6 and 8Gy have been shown to be as effective, with pain relief reported in around 80% of patients, to fractionated schedules delivering 30 to 40Gy over 2 to 4 weeks (Hoskin 1991; Hoskin 1992).
Patients with symptomatic disseminated bone metastasis despite hormonal manipulation may be managed with radioisotope therapy. This involves the systemic, intravenous administration of a radioactive isotope, such as strontium, rhenium or samarium, which is uptaken by the bone and will thus deliver a dose of radiation to the metastatic sites with possible pain relief on a type 2 level of evidence (Lewington 1991).
Patients with metastatic carcinoma of the prostate with vertebral metastases and initial cord compression may be adequately treated with radiotherapy to avoid paraplegia or, in the cervical cord, quadraplegia. The radiation field should seek to encompass all known sites of spinal canal involvement. Optimal dose fractionation to be delivered in this setting is uncertain. Whilst there are advocates for single dose treatment for spinal cord compression, it is more common practice to deliver doses of between 20 Gy in one week and 40 Gy in 4 weeks (Huddart 1997; Hardy 2002).
Chemotherapy has a well recognized role in the management of hormone-refractory prostate cancer (HRPC). Treatment activity of chemotherapy regimens has increased progressively from the 6.5-8.7% of the 80’s (Yagoda 1993) to the 20-48% (clinical response rate) of the 90’s trials with estramustine and vinblastine or etoposide (Hudes 1999; Pienta 1997); in the same time Tannock showed the possibility of a clinical benefit with the combination of mitoxantrone and prednisone over prednisone alone (Tannock 1996; Kantoff 1999). As a consequence of these results, but lacking any advantage in overall survival, chemotherapy has been longer considered as an active, but palliative, approach for the treatment of HRPC (symptom management) with some positive influence on quality of life (Berretto 2001). In recent years, however, new chemotherapy combinations of taxanes plus estramustine have been tested with clinical results in the range of 33-46% (mean 43%) for paclitaxel and 17-50% (mean 32%) for docetaxel. PSA response rates and median survivals were, respectively, 54 and 72% and 16.9 and 21.9 months (Hudes 1997; Haas 2001; Ferrari 2001; Kreis 1999; Petrylak 1999; Savarese 2001). These data have been recently confirmed by two large randomized phase III trials (TAX-327, 1.006 cases and SWOG 99-16, 770 cases) which tested docetaxel, alone or in combination with estramustine phosphate, against mitoxantrone and prednisone. Median overall survival of docetaxel-treated patients increased in both studies of about 2.5-3 months instead of a large incidence of treatment cross-over after progression. A positive influence of docetaxel-based chemotherapy on quality of life was also showed. These studies demonstrate, for the first time, a positive impact of chemotherapy on overall survival in HRPC patients, on a type 1 level of evidence (Tannock 2004; Petrylak 2004).
7. LATE SEQUELAE
7.1 Late sequelae related to surgery
When making treatment choices in early prostate cancer, patients must weigh the benefits against adverse events such as incontinence and impotence that may affect quality of life (QoL) (Fossa 1996; Litwin 1995).
7.1.1 Urinary control
The risk of urinary incontinence following radical prostatectomy varies from 5-10% when reported by surgeons to 19-31% when evaluated by patients through questionnaire (Fowler 1993; Zincke 1994; Catalona 1999; Walsh 2000; Stanford 2000). These differences resulted from different definitions of incontinence, time of evaluation after surgery and different patient populations. In a multivariate analysis 4 factors resulted independently associated with persistence of incontinence: increasing patient age (p <0.001), surgical technique (p<0.001), preservation of neurovascular bundles (p<0.01), and development of an anastomotic stricture (p<0.01) (Eastham 1996). Preservation of the maximum functional length of the urethra (Myers 1998) and nerve-sparing surgery seems to be the most important factors. A median time to complete recovery of urinary control of 6 weeks (with 92% and 95% continence rates after 12 and 24 months) was reported (Scardino 2000). In a questionnaire-based analysis on 428 patients, 12 months after surgery, 90.2% of the patients who had a (uni- or bilateral) nerve-sparing were considered continent (0-1 pad) while only 77.6% of the non-nerve-spared were dry. In men with persistent incontinence after radical prostatectomy the possibility of a bladder neck contracture should be considered. In cases without anastomotic stricture urodynamic study is warranted because of possible bladder dysfunction (Hammerer 1997).
7.1.2 Sexual Function
Post-operative recovery of erection function ranged rom 68-82% after a bilateral nerve-sparing to a 11-58% in the case of an unilateral nerve-sparing with more recent data showing in the latter case a potency rate of about 20% or less (11% according to the national medicare experience) (Quinlan 1991; Catalona 1999; Rabbani 2000; Noldus 2002; Fowler 1993). These data must be discussed when counseling patients before RRP. Recovery of erections may occur after more than 1 year following nerve-sparing RRP (Walsh 2000) of 72-86% between 12 and 18 months postoperatively (Walsh 2000; Rabbani 2000). Recovery of potency seemed to be age-related as initially recognized by Walsh and Donker (Walsh 1982). Several years later, a large series from the Johns Hopkins University confirmed these early data (Quinlan 1991). In young patients (<50 years old) there seems to be no difference in potency rates regarding the extent of nerve-sparing; between 50 and 60 years (when the overall potency rate decline) an uni- or bilateral nerve-sparing has a strong impact on erection recovery; patients 70 years or older have only tumescence after a unilateral nerve-sparing and a full erection in 22% of the cases after a bilateral preservation (Quinlan 1991). The quality of preoperative erections proved to be an independent predictor of erectile recovery rather than frequency of sexual intercourse (Rabbani 2000; Geary 1995). The surgeon experience seems to be another influencing factor (Catalona 1999; Kao 2000): postoperative potency rates increases with increasing number of nerve-sparing procedures performed (61% for less than 500 cases, 68% for 500-1000 cases, and 70% for 1000-1500 cases) (Catalona 1999). All the results might be influenced by the method of data collection with patient questionnaire-based outcome analysis showing the lower success rates.
7.2 Late radiation-induced side-effects
Late sequelae of conventional radiotherapy typically occur 3-6 months after treatment completion with the exception of erectile function, preserved in about 70-80% of the cases in the first year but only 30-60% thereafter. The incidence of late toxicity is lower for doses up to 64 Gy but increases with dose for treatments exceeding 70 Gy (from about 4% to 9% at 3 years) (Sandler 1995). The incidence of serious urinary sequelae (haematuria, cystitis, urethral stricture and/or bladder contracture) is low (about 7%), with urethral stricture the most frequent event and a previous transurethral resection of the prostate (TUR-P) the most frequent favouring cause in the case of a too early radiation treatment (Zelefsky 1993). Serious intestinal sequelae (proctitis, diarrhoea, rectal bleeding or stricture) occur in less than 3.5% of cases with a significant involvement of the anterior rectal wall as the most important variable for increased toxicity (Benk 1993). The advent of 3D-conformal radiotherapy, and more recently, of intensity modulated radiotherapy, has allowed significant escalation in prescription dose, while keeping the dose to the critical structures to relatively safe levels. The risk of late side-effects can be effectively assessed through the use of dose-volume histograms (DVH’s) (Greco 2003). Therefore, radiation-induced late toxicity, following high-dose radiotherapy with modern treatment techniques, is generally acceptable, and it usually entails rectal side-effects (Huang 2002). Patients treated with 3D-RT at high dose, however, may experience rectal bleeding (up to 17% at 5 years for doses ranging from 75 to 81 Gy). The implementation of intensity-modulated radiation therapy (IMRT) by reducing the volume of rectal wall exposed to high dose, has restulted in as significant reduction of late rectal bleeding (2% with IMRT vs. 17% with 3D-RT) (Zelefsky 2000).
8. FOLLOW UP
8.1 Follow-up after curative treatments
Patients who underwent potentially curative treatments such as radical prostatectomy or radical radiotherapy are at risk of relapse. Incidence, site and timing of relapse depend of Gleason Score, baseline PSA and clinical or pathological stage. Patients have to be followed at 3-4 monthly intervals with PSA, haemato-biochemistry and digital rectal exploration (DRE) during the first year, every 6 months for the following 2 years and then yearly. Trans-rectal ultrasound, bone scintigraphy and other imaging techniques should be used only as second line examinations in the case of clinical or biochemical (PSA) suggestion of relapse. Accepted cut-off levels for PSA are 0.2 ng/ml after radical prostatectomy (at least two determinations) and 3 consecutive increases after radical radiotherapy (Amling 2000; ASTRO 1997).
8.2 Follow-up for advanced disease
Patients submitted to hormone-therapy should be followed, during treatment, at 3-6 monthly intervals (depending on prognostic factors) with PSA, haemato-biochemistry, DRE, eventual trans-rectal ultrasound and symptom evaluation (especially bone pain). Imaging techniques should be repeated in the case of clinical and/or biochemical (PSA) evidence of progression (Sissons 1992).
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Prof. Georg Bartsch (Reviewer)
University of Innsbruck – Innsbruck, Austria
Dr. Sergio Bracarda (Associate Editor)
Ospedale Silvestrini – Perugia, Italy
Dr. Filippo de Braud (Editor)
START Clinical Editor – European Institute of Oncology – Milan, Italy
Dr. Ottavio de Cobelli (Author)
European Institute of Oncology – Milan, Italy
Dr. Gemma Gatta (Consultant)
Istituto Nazionale Tumori – Milan, Italy
Prof. Carlo Greco (Author)
Università della Magna Graecia – Catanzaro, Italy
Prof. Tommaso Prayer-Galetti (Author)
University of Padua, Italy
Dr. Riccardo Valdagni (Author)
Istituto Nazionale per lo Studio e la Cura dei Tumori – Milan, Italy