Prostate cancer should be recognized by palpation (lumps) or prostate-specific antigen (PSA) determination in patients suffering from urinary symptoms.
In addition to the plasma total PSA concentration, the ratio of free to total PSA and the PSA increase rate, also the age of the patient as well as the size and nodularity of the prostate gland are taken into account when assessing the probability of prostate cancer diagnosis and the need for further investigations.
In many countries, a peak of incidence was observed during the 1990's or early 2000's, with the rate of growth in the incidence slowing down since then. For the most part the peak is explained by the increasing use of PSA testing and the aging of the population.
Age is the most important single risk factor of prostate cancer.
The median age of men at the time of diagnosis is 70 years. Only 5% of the patients are under 60 years of age at diagnosis.
The risk is 2- to 3-fold if the patient's father or brother was diagnosed with prostate cancer.
The presence of androgens is necessary for the development of the cancer.
Recognized risk factors include high intake of dietary fat, obesity and smoking. The risk may possibly be diminished by ample exercise.
Asymptomatic prostate cancer is a common finding at post-mortem examination (in 30% of those over 50 years, in 70-80% of those over 80 years).
The proportion of small and localized cancers among all the diagnosed prostate cancers has increased.
Symptoms
There is no typical clinical picture.
The initial symptoms resemble those of bening prostatic hyperplasia. The symptoms may include
Rectal palpation of the prostate and plasma PSA determination are indicated in men who have symptoms suggesting prostatic disease.
The reference range is dependent on the age of the patient (see table T1).
In benign prostatic hyperplasia, the PSA concentration may be as high as 10 µg/l, but such a result in most cases means prostate cancer.
A concentration above 10 µg/l often indicates prostate cancer, and a concentration above 50 µg/l indicates metastatic cancer.
Prostate cancer is found in about 30% of the patients with a palpable nodule.
If total PSA concentration is in the range of 2.5-10 µg/l, the determination of free PSA is useful in assessing whether prostate biopsies should be obtained or not (table T2).
If total PSA concentration is in the range of 4-10 µg/l and the proportion of free PSA is more than 25%, the risk of prostate cancer is quite small and it is sufficient to follow up the patient.
If the proportion of free PSA is in the range of 10-20% while total PSA concentration is between 4 and 10 µg/l, the physician responsible for the care of the patient makes the decision concerning further management based on the findings in touch per rectum and on the symptoms. Either a control visit may be appointed or the patient may be referred to a urologist for possible prostate biopsy.
If the proportion of free PSA is less than 10% the patient should be referred to a urologist.
An increase in PSA concentration of more than 0.75 µg/l/year predicts cancer more accurately than age or total PSA concentration. Determination of the rate of increase should be based on three measurements ranging over at least one year.
Reference limits for normal total PSA concentration in men of different age groups
Age group (years)
Plasma PSA (µg/l)
40-49
<2.5
50-59
<3.5
60-69
<4.5
70-79
<6.5
PSA concentration and the probability of prostate cancer
Plasma PSA concentration
Probability of prostate cancer
Total PSA
0-2 µg/l
1 %
2-4 µg/l
15 %
4-10 µg/l
25 %
>10 µg/l
>50%
Proportion of free PSA when total PSA concentration is in the range of 4-10 µg/l
0-10%
56%
10-15%
28%
15-20%
20%
20-25%
16%
>25%
8%
Histological examination
The diagnosis is based on histological examination of needle biopsy specimens collected from the prostate during transrectal ultrasonography.
Six biopsy specimens are usually collected from each lobe of the prostate gland and/or targeted biopsies from the suspicious regions identified in MRI.
Biopsy has a sensitivity of about 60% in detecting cancer, so another biopsy should be considered if the plasma PSA concentration continues to increase even though the first biopsy proved to be normal.
Imaging
Prostate MRI assists professionals with adequate expertise in the diagnosis and assessment of local spreading of cancer. It can also be used to identify areas with suspected malignancy, from where targeted biopsies can be taken.
Staging
PSA is a useful test in assessing the spread of the disease.
Radioisotope scanning is the method of choice for detecting skeletal metastases. If plasma PSA is below 20 µg/l, the probability of bone metastases is below 1%. Bone radioisotope scan should be carried out in patients who have skeletal pain, PSA over 20 µg/l, poorly differentiated carcinoma (Gleason 8-10) or increased plasma alkaline phosphatase concentration.
Soft tissue metastases are examined with computed tomography.
Screening
Screening of men between the ages of 55 and 69 with PSA testing decreases mortality from prostate cancer in the same extent as mammography screening decreases mortality from breast cancer (20-29%). However, 781 men should be screened and 27 cases of prostate cancer detected to prevent one death from prostate cancer. The major problem with prostate cancer screening is overdiagnosis, i.e. carcinomas are detected that would not cause death or not even necessarily become symptomatic during the lifetime of the man. Patients whose disease will progress cannot be identified with present methods. Overdiagnosis easily leads to overtreatment with all the associated harms. For this reason it is not reasonable to start population-based screening programmes Psa for Screening of Prostate Cancerhttp://www.bmj.com/content/362/bmj.k3581.
Watchful waiting: T1-2NXM0, Gleason not more than 6, plasma PSA < 20 µg/l, no symptoms, age > 70 years. If the disease later progresses, hormonal therapy is usually commenced.
Active surveillance may be considered: T1-T2NXM0, Gleason not more than 6, plasma PSA < 10 µg/l, no symptoms, cancer found in no more than 2 biopsy samples (12 biopsies altogether), age < 70 years.
During active surveillance, the patient is followed up by an urologist. If the disease is activated, curative treatment is provided.
PSA measurements are initially done every 3 months. Attention is paid to the PSA doubling time (PSA-DT). The T stage is determined every 6-12 months by an urologist. Repeat biopsies are collected at individually specified intervals.
Alternatively, the follow-up is carried out with repeated magnetic resonance images.
Radical prostatectomy (robot-assisted, laparoscopic or open): T1b-2N0M0, Gleason 6-10, age < 70 years. Possible adverse effects include urinary incontinence and erectile dysfunction. Adverse Effects of Radical Prostatectomy
Radical external radiotherapy: T1-2, Gleason 6-10. Possible adverse effects include irritation of the bladder and rectum.
Treatment decisions are made in negotiation with the patient and possibly also with the family members.
The prognosis of low-risk patients seems to be similar after conservative treatment, radiotherapy and radical surgery, but in moderate- to high-risk patients, the prognosis seems to be somewhat better after radical surgery Radical Prostatectomy Versus Watchful Waiting for Newly Diagnosed Prostate Cancer. In a randomized trial comparing radical prostatectomy with watchful waiting, the rate of death from prostate cancer was lower in the prostatectomy group in men younger than 65 years of age (20.7 % vs. 14.6 %) during 15 years of follow-up 1.
Locally advanced cancer (T3-4NXM0)
Follow-up: T3-4NXM0, Gleason < 7, plasma PSA < 20 µg/l, no symptoms, age > 70 years
Radical surgery (robot-assisted, laparoscopic or open): T3N0M0, Gleason 6-10, plasma PSA < 20 µg/l, age < 70 years; neoadjuvant and adjuvant therapy at discretion. Surgical treatment is considered case-by-case.
Radical external radiotherapy: T3-4N0/1, Gleason 6-10; neoadjuvant and adjuvant therapy at discretion
Castration (LHRH analogue or antagonist therapy or orchiectomy): T3-T4NXM0, Gleason 6-10. Orchiectomy is effective and can be carried out even on very old patients under local anaesthesia. LHRH analogues and antagonists are an alternative to orchiectomy. The medicine is administered subcutaneously, usually with an interval of 1-6 months (video Injection of Goserelin Implant). The adverse effects include loss of libido, erectile dysfunction and hot flushes as well as weakened muscle strength and osteoporosis.
Bicalutamide (150 mg/day): T3-T4NXM0, Gleason 6-10. Adverse effects include gynaecomastia that can be prevented by one-off breast radiotherapy.
Advanced (metastatic) cancer
Metastatic cancer is initially treated by endocrinological means (surgical or pharmacological castration, anti-androgens) by which even a symptomatic patient usually becomes symptom-free for a variable length of time. Additionally, if the patient's general condition allows, cytostatic chemotherapy (docetaxel) is recommended. An alternative is a second-generation anti-androgen (ARSI, androgen receptor signaling inhibitor) or an androgen synthesis inhibitor.
Castration resistance will develop sooner or later; then the treatment options include
cytotoxic chemotherapy for symptomatic patients (the benefit is limited)
The 10-year survival rate in well-differentiated localized cancer is over 90%.
Life expectancy in metastatic cancer is on average 2-3 years.
Follow-up
The patient should be regularly followed up irrespective of whether the aim of the treatment has been curative or symptomatic.
It is important for the patient to know where or who to contact if necessary.
During follow-up visits the patient's symptoms (e.g. voiding problems, pains) are inquired about, prostate gland and lower abdomen are palpated and the following laboratory tests are performed: basic blood count with platelet count, plasma creatinine, plasma PSA and urine analysis + bacterial culture. Other diseases of the patient and the medication he uses are checked. If the general practitioner identifies signs of progress, a urologist is to be consulted with.
Doubling of the PSA concentration is an indication of the advancement of the disease and requires urological consultation.
Patients treated with radical prostatectomy or radiotherapy are initially followed up at the initial place of treatment for 1-2 years. In outpatient care, the patients are usually followed up at 6-month intervals for 5 years after the operation. After that, the control interval is prolonged to 12 months.
Follow-up of patients who have undergone radical prostatectomy can be organised also remotely, by determining merely PSA concentration every 6 months.
If there is no recurrence, the PSA concentration is not measurable after radical surgery.
After radiotherapy, an increase in the PSA concentration of 2 µg/l compared with the lowest measured value is a sign of recurrence.
A patient who has received brachytherapy is referred to specialized care if there is an increase in the PSA concentration in two subsequent measurements performed at a 3-month interval.
Patients receiving endocrine therapy have their first follow-up visit at the initial place of treatment. If the patient responds to the treatment the follow-up may be undertaken by his general practitioner at 3-6-month intervals.
If the time in remission has been long (more than 5 years), yearly controls are sufficient.
A clear increase in the PSA concentration in two subsequent measurements performed at a 3-month interval is a sign of recurrence. In this case, consultation with a urologist is warranted.
Metastatic cancer is usually followed up in specialized care.
Actively ask about the patient's symptoms and problems (pain, voiding problems, impotence, depression).
Emerging of skeletal pain is an indication for urological consultation.
Local tumour growth may cause voiding problems. Refer the patient to a urologist.
Chest x-rays are not indicated in routine follow-up, neither are other imaging investigations.
References
Bill-Axelson A, Holmberg L, Ruutu M, et al. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med 2011;364(18):1708-17. [PubMed]
Schröder FH, Hugosson J, Roobol MJ, et al. Screening and prostate cancer mortality: results of the European Randomised Study of Screening for Prostate Cancer (ERSPC) at 13 years of follow-up. Lancet 2014;384(9959):2027-35. [PubMed]
Hopstaken JS, Bomers JGR, Sedelaar MJP, et al. An Updated Systematic Review on Focal Therapy in Localized Prostate Cancer: What Has Changed over the Past 5 Years? Eur Urol 2022;81(1):5-33. [PubMed]
Fallah J, Zhang L, Amatya A, et al. Survival outcomes in older men with non-metastatic castration-resistant prostate cancer treated with androgen receptor inhibitors: a US Food and Drug Administration pooled analysis of patient-level data from three randomised trials. Lancet Oncol 2021;22(9):1230-1239. [PubMed]
Virgo KS, Rumble RB, de Wit R, et al. Initial Management of Noncastrate Advanced, Recurrent, or Metastatic Prostate Cancer: ASCO Guideline Update. J Clin Oncol 2021;39(11):1274-1305. [PubMed]