Prostate Cancer – Risk Factors, Symptoms, Investigations, Staging, Treatment

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prostate cancer

How a Patient with Prostate Cancer Presents?

To further understand the disease in a better way, have a look at the video below where CancerBro meets Mr. Poppy who has recently being diagnosed with prostate cancer.

CancerBro – Hi Mr. Poppy, how are you feeling today? Can I ask you a few questions related to your disease?

Mr. Poppy – I am feeling better now. Yes CancerBro, I will be happy to answer your questions please go ahead.

CancerBro: Mr. Poppy, how old are you and where are you from?

Mr. Poppy: I am 65 years old and I am from USA.

CancerBro: Tell me what were your initial complaints for which you consulted the doctor?

Mr. Poppy: For last one and half month I was having difficulty in passing urine. I had to go repeatedly for urination even during night, also the urine stream was not proper. Sometimes, I noticed blood in urine. Recently, I had difficulty in erection and also back pain.

CancerBro: Please tell me something about your diet and activity schedule.

Mr. Poppy: I used to eat red meat and fatty food, and due to my hectic work schedule, I rarely did any exercise.

CancerBro: Did anyone else in your family has been diagnosed with prostate cancer previously?

Mr. Poppy: Yes my father also had a prostate cancer.

CancerBro: Okay Mr. Poppy, thank you very much.

What are the Risk Factors of Prostate Cancer?

  • Prostate cancer is a disease of old age. More and more people are being diagnosed with the disease due to increasing life expectancy, by 90 years of age 50 to 60% of will have the disease.
  • Western countries has the highest incidence of this disease, highest being in the African American.
  • Asian migrated to the western countries have higher incidence than the native.
  • Red meat and fatty foods, containing saturated fatty acids increase the risk of prostate cancer.
  • Sedentary lifestyle with increasing obesity also increases the risk of prostate cancer. Regular physical activity decreases the mortality and improves outcome in patients with the disease.
  • Number of people previously affected with the disease increases the risk in other family members.
risk factors infographic

What are the Signs and Symptoms of Prostate Cancer?

Prostate cancer usually presents with hesitancy, nocturia, diminished urine stream and incomplete emptying of the bladder.

Less commonly, it may cause pelvic or perineal pain, erectile dysfunction or hematuria. And rarely, bone pain or pathological fractures.

Symptoms Infographic

What are the Symptoms of Advanced Stage Prostate Cancer?

Symptoms of advanced disease may be caused due to local involvement of nearby structures and metastasis to distant sites.

Local spread may cause:

  • Increased frequency of micturition
  • Getting up at night multiple times for urination
  • Sense of incomplete emptying of bladder
  • Interrupted steam of urine flow
  • Painful urination
  • Blood in urine or semen

Distant spread may cause:

  • Back pain or pain at bony sites
  • Chest discomfort, cough, breathlessness
  • Yellowish discoloration of eyes and/or urine

Most common sites of spread of prostate cancer are adrenal gland, bone, liver and lung.

What are the Investigations for Diagnosis and Staging of Prostate Cancer?

Now we move on to the diagnostic workup prostate cancer. The diagnostic modalities for prostate cancer are a digital rectal examination, serum markers, prostate biopsy, and imaging.

Prostate-specific antigen or PSA is the biomarker for prostate cancer. PSA may be falsely elevated in conditions other than prostate cancer. Most commonly seen are urinary tract infection, bladder catheterization, needle biopsy of prostate and transurethral resection of the prostate. Normal PSAs levels also vary with the age of a person. It is less than 2.5 in 40 to 49 years, less than 3.5 in 50 to 59 years, less than 4.5 in 60 to 69 years and less than 6.5 in 70 to 79 years of age.

But we can never be 100% sure just based on PSA. It guides us for further investigations and confirms the disease by DRE, biopsy, and imaging.

So to understand it better we come to the free to total PSA ratio. PSA levels of 4 to 10 are overlapping for benign hypertrophy of prostate and prostate cancer, so free to total PSA ratio will help us to differentiate these two conditions. If the ratio is less than 10%, it goes in the favor of cancer. If the ratio is less than 10%, it goes in the favor of cancer.

Next important investigation is a prostate biopsy. The prostate biopsy may be done under ultrasound or MRI guidance, but the baseline scan should be done as a biopsy may distort the architecture and make it difficult to analyze the scan reports.

Prostate biopsy is assigned a grade called as Gleason’s grade. For diagnosis of prostate cancer, multiple biopsies are taken from the prostate. In each biopsy sample, we do the Gleason’s scoring. The scoring is done out of 5, the most common or most predominant score of all the biopsy samples is called as the primary score. Whereas, the highest score of all the biopsy samples is known as the secondary score. The total score is calculated by adding a primary and secondary score. The minimum score is 3 in each so the minimum total score is 6. Score as 6 is called low grade, 7 is intermediate grade and score between 8 to 10 is high grade.

Investigations Infographic

What is TNM Staging of Prostate Cancer?

T Staging

T1 – It is clinically inapparent disease with no abnormality on palpation or imaging. It maybe an incidental finding on excision of prostate done for some other reason or it maybe diagnosed after biopsy of prostate done for elevated PSA.
 
T2 disease is localized to the prostate. It may be diagnosed with palpation or imaging. It is called as T2a when it occupies less than half of one lobe of the prostate.
 
T2 disease localized to the prostate T2b if it occupies more than 50% of one lobe of the prostate. T2b Remember that all cases of the T2 disease are confined to the prostate.
 
prostate cancer T Staging (T1 and T2) Infographic
 
Extracapsular extension of the tumor without any external organ infiltration is called as T3a. T3a And an extracapsular extension to involve seminal vesicles is called as T3b.
 
T3b T4 disease is infiltration of the adjacent organs. In this figure, the tumor infiltrates the perineal body.
 
T4 - tumor infiltrates the perineal body Here it extends posteriorly to involve the rectum.
 
T4 stage involves the rectum And here it extends superiorly to infiltrate the urinary bladder.
 
T4, extends posteriorly to urinary bladder It may also extend laterally to involve the pelvic wall.
 
T4, extends to pelvic wall prostate cancer T Staging (T3 and T4) Infographic

N Staging

N0 – No spread of tumor to nearby lymph nodes
 
N1 – Tumor has spread to regional lymph nodes

M Staging

M0 – No spread of tumor to distant body parts
 
M1 –  Spread to a distant body parts such as bones, lungs, liver, brain, etc.
 
N and M Staging

What is the Gleason’s Scoring and Grading for Prostate Cancer?

Gleason scoring system involves scoring of prostate cancer based on the extent of abnormality observed in the collected biopsy samples (usually the Gleason score ranges from 3 to 5 for a single biopsy sample).
 
Since prostate cancer is a multifocal disease, the score for different biopsy samples collected from the same patient may differ. Thus, score of specimen with most predominant Gleason score is added to the highest Gleason score observed, to give overall Gleason score (that may range from 6 to 10). Further, Gleason grade groups (1 to 5) are derived according to the following table:

 

Gleason Grade Group Gleason Score Gleason Pattern
1 </=6 </=3+3
2 7 3+4
3 7 4+3
4 8 4+4, 5+3, 3+5
5 9 or 10 4+5, 5+4, 5+5

What are the 4 Stages of Prostate Cancer?

Once T, N, M, PSA, and grade group are determined through different diagnostic techniques, this information is combined to assign an overall stage (from 0 to IV) to the disease.
 
Stage TNM Score, PSA (ng/mL), Grade Group (GG)
I T1a-2 N0 M0 PSA<10 GG=1
IIA T1a-2a N0 M0 PSA>/=10,<20 GG=1
  T2b-2c N0 M0 PSA<20 GG=1
IIB T1-2 N0 M0 PSA<20 GG=2
IIC T1-2 N0 M0 PSA<20 GG=3-4
IIIA T1-2 N0 M0 PSA>/=20 GG=1-4
IIIB T3-4 N0 M0 Any PSA GG=1-4
IIIC Any T N0 M0 Any PSA GG=5
IVA Any T N1 M0 Any PSA Any GG
IVB Any T Any N M1 Any PSA Any GG

What is the Natural History of Prostate Cancer?

This is the prostate cancer natural history. As you can see in the figure it progresses very slowly and the patient may survive for years after diagnosis.

prostate cancer natural history The first peak correlates with localized disease and is treated with local therapy in most of the cases. We will discuss this in detail later.

The second peak correlates with recurrence after local therapy or metastatic disease. It is treated with local or systemic therapy.

The third peak correlates with the castrate-resistant prostate cancer, that is the disease which has progressed on hormonal therapy. It is usually treated with chemotherapy but other agents may also be used.

Androgen Deprivation Therapy for Prostate Cancer

https://youtu.be/0M3JMGn8_jY The next treatment modality is androgen deprivation therapy. For this, we first have to understand the hormonal axis causing the testosterone release.

Androgen deprivation therapy

The pituitary gland releases LH and FSH, which directly acts on the testis to release testosterone.

ACTH released from the pituitary gland acts on the adrenal gland to release DHEA, which subsequently gets converted into testosterone.

The testosterone released from testis and adrenal gland enters the prostate cell and gets converted into DHT which causes the growth and survival of prostate cancer cells.

We can block this pathway, to reduce the action of testosterone on prostate cancer cells. GnRH agonists or antagonists prevent the release of LH, FSH, and ACTH from the pituitary gland.

GnRH agonists or antagonists Then come the cytochrome 17P inhibitors that prevent the release of testosterone from the testis and adrenal gland.

cytochrome 17P inhibitor And finally, there are androgen receptor blockers that prevent the binding of testosterone to prostate cancer cells, thereby preventing its action.

androgen receptor blockers

Another method for androgen deprivation is surgical castration in which both testes are removed. Unlike medical construction, it is a one-time procedure.

What is the Treatment for different stages of prostate cancer?

Very Low to Low-Risk Disease

T1a-2 N0 M0, PSA<10, GG=1

Active surveillance is the best approach in such cases. The patient should be screened frequently for any sign of disease progression. No other treatment is generally recommended.

Intermediate-Risk Disease

T2b-2c N0 M0 PSA<20 GG=1  TO  T1-2 N0 M0 PSA<20 GG=3-4

Active surveillance is the first choice of treatment for elderly patients with other complications and whose life expectancy is less than 10 years. For younger patients without any other health issue, radical prostatectomy (surgical removal of the prostate gland) and/or radiotherapy is generally recommended. In case of high PSA level or high Grade group, androgen deprivation therapy may also be employed to prevent disease recurrence.

High-Risk Disease

T1-2 N0 M0 PSA>/=20 GG=1-4 TO Any T N0 M0 Any PSA GG=5

Radiotherapy in combination with androgen deprivation therapy is considered as the standard treatment. Radical prostatectomy followed by removal of pelvic lymph nodes and radiotherapy may also be considered. In case of an elderly patient, less intense treatment is generally recommended. Such patients can be treated with androgen deprivation therapy alone or active surveillance may be considered if life expectancy is very low.

Metastatic Disease

Low volume stage IV disease with limited spread of disease to bones can be treated with androgen deprivation therapy with or without radiotherapy as standard treatment.

For high volume Stage IV disease with a vast spread of disease to distant organs, chemotherapy plus androgen deprivation therapy is considered as the standard treatment.

Palliative therapy like transurethral resection of the prostate (TURP) for bleeding and urinary obstruction or a bisphosphonate/radiopharmaceutical treatment to manage bone pain /disease can also be employed as and when required.

Metastatic hormone sensitive disease treatment
Prostate Cancer Treatment -Metastatic (Castrate – Naive)

Role of Radiopharmaceuticals in the treatment of Prostate cancer?

Various radiopharmaceuticals (e.g. Radium-223, Strontium-89, and Samarium-153) are used for the palliation of pain due to bone metastasis that commonly occurs in the case of advanced-stage prostate cancer.

Radium-223

It is an alpha particle-emitting radioactive agent, which is preferentially taken up by rapidly growing bone cells within the metastatic bone lesions due to its chemical similarity with calcium. Within the metastatic bone lesions, Ra-223 kills cancer cells by emitting alpha-rays and inducing double-strand DNA breaks.

Thus, Ra-223 has a specific action against bone metastases resulted from prostate cancer and helps in improving the survival of patients with CRPC and bone metastasis.

It has been approved for treatment of metastatic CRPC in patients with symptomatic bone metastases and no known visceral metastases. It can be safely combined with secondary hormonal therapy drugs approved for the treatment of metastatic CRPC, e.g. abiraterone or enzalutamide.

Strontium-89 (89Sr) and Samarium-153 (153Sm)

These are beta-emitting radiopharmaceuticals that specifically target bone metastases in prostate cancer. The beta-emitters do not have a survival advantage as that of Ra-223 but can be used for the palliation of pain associated with wide-spread bone metastases.

These agents provide significant pain relief with minimum side effect compared to other palliative treatments in patients with multifocal bone pain and who are not the candidate for chemotherapy.

Castrate Resistant Prostate Cancer Treatment

After some years of starting androgen deprivation therapy, PSA may start rising, or there may be a disease progression on scans. This state is called as castrate-resistant prostate cancer.

If the patient has localized CRPC, then the treatment options are the observation or androgen deprivation therapy with a different agent that used previously.

And for metastatic CRPC, the treatment options are androgen deprivation therapy, chemotherapy, cancer vaccine or bone-directed therapy.

CRPC is the disease which has progressed on GnRH analogs, so non-GnRH analogs are used for the treatment, such as androgen receptor blockers or 17 hydroxylase inhibitors.

Castrate Resistant Disease Treatment

Recurrent Prostate Cancer Treatment

The second peak correlates with recurrence after local therapy or metastatic disease. We will discuss it one by one.

Recurrence after surgery may be in the form of PSA persistence, that is a failure to fall to normal, or PSA recurrence, that is, rising after becoming undetectable.

And recurrence after radiation therapy may be in the form of rise in PSA or positive DRE. For localized recurrence, the treatment options are observation, surgery if initially treated with radiotherapy, radiotherapy if initially treated with surgery and androgen deprivation therapy.

And for metastatic recurrence, androgen deprivation therapy is the mainstay of treatment. The patients who present directly with metastatic disease are treated directly with hormonal therapy and chemotherapy may be added in some patients who present with high volume disease. When we use androgen deprivation therapy for the first time for localized, metastatic or recurrence after local therapy, it may be in form of medical or surgical castration. GnRH agonists or antagonists are used for medical castration, and for surgical castration, both the testes are removed, called as bilateral orchiectomy.

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