Immunotherapy for Prostate Cancer

The purpose of immunotherapy in prostate cancer is to remove the cancer cells or control the growth of the cancer cells by restoring the natural function of the immune cells, T cells are stimulated and strengthened in vitro, so that after being introduced back to patient’s body, they will be able to identify the prostate cancer cells and destroy them.

Proteins such as PSA, PSMA, PAP and a few others are presented on the surface of the prostate cancer cells, they are recognized by the immune system as ‘foreign’ to the human body, and are supposed to be destroyed by the T cells in the immune system. However, immune system’s failure in identifying these proteins, causing uncontrolled growth of the prostate cancer cells.

Definition

Prostate cancer

In the vast majority of cases, the prostate cancer starts in the gland cells – this is called adenocarcinoma. In this article, prostate cancer refers just to adenocarcinoma.

Prostate cancer is mostly a very slow progressing disease. In fact, many men die of old age, without ever knowing they had prostate cancer – it is only when an autopsy is done that doctors know it was there. Several studies have indicated that perhaps about 80% of all men in their eighties had prostate cancer when they died, but nobody knew, not even the doctor.

Experts say that prostate cancer starts with tiny alterations in the shape and size of the prostate gland cells – Prostatic intraepithelial neoplasia (PIN).

Doctors say that nearly 50% of all 50-year-old men have PIN. The cells are still in place – they do not seem to have moved elsewhere – but the changes can be seen under a microscope. Cancer cells would have moved into other parts of the prostate. Doctors describe these prostate gland cell changes as low-grade or high-grade; high grade is abnormal while low-grade is more-or-less normal.

Any patient who was found to have high-grade PIN after a prostate biopsy is at a significantly greater risk of having cancer cells in his prostate. Because of this, doctors will monitor him carefully and possibly carry out another biopsy later on.

Classification

Classification of prostate cancer

It is important to know the stage of the cancer, or how far it has spread. Knowing the cancer stage helps the doctor define prognosis – it also helps when selecting which therapies to use. The most common system today for determining this is the TNM (Tumor/Nodes/Metastases). This involves defining the size of the tumor, how many lymph nodes are involved, and whether there are any other metastases.

When defining with the TNM system, it is crucial to distinguish between cancers that are still restricted just to the prostate, and those that have spread elsewhere. Clinical T1 and T2 cancers are found only in the prostate, and nowhere else, while T3 and T4 have spread outside the prostate.

There are many ways to find out whether the cancer has spread. Computer tomography will check for spread inside the pelvis, bone scans will decide whether the cancer has spread to the bones, and endorectal coil magnetic resonance imaging will evaluate the prostatic capsule and the seminal vesicles.

The Gleason Score

A pathologist will look at the biopsy samples under a microscope. If cancer tissue is detected, the pathologist then grades the tumor. The Gleason System of grading goes from 2 to 10. The higher the number, the more abnormal the tissues are compared to normal prostate tissue.

Two numbers are added up to get a Gleason score:

  1. A number from 1 to 5 for the most common pattern observed under the microscope. This is the predominant grade and must be more than 51% of the sample.
  2. A number from 1 to 5 for the second most common pattern. This is the secondary grade and must make up more than 5% but less than 50% of the sample.

A Gleason score of 7 can have two meanings. Look at these two examples below:

  1. If the predominant grade is 3 and the secondary grade is 4, the Gleason score is 7.
  2. If the predominant grade is 4 and the secondary grade is 3, the Gleason score is also 7.

However, the first example, with a predominant score of 3, has a less aggressive cancer than the second example, with a predominant score of 4.

It is crucial that the tumor is graded properly, as this decides what treatments should be recommended.

Signs & Symptoms

Signs and symptoms of prostate cancer

During the early stages of prostate cancer there are usually no symptoms. Most men at this stage find out they have prostate cancer after a routine check up or blood test. When symptoms do exist, they are usually one or more of the following:

  • The patient urinates more often
  • The patient gets up at night more often to urinate
  • He may find it hard to start urinating
  • He may find it hard to keep urinating once he has started
  • There may be blood in the urine
  • Urination might be painful
  • Ejaculation may be painful (less common)
  • Achieving or maintaining an erection may be difficult (less common).

If the prostate cancer is advanced the following symptoms are also possible:

  • Bone pain, often in the spine (vertebrae), pelvis, or ribs
  • The proximal part of the femur can be painful
  • Leg weakness (if cancer has spread to the spine and compressed the spinal cord)
  • Urinary incontinence (if cancer has spread to the spine and compressed the spinal cord)
  • Fecal incontinence (if cancer has spread to the spine and compressed the spinal cord).
Causes

Causes of prostate cancer

Nobody is really sure of what the specific causes are. There are so many possible factors, including age, race, lifestyle, medications, and genetics, to name a few.

1) Age

Age is considered as the primary risk factor. The older a man is, the higher is his risk. Prostate cancer is rare among men under the age of 45, but much more common after the age of 50.

2) Genetics

Statistics indicate that genetics is definitely a factor in prostate cancer risk. It is more common among certain racial groups – in the USA prostate cancer is significantly more common and also more deadly among Afro-Americans than White-Americans. A man has a much higher risk of developing cancer if his identical twin has it. A man whose brother or father had/had prostate cancer runs twice the risk of developing it, compared to other men.

Studies indicate that the two faulty genes – BRCA 1 and BRCA 2 – which are important risk factors for breast cancer and ovarian cancer, have also been implicated in prostate cancer risk.

In a study scientists found seven new sites in the human genome that are linked to men’s risk of developing prostate cancer.

Faulty BRCA2 gene linked to aggressive form of prostate cancer – researchers at the The Institute of Cancer Research, UK, reported in the Journal of Clinical Oncology (April 2013 issue) that men who have inherited the faulty BRCA2 gene are more likely to have the faster-spreading type of prostate cancer. The scientists say these men should receive treatment immediately after diagnosis with surgery or radiation therapy, rather than receive the “watchful waiting” approach.

Senior author Ros Eeles wrote that experts have already known that those with the faulty BRCA2 gene have a higher risk of developing prostate cancer. This is the first large study to demonstrate that the faulty gene is also linked to a faster spread of the disease and poorer survival.

This new discovery will make some health authorities around the world rethink their policies and procedures. In the United Kingdom, the National Health Service offers the same prostate cancer treatment for both carriers and non-carriers of the faulty BRCA2 gene.

Prof. Eeles said “It must make sense to start offering affected men immediate surgery or radiotherapy, even for early-stage cases that would otherwise be classified as low-risk. We won’t be able to tell for certain that earlier treatment can benefit men with inherited cancer genes until we’ve tested it in a clinical trial, but the hope is that our study will ultimately save lives by directing treatment at those who most need it.”

3) Diet

A review of diets indicated that the Mediterranean diet may reduce a person’s chances of developing prostate cancer. Another study indicates that soy, selenium and green tea, offer additional possibilities for disease prevention – however, a more recent study indicated that combination therapy of vitamin E, selenium and soy does not prevent the progression from high-grade prostatic intraepithelial neoplasia (HGPIN) to prostate cancer. A diet high in vegetable consumption was found in a study to be beneficial.

A US pilot study on men with low risk prostate cancer found that following an intensive healthy diet and lifestyle regime focusing on low meat and high vegetable and fruit intake, regular exercise, yogastretching, meditation and support group participation, can alter the way that genes behave and change the progress of cancer, for instance by switching on tumor killers and turning down tumor promoters.

Other studies have indicated that lack of vitamin D, a diet high in red meat may raise a person’s chances of developing prostate cancer.

A study published in the journal Clinical Cancer Research suggests vitamin D deficiency may predict aggressive prostate cancer.

4) Medication

Some studies say there might be a link between the daily use of anti-inflammatory medicines and prostate cancer risk. A study found that statins, which are used to lower cholesterol levels, may lower a person’s risk of developing prostate cancer.

5) Obesity

A study found a clear link between obesity and raised prostate cancer risk, as well as a higher risk of metastasis and death among obese people who develop prostate cancer.

6) Sexually transmitted diseases (STDs)

Men who have had gonorrhea have a higher chance of developing prostate cancer, according to research from the University of Michigan Health System.

7) Agent Orange

Veterans exposed to Agent Orange have a 48% higher risk of prostate cancer recurrence following surgery than their unexposed peers, and when the disease comes back, it seems more aggressive, researchers say. Another study found that Vietnam War veterans who had been exposed to Agent Orange have significantly increased risks of prostate cancer and even greater risks of getting the most aggressive form of the disease as compared to those who were not exposed.

8) Enzyme PRSS3 linked to aggressive prostate cancer

Scientists from the Mayo Clinic, Florida, reported in Molecular Cancer Research that PRSS3, an enzyme, changes the environment of prostate cancer cells, making the cancer much more likely to metastasize.

Senior researcher, Evette Radisky, Ph.D., said “This molecule is a protease, which means it digests other molecules. Our data suggests PRSS3 activity changes the environment around prostate cancer cells – perhaps by freeing them from surrounding tissue – to promote malignancy and invasiveness. I don’t think PRSS3 is the only factor involved in driving aggressive prostate cancer, but it may be significant for a certain subset of this cancer – the kind that is potentially lethal.”

Treatment

Treatments for prostate cancer

The following treatments are separated into early stage and advanced stage prostate cancers.

Early stage prostate cancer

If the cancer is small and contained – localized – it is usually managed by one of the following treatments:

  • Watchful waiting – not immediate treatment is carried out. PSA blood levels are regularly monitored.
  • Radical prostatectomy – the prostate is surgically removed.
  • Brachytherapy – radioactive seeds are implanted into the prostate.
  • Conformal radiotherapy – the radiation beams are shaped so that the region where they overlap is as close to the same shape as the organ or region that requires treatment, thus minimizing healthy tissue exposure to radiation.
  • Intensity modulated radiotherapy – beams with variable intensity are used. An advanced form of conformal radiotherapy usually delivered by a computer-controlled linear accelerator.
    Treatment recommendations really depend on individual cases. In general, if there is a good prognosis and the cancer is in its early stages, all options can be considered. However, they all have their advantages and disadvantages. The patient should discuss available options thoroughly with his doctor.

More advanced prostate cancer

If the cancer is more aggressive, or advanced, the patient may require a combination of radiotherapy and hormone therapy. Radiotherapy requires treatment on an everyday basis for up to about eight weeks. Radical surgery is also an option – the prostate is removed. Traditional surgery requires a hospital stay of up to ten days, with a recovery time that can last up to three months. Robotic keyhole surgery has the advantage just a couple of days in hospital, followed by a much shorter recover period. However, even robotic keyhole surgery may not be ideal for very elderly patients.

In advanced prostate cancer hormone therapy is very effective in slowing down, and even stopping the growth of cancer cells. Even if the hormone therapy stops working after a while, there are still other options the patient will be able to discuss with his doctor, such as participating in clinical trials.

Radioactive injection helps advanced prostate cancer patients live longer – scientists at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, UK, reported in NEJM (New England Journal of Medicine) that radium-233, a radiation injection, directly targets tumors in the bone delivering short range radiation, causing minimal damage to healthy tissue. Radium, like calcium, is absorbed by the bone.

Delivering estrogen through skin patches may be an easier and safer way to treat prostate cancer than the hormone therapies that are currently used, British researchers explained in Lancet Oncology (March 2013 issue).

In May 2013, the US FDA approved Xofigo (radium Ra 223 dichloride) for metastatic castration-resistant prostate cancer that has reached bones but not other organs. Enzalutamide is taken in combination with docetaxel, another cancer medication.

Richard Pazdur, M.D., from the FDA, said “Xofigo binds with minerals in the bone to deliver radiation directly to bone tumors, limiting the damage to the surrounding normal tissues. Xofigo is the second prostate cancer drug approved by the FDA in the past year that demonstrates an ability to extend the survival of men with metastatic prostate cancer.”

Xtandi (enzalutamide) was approved by the FDA in August 2012 for patients with metastatic castration-resistant prostate cancer that has spread or recurred.

Complications

Possible complications

  • Metastasis – the cancer can spread to other parts of the body through the bloodstream or the lymphatic system to other organs or bones. If the cancer spreads to the ureters, the tubes that carry urine from the kidneys to the bladder, there is a risk of serious kidney problems.

    If the cancer spreads to the bones, there may be pain and fractures. Doctors say that when prostate cancer has spread to other parts of the body, it can no longer be cured, but may possibly be controlled.

  • Incontinence – the prostate cancer itself, or treatments can cause urinary incontinence.
  • Erectile dysfunction – the prostate cancer or prostate cancer treatment can lead to erectile dysfunction – the inability to achieve a penile erection, or maintain one.
  • Metabolic factors – a man’s risk of dying from prostate cancer is much higher if he has high blood pressure, raised blood sugar levels, high blood lipid levels, and a high BMI (body mass index), which collectively are known as metabolic factors. This was reported in the journal Cancer (October 2012 issue) by scientists from Umeå University in Sweden.