Prostate cancer is a common ailment in older adults. It is currently the most commonly diagnosed cancer type in males. It is also the second cause of cancer-related death in males.
But not all types of prostate cancer are dangerous, and only aggressive cancer leads to advanced disease.
Every step in the clinical management of prostate cancer is complex and highly variable. From screening to watchful waiting and advanced prostate cancer management, almost everything related to this disease is currently not carved in stone. New advances and statistics contribute to advancing our understanding of the disease. Thus, management guidelines are always subject to change.
In this article, we’re reviewing the state-of-art in advanced prostate cancer management. Stage 4 prostate cancer causes a variety of health problems and complications. Thus, it is essential to identify and understand the disease to prevent late-stage cancer in high-risk patients.
What is stage 4 prostate cancer?
Stage IV prostate cancer is an advanced and aggressive cancer that spreads beyond the prostate gland. Prostate cancer cells are very different from the original tissue, spreading to other organs or lymph nodes. It is usually associated with a very high PSA level, too.
Prostate cancer grouping in 4 stages takes into consideration different staging systems. One of them is the TNM staging, which describes the size and extent of cancer. In stage IV prostate cancer, the tumor has grown very large, usually beyond the gland.
However, regardless of the size and extent of cancer, it will be stage 4 when it has already spread to distant tissues. The disease usually takes lymph nodes in stage 4 prostate cancer. And metastasis is the spread of cancer to other parts of the body. It can be distant lymph nodes, bone tissue, or any other organ.
Doctors also consider the Gleason score to define stage 4 prostate cancer. This score takes into consideration how cancer cells look like under the microscope. In stage 4, prostate cancer, cancer cells are aberrant and very different from healthy tissue. They lose all of their characteristics, including the adhesion to other cells. That’s why they are more likely to spread to other tissues (1).
We can practically summarize stage 4 prostate cancer by saying that it is metastatic prostate cancer. It is a late stage of the disease, associated with various complications and a poor prognosis.
Stage 4 prostate cancer is associated with a variety of signs and symptoms. Clinical presentation depends on the complications in each individual patient. However, we can find the usual symptoms of prostate cancer. They are mostly related to the urinary function. Additionally, we can find in patients other symptoms associated with late-stage disease.
Symptoms of prostate cancer in different stages (2):
- Increased urinary frequency: This is one of the earliest symptoms of prostate cancer. In stage 4 prostate cancer, it is more severe and bothersome. Patients wake up several times to urinate at night and affect their quality of life.
- Weak urinary stream: This is also an early symptom that worsens in stage 4. The stream of urine is weak and intermittent. Some patients need to push very hard to urinate.
- Urinary dribble: Patients experience urinary dribble at the end of voiding and after urinating. This is a common cause of wet underwear and is often confused with incontinence.
- Incontinence: Stage 4 prostate cancer patients often develop overflow incontinence. The tumor creates a significant bladder outlet obstruction. The bladder fills above its limits. Thus, it empties when it cannot hold more urine.
Symptoms of late-stage prostate cancer (2):
- Weight loss: This symptom is common in almost all types of cancer. It is part of a wasting syndrome in cancer known as cachexia. Tumors demand a lot of energy and nutrients, depriving patients of them. They often experience a significant loss of appetite. Thus, their weight loss reaches and sometimes surpasses 5% of body weight in 6 months without a substantial change in the dietary habits or physical activity levels.
- Bone fractures: The most common site of metastasis in prostate cancer is bone tissue. In the bone, metastasis changes tissue metabolism and nutrient distribution. The bone does not have enough resources to continue bone renovation and weakens. This leads to fragile bones with a higher chance of pathologic fractures.
- Bone marrow suppression: In many cases, bone metastasis reaches the bone marrow. When that happens, cancer causes changes in the formation of different blood cell lines. That’s why anemia (a reduction of red blood cells) is so common in these patients. In more severe cases, it leads to spinal cord compression and significant bone marrow suppression.
- Pain: There are multiple sources of pain in stage 4 prostate cancer. One of them is the prostate and its surrounding tissues. Patients often feel a lump or a sensation of painful weight or fullness in the rectum. They can experience pelvic pain, painful ejaculation, and similar symptoms. Additionally, when stage 4 cancer reaches the bone tissue, it also causes bone pain. Bone pain is often described as dull pain with varying intensities.
- Edema: A larger tumor can lead to a blockage of the lymphatic or venous draining system. If that’s the case, patients may experience edema (swelling) in the lower extremities.
We have mentioned above how the Gleason score is important to identify stage 4 prostate cancer. This is because late-stage cancer is very different from the surrounding tissue. These differences are fundamental for identifying cancer and for the growth and spread of the tumor.
Stage 4 tumor cells have overlapping mutations in the DNA. Such mutations are combined with the activation and inactivation of different genes. In the end, these cells lose their differentiation and become completely aberrant. When normal cells can trigger apoptosis when something goes wrong, these cells become immortal. When normal cells divide only when required, these cells undergo uncontrolled division. When normal cells tightly adhere to their own tissue, these cells lose their grip and migrate to other tissues.
It is difficult to know which patients will develop stage 4 prostate cancer. What is the difference between those who stay with slow-growing cancer and those who transform into aggressive cancer? What causes stage 4 prostate cancer? The difference lies in the number and severity of genetic mutations in the cells. The more risk factors an individual has, the more likely it will be to grow an aggressive tumor (2).
It is difficult to trace the exact causes of prostate cancer in a given patient. However, we can detect certain conditions and circumstances in which prostate cancer is more common.
That is the definition of risk factors. They make it more likely to develop prostate cancer, and some of them are associated with a more aggressive disease. The more risk factors a patient has, the more likely it will be to grow a more aggressive cancer.
We can summarize the more important risk factors in two groups. They are modifiable risk factors (those we can change at a given moment) and non-modifiable risk factors (those we cannot change in any way).
Modifiable risk factors (3):
- Diet and nutrition: Our diet can influence our susceptibility to cancer in general and prostate cancer in particular. However, there is not enough research to make a conclusion, and we still have some conflicting evidence. Still, it is possible to point out certain foods and substances on the blacklist. For example, we should avoid alcohol and reduce red meat, dairy, and other sources of saturated fat.
- Exercise and BMI: Studies show that being sedentary increases the risk of prostate cancer. The same happens with obese individuals—a BMI of 30 or more increases the risk of prostate cancer and a more aggressive type. According to studies, being obese is also a risk factor to experience recurrence of prostate cancer after treatment.
- Vasectomy: We still don’t know why, but patients with a vasectomy have a slightly higher risk of prostate cancer.
Non-modifiable risk factors (3):
- Old age: Age is one of the most important non-modifiable risk factors. Prostate cancer is very rare before 40 years of age. The risk increases as the age go up, and most diagnoses are made in men of 65. After 70 years, an average of 50% of men will have prostate cancer. Most of them won’t be diagnosed because their condition is not aggressive.
- Family history: Prostate cancer is more common in men with a family history. It is more relevant when family history comes from first-degree relatives (father and brothers). The disease runs in families similar to other types of cancer due to genetic predisposition. Prostate cancer genes in affected families are usually associated with the androgen receptor’s function in the prostate gland.
- African American origin: For similar genetic predisposition, prostate cancer is more common in men of African American origin. Caucasians have an intermediate risk and Asians a lower risk. Lifestyle and culture contribute to this predisposition as well as genetics.
- Hormonal factors: Androgens are fundamental for prostate function. This gland has important androgen receptors that trigger many functions in the cell. Thus, the relationship between androgens and high levels of DHT can increase the risk.
Patients with the symptoms listed above and one or more risk factors should be screened for prostate cancer. When doctors find a suspicious case of stage 4 prostate cancer, they perform a variety of tests.
They should include a complete blood count, serum creatinine, alkaline phosphatase levels, and a liver profile test. The PSA test is a fundamental part of the diagnosis, as well as the free-to-total PSA ratio. However, some patients with aggressive cancer may not have high PSA levels. Another critical exam is a urinalysis and urine culture in case of abnormal results.
In high-risk patients with symptoms or a combination of indicatives of aggressiveness, the Gleason score is a fundamental tool. Patients with a high Gleason grade have a higher risk of stage 4 prostate cancer. Thus, they are recommended a series of studies that include:
- Molecular and histologic markers: There are very specific markers of aggressiveness. They are useful to evaluate the progression of prostate cancer in a given patient. They include p21, p53, DNA ploidy studies, E-cadherin, and kallikrein 2. There is also a histologic marker of angiogenesis known as microvessel density.
- Bone scans: Prostate cancer predominantly migrates to distant lymph nodes and bone tissue. This type of study is recommended in patients with a Gleason score of 7 or more, especially when the PSA level is 20 ng/mL or more. It is also recommended in patients with symptoms of metastasis, regardless of any other test or marker. Negative results do not automatically rule out metastasis because even when metastasis happens, it takes up to 5 years to show up in a bone scan.
- X-rays, CT, and MRI: These imaging studies are also essential to rule out metastasis in different organs. It is particularly helpful to visualize pelvic lymph nodes. It is also useful to spot metastasis in the liver, lungs, or hydronephrosis.
Most patients with stage 4 prostate cancer display evident symptoms. Their age group, symptoms, and lab tests are usually enough to know what is happening. However, in some cases, doctors may need to run additional tests to rule out other diseases.
One of them is Paget disease, which causes susceptibility to bone fractures and other symptoms of bone metastasis. Patients with neurologic symptoms should also rule out other causes independent from prostate cancer. For example, in some cases, there is a coexistence of prostate cancer and lymphoma in the same patient (4, 5).
Before any treatment attempt is made, doctors should know whether cancer has spread locally (as in the seminal vesicles) or extended areas of the body.
In most cases of prostate cancer, hormone therapy (androgen suppression therapy) is recommended. This therapy increases the survival rate of prostate cancer patients, even those with metastasis. But sooner or later, prostate cancer becomes resistant to this therapy.
That’s when we call it hormone-refractory prostate cancer. Besides antiandrogens, doctors may use gonadotropin-releasing hormone analogs. They decrease serum testosterone by reducing LH and FSH levels. Other treatments include (6):
- Bisphosphonates: Useful for patients with bone mineralization problems due to bone metastasis. They inhibit the activity of the osteoclasts and the dissolution of bone crystals.
- Corticosteroids: They are usually combined with antiandrogens for more effectiveness. They have potent anti-inflammatory properties and modulate the immune response.
- Chemotherapy agents: They may be used to inhibit proliferation and further growth.
- Immunologic agents: This type of therapy stimulates the immune system to build a more robust response against cancer. They use autologous cellular immunotherapy agents.
- Radiotherapy: Radiation therapy is mainly recommended in locally advanced prostate cancer. It can be used in distant metastasis, too, but only as palliative therapy. For example, radiotherapy can be used when bone metastases lead to severe pain, and patients turned to hormone-refractory disease.
- Radium 223 dichloride: Also known as Xofigo, it is a radioactive agent useful for patients with bone metastasis and no known metastasis in other organs. This therapy moderately improves the survival rate and has been in circulation since 2013.
- Suramin: It inhibits growth factors, and it is useful in patients with the hormone-refractory disease. It is usually used combined with other drugs listed above.
- Cabazitaxel: It is a recent inhibitor of microtubules. It is not a first-line treatment but can be used along with prednisone in cancer patients who were previously treated with docetaxel.
- Enzalutamide and apalutamide: These agents inhibit the androgen receptor and are useful in patients who no longer respond to androgen deprivation therapy. They are both very recent options for castration-resistant prostate cancer.
The prognosis is poor, but patients should receive supportive therapy throughout their disease. They may need pain management medication, especially in terminal patients.
It may also be recommended in patients who have not responded appropriately to therapy. They are generally recommended a low-fat diet and including vegetables such as tomato, broccoli, and other sources of dietary antioxidants.
In the case of a pathologic fracture or paralysis due to the spinal cord’s compression, these patients should be hospitalized and immobilized to prevent further damage (6).
When a prostate tumor has turned into metastatic cancer, the diagnosis and prostate cancer treatment changes radically. These patients are sometimes detected after radical prostatectomy when the prostate biopsy shows a very high Gleason score.
Even if it looks like localized prostate cancer, doctors need to examine distant and nearby lymph nodes, imaging exams, and other traces of the metastatic disease.
According to clinical trials, treatment for this type of cancer increases life expectancy. But the relative survival rate is relatively low. In these cases, hormone therapy is often recommended as a first-line option. Other treatments include radiotherapy, corticosteroids, immunotherapy, and much more. It is also essential to provide supportive therapy and clarify to the patient and the family that the prognosis is not optimistic.