This article was written in collaboration with Dr. Michael Bivins, Dr. Carrie Lenneman, and Dr. Mollie deShazo.
The most common cause of death in men is cardiovascular disease, followed by cancer. Prostate cancer is the number one cause of cancer in men. The numbers are staggering. In 2019, 3,650,000 men were diagnosed with prostate cancer. That number is expected to climb to 5,017,810 by 2030. In the U.S., there were 174,000 new cases of prostate cancer in 2019 with an estimated 31,000 patients dying from cancer.
In patients who survive prostate cancer, cardiovascular disease becomes the predominant cause of morbidity and mortality after 10 years. Mitigating cardiovascular disease in cancer patients not only improves the cardiovascular specific but also the cancer-specific mortality.
For these reasons, the US Preventive Service Task Force recommends PSA (Prostate-specific antigen) screening after an informed discussion with the patient.
What Does It Mean if Your PSA Is Elevated?
The majority of patients with a PSA of < 4ng/mL will have a normal prostate (10-15% may have cancer if a biopsy is done). PSA levels go up slightly as we get older. Sometimes, inflammation of the prostate (infection, sexual activity) can raise the levels. Other times, taking the male hormone testosterone can raise the levels as well. In patients with a borderline PSA level (4-10 ng/mL), prostate cancer is present in 25% of the cases. That number rises to 50% if the PSA is > 10 ng/mL.
The frequency of cancer is increased in patients with a family history of prostate cancer (especially if a family member is diagnosed before the age of 50) and in the African-American population. The patients are usually referred to a urologist, who will take a detailed clinical history and physical exam that will include an exam of the prostate. Following this, a prostate biopsy will be performed, and different imaging studies will be required to stage cancer. These may include CT/MRI of the pelvis and bone scan to determine whether the cancer is localized or advanced with metastasis.
What if You Have Localized Prostate Cancer?
Localized prostate cancer means that the cancer is growing inside the prostate and has not spread to other parts of the body. Often, localized prostate cancer is slow-growing, may not need any treatment at all, and may be set for active surveillance. The treatment approach is determined by evaluating whether the patient is at risk of progression to disseminated or fatal disease. Several criteria are taken into consideration and include age at diagnosis, the PSA level, the pattern of cancer differentiation at pathology (called the Gleason score), whether the cancer is locally advanced or not, and the percentage of positive biopsies (>34% of positive biopsy cores yielding a higher risk of recurrence).
Usually, patients at low risk will require active surveillance unless they have a higher probability of progression. Prostatectomy or radiation may be offered then and can be considered curative.
Patients at intermediate and high risk of progression will usually be treated with prostatectomy or radiation combined with androgen deprivation therapy to lower the testosterone levels since research has suggested that testosterone fuels prostate cancer growth.
Treatment in this population often includes the addition of newer novel androgen synthesis blockage (abiraterone) as well.
In the diagnosis of localized prostate cancer at high risk for recurrence (2 of 3: Gleason 8+, T3/4, PSA 40+), the addition of 2 years of abiraterone and prednisone leads to improvement in progression-free survival and overall survival. Risks of this additional therapy include but are not limited to hypertension, CV events, liver function abnormalities, and fatigue. Generally, abiraterone is well tolerated.
What Is Androgen-Deprivation Therapy (ADT)?
Androgen deprivation therapy (ADT) or castrate therapy is indicated for newly diagnosed metastatic disease, a localized disease with high-risk features, PSA rising during treatment, or after prostatectomy.
There are two types of ADT: Luteinizing hormone-releasing hormones (LHRH) agonists such as leuprolide (Lupron or Eligard) and Gonadotropin-releasing hormones (GnRH) antagonists such as Degarelix (Firmagon) and the pill Orgovyx. They produce a lowering of the testosterone and provide a medical castration. ADT is used in approximately 40% of patients at some point in their prostate cancer. ADT is considered a medical castration with results in a severe lowering of the testosterone and estrogen levels and anticancer response.
ADT can improve the likelihood of survival, but many men will still progress to hormone-refractory prostate cancer.
What if You Have Advanced Prostate Cancer?
Patients can develop advanced prostate cancer without metastasis if the PSA starts rising 0.2 ng/mL after prostatectomy or rises to >2 ng/mL after radiation, particularly if the rise occurs within 2 years of treatment. In these instances, watchful waiting, entering a clinical trial, or treatment with ADT are options. Hormonal therapy such as androgen-deprivation therapy (ADT) can limit disease progression but produces adverse effects.
If a patient is diagnosed for the first time with prostate cancer with metastasis (in the lymph nodes or the bones), ADT combined with novel androgen blockade (abiraterone, enzalutamide, etc.) with or without combination with docetaxel is considered the primary approach. The same applies to patients with recurrence of cancer (with or without metastasis). Oncologists often refer to therapy as “double therapy” (ADT + novel androgen blockade) or triplet therapy when docetaxel is added to the doublet therapy. Cancer remains incurable, but the combination therapies have been shown to appreciably improve survival and slow the progression of the disease.
Androgen-Deprivation Therapy and the Risk of Atherosclerotic Heart Disease
In 2018, the FDA issued a warning about the GnRH agonists associated with increased diabetes mellitus, myocardial infarction, stroke, and death. ADT can cause metabolic derangement that can increase the cardiovascular risk, particularly in patients with previous cardiac disease, previous cardiac risk factors, or prolonged ADT treatment. Approximately 90% of men receiving ADT have baseline risk factors for coronary disease. Profound hypogonadism caused by ADT is associated with a variety of adverse health consequences: central adiposity, glucose intolerance, sarcopenia or muscle atrophy, and significantly reduced exercise tolerance within 3-6 months of treatment. This could obviously favor the development of atherosclerosis, but cardiac complications occur more rapidly.
Several questions remain unanswered: How do we monitor for cardiovascular events? Which ADT is optimal for patients with cardiovascular disease: GnRH agonists such as Leuprolide or GnRH antagonists such as Relugolix? There are GnRH receptors in the heart and the blood vessels, but little is known about their role. What is the effect of preventive measures such as statin therapy or exercise? Which ADT should we be using?
Major adverse cardiac events (MACE) occurred in 2.9% of patients with Relugolix (Orgovyx) vs 6.2% of men on Lupron in the HERO trial. Alternatives also include orchiectomy, which is permanent and requires an invasive procedure.
In the meantime, the American Heart Association is proposing the monitoring for risk factors and metabolic syndrome every 3 months by emphasizing the ABCDE of prevention: awareness, blood pressure, cholesterol/cigarette smoking, diabetes mellitus/diet, and exercise.
Hypertension With Enzalutamide and Abiraterone
Hypertension is a common side effect that clinicians and patients starting Enzalutamide and Abiraterone need to address. A meta-analysis study of 7 prospective prostate cancer trials by Iacovelli et al. found that high-grade hypertension (BP > 160/100 mmHg) was significantly higher in both Enzalutamide and Abiraterone, irrespective of steroid dose. This and other studies emphasize the importance of discussing HTN monitoring and management with patients when being treated for prostate cancer.