Stage IV (D) Prostate Cancer

Overview

A stage IV prostate cancer is said to exist if the final evaluation shows that the cancer has spread to distant locations in the body, which usually includes bones. Stage IV disease may be further classified as the following depending on the extent of the cancer (tumor):

  • The tumor has spread to pelvic lymph nodes or is obstructing the ureters (the tubes from the kidneys to the bladder), or both.
  • Cancer spread (metastasis) to lymph nodes outside the pelvic area, bone involvement, or spread to other distant parts of the body.

Patients diagnosed with stage IV prostate cancer can be broadly divided into two groups. Patients with cancer locally confined to the pelvis, but involving adjacent organs or lymph nodes have localized stage IV or D1 prostate cancer. Patients with disease that has spread to distant organs, most commonly the spine, ribs, pelvis and other bones have metastatic stage IV or D2 prostate cancer.

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Prostate cancer diagnosed in this stage is often difficult to cure, although patients may live for several years with effective treatment.  Recent advances in treatment have resulted in new treatment options that reduce symptoms and improve survival. Each person with prostate cancer is different, and the specific characteristics of your condition will determine how it is managed. The following general overview of the treatment of stage IV prostate cancer is intended to help educate you about treatment options and to facilitate a shared decision-making process with your treating physician.

Treatment of Metastatic Stage IV or D2 Prostate Cancer

Prostate cancer that has spread to distant organs and bones is treatable, but not curable with current standard therapies. Hormone therapy has been the standard treatment of metastatic prostate cancer for many years. Metastatic prostate cancer usually can be controlled with hormone therapy for a period of time, often several years.  Advances in chemotherapy, immunotherapy, and hormone therapy have expanded the treatment options available for patients with advanced prostate cancer in recent years.1

Hormone Therapy

Hormone therapy deprives a man’s body of male hormones necessary for prostate cancer to grow. Initial hormone therapy for prostate cancer can be achieved with orchiectomy or luteinizing hormone-releasing hormone (LHRH) analogues, alone or in combination with an anti-androgen.

Newer hormonal medications that inhibit the synthesis of androgen (abiraterone) and block androgen receptor signaling (enzalutamide) are now FDA-approved for the treatment of metastatic prostate cancer after treatment with chemotherapy, and are being evaluated for earlier use in the disease.2, 3, 4, 5, 6

Abiraterone (Zytiga®) Abiraterone is an oral targeted agent that blocks the production of androgens not only by the testes, but also by the adrenal glands and the tumor itself.  Abiraterone when administered with prednisone has been shown to improve quality of live and delay patient-reported pain progression in HRPC patients.  Although this medication is generally well-tolerated, side effects may include fatigue, high blood pressure, and electrolyte or liver abnormalities and patients need to be monitored regularly.2, 3, 6

Enzalutamide (Xtandi®) Enzalutamide targets multiple steps in the androgen-receptor–signaling pathway, interfering with molecular pathways that help the prostate cancer grow. What’s more, the drug does not cause side effects commonly associated with chemotherapy, such as nausea and hair loss. Enzalutamide has been shown to improve survival, reduce the risk of cancer progression, and delay the need for additional chemotherapy in men with HRPC.3, 5

Chemotherapy

Chemotherapy, like hormone therapy is a systemic therapy in that the cancer-fighting drugs circulate in the blood to parts of the body where the cancer may have spread and can kill or eliminate cancers cells at sites great distances from the original cancer.  Several chemotherapeutic drugs have demonstrated the ability to kill prostate cancer cells in patients with advanced prostate cancer. In particular, the chemotherapy drugs mitoxantrone (Novantrone®), docetaxel (Taxotere®), paclitaxel and estramustine have all been demonstrated to have some effectiveness in treating prostate cancer.7, 8

Docetaxel chemotherapy was demonstrated to improve survival of men with advanced HRPC in 2004 and has remained the mainstay of chemotherapy often utilized in combination with prednisone or estramustine. The results of a more recent study conducted by researchers at the Dana-Farber Cancer Institute recently confirmed the role of docetaxel chemotherapy. Docetaxel when administered with androgen-deprivation therapy (ADT) to metastatic prostate cancer patients was found to extend overall survival by more than 13 months.9 These results were reported at the 2014 American Society of Clinical Oncology meeting held in Chicago. The study included 790 men with hormone-sensitive metastatic prostate cancer. Patients were treated with standard ADT and compared with those treated with ADT plus docetaxel. Men treated with ADT/docetaxel had a median overall survival rate of 57.4 months compared to only 44 months for those treated with ADT alone. Importantly, for men with a high disease burden at the beginning of the study, the survival difference was even greater: a median overall survival of 49.2 months versus 32.2 months.

More recently, several new chemotherapy and targeted therapy drugs have been approved for the treatment of advanced prostate cancer. A Targeted therapy is one that is designed to treat only the cancer cells and minimize damage to normal, healthy cells. Treatments that “target” cancer cells may offer the advantage of reduced treatment-related side effects and improved outcomes. Doctors are working to determine the best sequence, combinations, and timing of utilization of newer chemotherapy and targeted therapy drugs.

Cabazitaxel (Jevtana®): Cabazitaxel is administered intravenously and has been demonstrated to improve time to cancer progression and overall survival in men with HRPC previously treated with docetaxel.   Cabazitaxel’s primary side effect is neutropenia, and it is recommended that patients receive a white blood cell growth factor if they are at high risk of this complication.10

Immunotherapy

Biological therapy is referred to by many terms, including immunologic therapy, immunotherapy, or biotherapy. Biological therapy is a type of treatment that uses the body’s immune system to facilitate the killing of cancer cells. Types of biological therapy include interferon, interleukin, monoclonal antibodies, colony stimulating factors (cytokines), and vaccines.  Biologic therapies are being developed for the treatment of prostate cancer.

Sipuleucel-T( Provenge®): Sipuleucel-T is an immunotherapy that prompts the body’s immune system to respond against the cancer. A Phase III clinical trial that contributed to the FDA approval of sipuleucel-T was a study known as IMPACT (Immunotherapy for Prostate Adenocarcinoma Treatment) which demonstrated an improvement in overall survival for men treated with sipuleucel-T. The main side effects reported were chills, fever, and headache.11

Treatment of Bone Complications

Patients with advanced prostate cancer can have cancer cells that have spread to their bones, called bone metastases.  Bone metastases commonly cause pain, increase the risk of fractures, and can lead to a life-threatening condition characterized by an increased amount of calcium in the blood called hypercalcemia.  Treatments for bone complications may include drug therapy or radiation therapy.12

Zoledronic acid (Zometa®): Zoledronic acid is a bisphosphonate drug that can effectively prevent loss of bone that occurs from cancer that has spread to the bones thereby reducing the risk of fractures, and decreasing pain. Bisphosphonate drugs work by inhibiting bone resorption, or breakdown. Zoledronic acid may be used to reduce the risk of complications from bone metastases or to treat cancer-related hypercalcemia,

Denosumab (Xgeva™): Denosumab targets a protein known as the RANK ligand. This protein regulates the activity of osteoclasts (cells that break down bone). Studies have suggested that Denosumab may be more effective than Zoledronic acid at delaying bone complications in prostate cancer patients with bone metastases.  Denosumab is associated with side effects including hypocalcemia (low levels of calcium in the blood) and osteonecrosis of the jaw (death of bone in the jaw).15

Xofigo® (radium Ra 223 dichloride): Radium 223 is a targeted radiopharmaceutical agent that binds with minerals in the bone to deliver radiation directly to bone tumors, thereby limiting the damage to the surrounding normal tissues. The U.S. Food and Drug Administration (FDA) approved the drug in May 2013 after a trial known as Alpharadin in Symptomatic Prostate Cancer Patients (ALSYMPCA) was stopped early after an interim analysis showed that treatment with significantly improved survival.16 

Radiation therapy: Pain from bone metastases may also be relieved with radiation therapy directed to the affected bones.

Treatment of Localized Stage IV or D1 Prostate Cancer Prostate cancer may not be diagnosed until it has invaded adjacent organs, such as the rectum or bladder, or spread to lymph nodes in the pelvis. When this occurs, surgery (radical prostatectomy) is seldom an effective treatment. Current treatment involves a combination of external beam radiation therapy (EBRT) and hormone therapy. In localized stage IV prostate cancer, hormone therapy and radiation therapy are often given together and studies have demonstrated that patients treated with radiation therapy and immediate hormonal therapy are more likely to be alive 5 years from initiation of treatment without evidence of cancer progression or development of distant metastatic disease than patients treated with radiation and delayed hormonal therapy. The combination of radiation and immediate hormonal therapy appear to increase the survival of some patients.1

Strategies to Improve Treatment

The progress that has been made in the treatment of prostate cancer has resulted from development of better treatments that were evaluated in clinical studies. Future progress in the treatment of prostate cancer will result from patients continued participation in appropriate clinical trials. Developing novel immunotherapy and single or multi-agent chemotherapy treatments for patients with advanced prostate cancer is the main area of active investigation.

Immunotherapy: Novel vaccine strategies to harness the immune system are being tested, such as PROSTVAC in asymptomatic, chemotherapy-naïve men prostate cancer Other immune based strategies include inhibition of immune check points using Ipilimumab, which is a monoclonal anti-CTLA4 antibody that binds to a receptor on T cells, blocking CTLA4 and, in turn, activating T-cell anti-tumor activity.

Chemotherapy: Because hormone therapy is not curative and only controls metastatic prostate cancer for a certain amount of time, efforts are underway to discover more effective systemic therapy. Combining agents with novel or different mechanisms of killing prostate cancer cells with docetaxel remains an area of significant interest.

Custirsen is a novel chemotherapy drug that inhibits the production of clusterin, a protein associated with treatment resistance in a number of cancers, including prostate cancer.

Orteronel is a CYP17A inhibitor but is more specifically a 17,20-lyase inhibitor. It is currently being tested in a phase III trial comparing orteronel and prednisone to placebo and prednisone.

Tasquinomod is an orally active quinoline-3-carboxamide that has anti-angiogenic and anti-tumor properties.

References

1 http://www.auanet.org/education/guidelines/prostate-cancer.cfm

2 Basch E, Autio K, Ryan CJ, et al: Abiraterone acetate plus prednisone versus prednisone alone in chemotherapy-naive men with metastatic castration-resistant prostate cancer: patient-reported outcome results of a randomised phase 3 trial. The Lancet Oncology. 2013; 14(12):1193-1199.

3 Beer TM, Armstrong AJ, Sternberg CN, et al: Enzalutamide in men with chemotherapy-naive metastatic prostate cancer (mCRPC): Results of phase III PREVAIL study. Presented at the 2014 Genitourinary Cancers Symposium. Journal of Clinical Oncology. 2014; 32 (supplement 4; abstract LBA1).

4 Nelson J, Banato A, Battistini B, Nisen P.  The endothelin axis: emerging role in cancer. Nat Rev Cancer2003;3(2):110-116.

5 Scher HI, Fizazi K, Saad F et al: Increased survival with enzalutamide in prostate cancer after chemotherapy. N Eng J Med 2012; 367: 1187.

6 de Bono JS, Logothetis CJ, Molina A et al: Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011; 364: 1995.

7 Tannock I, de Wit R, Berry W, et al.Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for Advanced Prostate Cancer. New England Journal of Medicine. 2004; 351:1502-1512.

8 Petrylak D, Tangen C, Hussain M, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. New England Journal of Medicine. 2004; 351:1513-1520.

9 Sweeney C., et al. Impact on overall survival with chemohormonal therapy versus hormonal therapy for home-sensitivity newly metastatic prostate cancer: An ECOG-led phase III randomized trial. ASCO 2014; Abstract LBA2.

10 de Bono JS, Oudard S, Ozguroglu M et al: Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomized open-label trial. Lancet 2010; 376: 1147.

11 Kantoff PW, Higano CS, Shore ND et al: Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010; 363: 411.

12 Higano C, Shields A, Wood N, et al. Bone mineral density in patients with prostate cancer without bone metastases treated with intermittent androgen suppression. Urology 2004;64(6):1182-6.

13 Saad F, Gleason D, Murray R, et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. Journal of the National Cancer Institute 2002; 94:1458-1468.

14 Smith MR, Eastham J, Gleason DM, et al. Randomized controlled trial of zoledronic acid to prevent bone loss in men receiving androgen deprivation therapy for nonmetastatic prostate cancer. Journal of Urology 2003; 169:2008-2012.

15 Smith MR, Saad F, Coleman R et al. Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet. Early online publication November 16, 2011.

16 Michalski J, Sartor O, Parker C, et al. Radium-223 dichloride (Ra-223) impact on skeletal-related events, external-beam radiotherapy (EBRT), and pain in patients with castration-resistant prostate cancer (CRPC) with bone metastases: Updated results from the phase III ALSYMPCA trial. Proceedings of the 55th Annual Meeting of the American Society of Radiation Oncology. International Journal of Radiation Oncology Biology Physics. 2013; 87(2): S108-S109. Abstract 265.

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