	In 2000, Dr. Howard Scher published the then-current practice algorithm for the various stages of prostate cancer. Healthcare practitioners used that algorithm almost exclusively and virtually unchanged for the ensuing 10 years. Then, in the spring of 2010, the algorithm changed substantially for patients with advanced prostate cancer. Two new therapies were approved for use in patients with post-docetaxel, metastatic, castration-resistant, progressive prostate cancer, and something happened that scientists had long worked toward. In April 2010, the US Food and Drug Administration approved sipuleucel-T (Provenge®, Dendreon Corporation), an immune therapy and the first treatment for pre-chemotherapy use. Patients with castration-resistant and metastatic disease now had a treatment that would help the body fight its own cancer. This white paper focuses on the new immunotherapy, Provenge.

	Prostate cancer is the second most common cancer in men worldwide, with an estimated 903,500 new cases and 258,400 deaths in 2008.

 In 2012, about 241,740 men will be newly diagnosed with prostate cancer in the United States alone.

 Widespread use of screening with digital rectal examination and prostate-specific antigen (PSA) testing has led to an increasing proportion of prostate cancers that are localized at diagnosis, and fewer patients present initially with metastatic disease. In 1998, a retrospective data analysis suggested that 6.4% of presenting cases were stage 4. Most newly diagnosed patients with prostate carcinoma are asymptomatic and have moderately differentiated and organ-confined disease.

 However, about one-third of men who have undergone primary treatment with either prostatectomy or radiation therapy need additional therapy because of progressive disease.

	The standard systemic therapy for patients who progress after primary treatment is androgen deprivation.

 Currently, androgen-deprivation therapy (ADT), luteinizing hormonereleasing hormone (LHRH) agonists in combination with anti-androgen, is used for palliative treatment of advanced carcinoma of the prostate and as adjuvant therapy with radiation therapy.

 ADT tends to be used widely in other patient scenarios, including biochemical recurrence, locally advanced disease, lymph node metastasis, and asymptomatic metastatic disease, despite the fact that overall survival has not been demonstrated in clinical trials for ADT in metastatic disease.

 The median duration of response to ADT is about 10 years; however, almost all men on ADT eventually develop disease that is resistant to some hormonal regimens, which classifies a patient as having hormone-refrectory disease. Some men respond to secondary hormonal treatments, but when their disease is resistant to all hormonal manipulations, they have castration-resistant prostate cancer (CRPC).

	Clinical trials have demonstrated that a substantial proportion of men with CRPC go on to develop metastases. One study showed that 84% of men with CRPC had bone metastases at diagnosis; in another, 95% did. Men with no metastases at diagnosis commonly also develop metastases after diagnosis.

 Prostate cancer still remains the second most common cause of death in men in the United States.

	Castration-resistant disease is manifested in several ways.

		Rising PSA values despite hormonal therapy

		New sites of metastatic disease on radiographic imaging

		Clinical symptoms of the disease, such as fatigue, anorexia, or bone pain (with radiographic confirmation of metastatic disease)

	CRPC is aggressive, with median bone metastasis—free survival of 25 months (bone is the most common site of metastasis).

 Until recently, the initial treatment approach has been ADT to control PSA with an anti-androgen drug and LHRH agonist.

 Upon further disease progression, chemotherapy often is used to control symptoms and extend survival.

	In most patients with prostate cancer, clinical prognostic factors are used to identify patients at risk for metastatic disease.

 One such prognostic tool is the Gleason score. A Gleason grade predicts how fast cancer might spread on a scale of 1—5. One biopsy sample may have two Gleason grades, which are added together to provide a Gleason score. The higher a Gleason score, the more likely the cancer is to spread.

	Patients at high risk for the development of metastatic disease are those with Gleason score of 8 and higher, PSA greater than 20, and clinical stage T3-4.

 High serum PSA, rapid PSA doubling time, higher clinical stage, and the presence of extracapsular extension or seminal vesicle invasion of the tumor are other indicators that a patient is more likely to develop metastatic disease.

 Once patients become castration resistant, the time to development of bone metastases is impacted by a baseline PSA higher than 10 and a rapid PSA velocity.

 These two factors have been significantly associated with shorter time to first bone metastasis and also predicted overall survival and bone metastasis—free survival.

	Metastases from prostate cancer predictably go to the bone and lymph nodes. In fact, bony metastases can be found in approximately 85% of patients with end-stage prostate cancer, whereas as many as 60% of patients have lymph node metastases on autopsy.

 Additionally, men with progressive CRPC may have occult metastatic disease. A recent trial suggested that in patients believed to have non-metastatic disease, about 30% of CRPC patients had metastatic disease upon imaging despite a lack of symptoms or other indicators.

 Taking that statistic into consideration, routine metastatic workup should be done on high-risk patients who become castration-resistant, specifically those with poor prognostic indicators, including high grade Gleason scores, rapid PSA doubling time, and those with locally advanced disease at the time of diagnosis. Common methods of evaluating a man for the presence of metastatic disease include computed tomography scans of the abdomen and pelvis and a full-body bone scan. Rarely, if a patient has pulmonary symptoms, a chest x-ray or computed tomography of the chest may be done to evaluate for disease in the thorax.

	ADT for metastatic prostate cancer is not curative and has not been proven to prolong survival.

 Treatment-related side effects can adversely affect quality of life. The optimal timing to initiate treatment with ADT in patients with metastatic disease remains uncertain and is largely determined by the provider and the patient, given all of the known risks and benefits.

	The choice of whether to treat and how to treat metastatic prostate cancer also must be made based on the goals of treatment. In the setting of metastatic prostate cancer, patients generally receive ADT for the duration of their lives unless they opt for intermittent ADT; in such cases, testosterone is allowed to recover periodically. For these men with metastatic prostate cancer, the goal is generally to prolong survival, but the goal also may be to relieve symptoms from adverse side effects.

	The time to initiate ADT, the benefits of maximum androgen blockade (MAB), the management of adverse events associated with ADT, the role of intermittent ADT, and the benefits of secondary hormonal therapies remain unresolved.

 The critical issues are whether there is a benefit from early initiation of ADT and how large such a benefit is for asymptomatic patients.

	Sequential androgen blockade (SAB) has been evaluated and does reduce PSA levels. However, the survival benefit is unkown. Nevertheless, historically, multiple hormonal manipulations have been used before systemic chemotherapy. Secondary hormonal treatment options have included withdrawal of anti-androgen, anti-androgen monotherapy, cytochrome P450 inhibitors, estrogen therapy, and corticosteroids.

	Thus, there remains a substantial unmet need for men with metastatic prostate cancer for a therapy that controls disease while maintaining quality of life.

	Immune Therapy for Metastatic Prostate Cancer

	The development of sipuleucel-T vaccine was based on the concept of antigen presenting cells (APCs). These cells “present” antigens in a form that T cells can recognize. APCs are a group of white blood cells (WBCs) that include dendritic cells, macrophages, and B lymphocytes (B cells). These cells express major histocompatibility complex (MHC) class II and MHC class I molecules, which can stimulate CD4+ T-helper cells and CDS+ T cytotoxic cells, respectively. Invaders are first engulfed and brought inside the cell. They are then broken down into their antigens and are moved to the cell surface, where they are recognized by T -cell receptors.

	When there is a match between the T cell and the antigen, the T cell is stimulated and starts to produce several cytokines and other chemical messengers that include, but are not limited to, interleukin-12 (IL-12), granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factoralpha (TNF-cx), cytotoxic T cells, and B cells. Cytotoxic T cells are especially effective in destroying abnormal body cells, including cancerous cells.

	Prostate cancer cells express a number of tumor-associated antigens (which cause the immune system to produce antibodies against it), which can then serve as targets for immunotherapy (prostatic acid phosphatase [PAP], for example).

	Dendritic cells are efficient antigen-presenting cells (APCs) that initiate an antigen-specific immune response via uptake, processing, and presentation of antigens to T cells. In order for the immune system to be effective, T cells must be able to recognize the multitude of foreign molecules the body encounters without attacking the host.

		FIGURE 1. Provenge (sipuleucel-T) Mechanism of Action

		Provenge activates immune cells to target and attack prostate cancer.

	Provenge: The First Immunotherapy for Prostate Cancer

	Provenge (sipuleucel-T, Dendreon Corporation) is a therapeutic vaccine that is prepared from autologous peripheral blood mononuclear cells obtained by apheresis. These cells, including APCs, are activated ex vivo during a defined culture period with a recombinant human protein. This recombinant protein is comprised of PAP, an antigen expressed in prostate cancer, linked to human granulocyte-macrophage colonystimulating factor (GM-CSF), an immune cell activator. These activated cells are Provenge, and they are then infused back into a patient about three days after original harvesting. For Provenge’s mechanism of action, see 

	Provenge is an autologous active cellular immunotherapy for treatment of prostate cancer. The IMPACT trial studied the therapy in patients with asymptomatic or minimally symptomatic metastatic CRPC during a randomized, double-blind, controlled phase 3 trial. The results demonstrated a significant prolongation of overall survival.

 Supplemental analyses, including overall survival based on additional events collected prior to study closure, are reported later in this paper.

	In the IMPACT trial, asymptomatic and minimally symptomatic men with metastatic CRPC were randomly assigned to Provenge or to a control consisting of non-activated, autologous, peripheral blood mononuclear cells. Following progression, 64% of patients in the control group crossed over to a non-randomized, open-label protocol to receive an investigational autologous immunotherapy made from cryopreserved cells. The trial found a significant prolongation in overall survival with Provenge compared to control (the 36-month survival rate was 32% versus 23%, respectively).

 Immunologic assessment of the patients in the IMPACT trial provided additional evidence of effects from Provenge. Antibody titers against the antigen were more frequent in those treated with Provenge, as were antibodies against PAP, T-cell proliferation, and T-cell function.

 Patients were randomized (2:1) to receive three doses of sipuleucel-T (n = 341) or control (n = 171) intravenously at two-week intervals. Patients were stratified by primary Gleason grade, number of bone metastases, and bisphosphonate use.

	Prognostic factors were well-balanced; median predicted overall survival of patients in the sipuleucel-T and control arms was 20.3 and 21.2 months, respectively.

 At the time of data cutoff, overall survival was significantly prolonged for patients receiving sipuleucel-T (hazard ratio = 0.775; 

 = 0.032). Results were consistent in multiple patient subgroups, including prognostic groups. In the updated analysis after 349 deaths, the estimated median follow-up time was 36.5 months. Sipuleucel-T treatment effect remained significant. Unchanged were the median survival of 25.8 and 21.7 months and survival probability at 36 months of 32.1% and 23.0% in the sipuleucel-T and control arms, respectively.

	Infusion-related adverse events reported more commonly in the sipuleucel-T than in the control arm included chills, fever, headache, influenza-like illness, myalgia, hypertension, hyperhidrosis, and groin pain. Most events were grade 1 or 2 in severity, occurred within one day after infusion, and resolved in one to two days.

 Overall, only three patients in the sipuleucel-T group were unable to receive all three infusions because of infusion-related adverse events.

	In April 2010, the U.S. Food and Drug Administration approved Provenge for patients with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer.

 The approval was based on the findings of prolonged overall survival in the IMPACT trial.

	Given the aggressive nature of metastatic CRPC and the supposition that immunotherapy may take time to generate an effective immune response, it is critical to identify patients with CRPC who are at risk for developing metastases as early as possible in order to initiate immunotherapy at the onset of metastatic disease.

 Thus, when a castration-resistant patient develops metastatic disease, Provenge may be considered. The 2012 National Comprehensive Cancer Network guidelines for prostate cancer indicate that for an asymptomatic or minimally symptomatic patient with metastatic disease and castration-resistant disease, Provenge may be an appropriate first-line option.

	Provenge is indicated for patients with metastatic CRPC who are asymptomatic or minimally symptomatic (meaning there is no need for narcotic use for cancer-related pain).

 Nurses are actively involved in the identification of appropriate patients for Provenge treatment thorough chart audits, comprehensive reviews of disease history, and clinical assessment at visits.

	Ensuring that appropriate (high-risk) patients are imaged for metastatic disease every three to six months may lead to the identification of metastatic disease at its onset, leading to earlier access to treatment options such as immunotherapy. Nurses also assess patients’ performance status and administer inventories of pain and quality of life, the results of which can be useful in determining changes in quality of life and the onset of disease-related symptoms. Discovery of symptoms may prompt testing for metastatic disease.

	Because nurses often are the first source of patient contact, they are in a critical position to intercede early in the disease process or when patients report any disease-related symptoms and changes in clinical status. In practice, nurses are instrumental in making suggestions and recommendations regarding appropriateness for trials, treatments, and novel therapies.

	Consider a 68-year-old man, Don, with history of radical prostatectomy seven years ago with seminal vesicle involvement noted at the time of surgery. At the time of surgery, his Gleason score was 8. At 2.5 years after surgery, he started an LHRH agonist and bicalutamide for biochemical failure. After 19 months on combined androgen blockade, however, his PSA started to rise again, consistent with castration-resistant disease. Bicalutamide was stopped, with an anti-androgen withdrawal response noted. Five months later, with his PSA rising again, Don denies any symptoms other than expected hormonal side effects. He works full-time outside the home and travels regularly.

	Having done an extensive review of this patient’s medical history, the nurse is able to identify that he has indicators of a high risk of rapidly developing metastatic disease (i.e., seminal vesicle involvement, Gleason score). At the physician’s direction, the nurse arranges for imaging immediately and then every three to six months because of his high risk. After 12 months of imaging every four months, the healthcare team discovers two areas of bony destruction on bone scan with a negative computed tomography scan of the abdomen and pelvis. Don is now considered to be a patient with metastatic castration-resistant prostate cancer. He remains asymptomatic and active.

	When considering a treatment modality, healthcare practitioners must understand the differences among the available standard options, the settings in which the various therapies are used, as well as the expected outcomes of the treatments. Chemotherapy, for example, has a proven survival benefit but does not have a National Comprehensive Cancer Network category 1 recommendation until a patient is symptomatic from his disease, is progressing rapidly, or has visceral disease.

 Alternatively, the use of secondary hormonal agents, such as bicalutamide or ketoconazole, may achieve a meaningful response for patients with metastatic castration-resistant prostate cancer, yet a survival benefit in randomized phase 3 trials has not yet been shown.

 Immunotherapy is indicated for patients who are asymptomatic or minimally symptomatic, have good performance status, and have no hepatic metastisis, and it has proven survival benefit.

	Once an appropriate patient has been identified, the process of facilitating his access to immunotherapy may begin. The nurse plays a vital role in guiding patients at this stage, reviewing the mechanism of action of immunotherapy with the patient and emphasizing what he can expect. The conversation should stress that Provenge is neither a chemotherapy nor a hormonal therapy; it is a treatment that uses cells from the patient’s own immune system to provide personalized therapy. An important point in initial educational discussions it that the primary goal of the clinical trials of Provenge was not to lower PSA but to prolong survival and that it has been proven to help patients live longer, even if they do not have a discernible decline in PSA during or after treatment. Once a patient understands the goals of immunotherapy, the nurse explains how he may achieve those goals, with an emphasis on all of the support available to make the patient’s course of immunotherapy as successful as possible.

	A frank discussion is vital among the nurse, patient, anhis support person or caregiver regarding treatment with Provenge. A dedicated commitment to the determined treatment schedule is essential because it is created individually and specifically for each patient. The apheresis material and Provenge each have a strict expiration date and time.

 Consequently, the patient must be instructed to arrive on time for scheduled appointments and be aware of and willing to adhere to this commitment prior to embarking on the therapy. Before therapy, a patient’s treatment and disease history should be reviewed, as well as active concurrent medications. Given the mechanism of action of Provenge, patients may not be on concomitant systemic steroid therapy during treatment with the immunotherapy, although inhaled steroids are acceptable.

	Once a patient is ready to move forward with Provenge, an initial physical assessment establishes that the patient remains asymptomatic or minimally symptomatic with a strong performance status. The Eastern Cooperative Oncology Group measures performance status on a 0—5 scale (0 = fully independent to 5 = dead). The score signifies how a patient’s disease is progressing, reflects how the disease affects activities of daily living, and is used to determine appropriate treatment and prognosis.

 A score of 0—1 is appropriate for Provenge therapy.

	Before therapy, the nurse evaluates whether the patient has adequate venous access to support the apheresis necessary to create the immunotherapy and the actual Provenge infusion. Generally, a peripheral line may be used; a central venous catheter may be used after thorough evaluation by the nurse.

 In such cases, the nurse should educate the patient about catheter care to prevent and recognize infections and clots because they can delay Provenge doses. These determinations and education are important steps prior to the first apheresis appointment to minimize the number of intravenous sticks a patient must endure.

Articles

In April 2010, the FDA approved sipuleucel-T for patients with castration-resistant and metastatic prostate cancer, providing a new treatment that would help the body fight its own cancer.

Sandra Kelly, RN, MS, NP, Nurse Practitioner, Brigham & Womenâ€™s HospitalAllison Tyler, RN, BSN, OCNÂ®, CCRP, Staff Nurse, Cleveland Clinic

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Immunotherapy: Personalized Treatment for Advanced Prostate Cancer