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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.
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 2008.1 In 2012, about 241,740 men will be newly diagnosed with prostate cancer in the United States alone.2 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.3,4 However, about one-third of men who have undergone primary treatment with either prostatectomy or radiation therapy need additional therapy because of progressive disease.5
The standard systemic therapy for patients who progress after primary treatment is androgen deprivation.6 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.6 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.6 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).6,7,8
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.8 Prostate cancer still remains the second most common cause of death in men in the United States.2
Castration-resistant disease is manifested in several ways.8
CRPC is aggressive, with median bone metastasis—free survival of 25 months (bone is the most common site of metastasis).8 Until recently, the initial treatment approach has been ADT to control PSA with an anti-androgen drug and LHRH agonist.9 Upon further disease progression, chemotherapy often is used to control symptoms and extend survival.10
In most patients with prostate cancer, clinical prognostic factors are used to identify patients at risk for metastatic disease.11,12 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.2
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 T3-4.11 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.13 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.14 These two factors have been significantly associated with shorter time to first bone metastasis and also predicted overall survival and bone metastasis—free survival.14
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.11,15 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.16 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.11
ADT for metastatic prostate cancer is not curative and has not been proven to prolong survival.17 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.17
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.6 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.6
Thus, there remains a substantial unmet need for men with metastatic prostate cancer for a therapy that controls disease while maintaining quality of life.
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.18
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).18
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.18
Provenge activates immune cells to target and attack prostate cancer.
Image courtesy of Dendreon
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 Figure 1.
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.19 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).19 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.19 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.19
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.19 At the time of data cutoff, overall survival was significantly prolonged for patients receiving sipuleucel-T (hazard ratio = 0.775; P = 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.19,20
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.19 Overall, only three patients in the sipuleucel-T group were unable to receive all three infusions because of infusion-related adverse events.19
In April 2010, the U.S. Food and Drug Administration approved Provenge for patients with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer.21 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.22 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.23
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).20 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.23 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.24 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.20,23
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.20 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.20
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.25 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.20 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.
At initial assessment, the patient completes the Dendreon ON Call Patient Enrollment Form. This enables Dendreon ON Call to review the patient’s benefit coverage to determine what, if any, out-of-pocket expenses the patient will incur. [See below for information about Dendreon ON Call.]
Don remains free of symptoms and does not want a therapy that would interrupt his active lifestyle or cause persistent side effects. The physician suggests Provenge, and Don expresses interest. The nurse begins the critical patient education regarding immunotherapy and does the initial assessment. Don has adequate peripheral venous access, so the team completes the Patient Enrollment Form and submits it to Dendreon ON Call.
Treatment with a therapeutic vaccine is unlike conventional therapy in numerous ways. Many patients and caregivers are not familiar with the specifics of immunotherapy, so thorough education is essential, beginning as soon as treatment with Provenge becomes an option and continuing throughout the
Apheresis is the procedure during which the necessary immune cells are separated from the patient’s blood and then used in the creation of the patient’s personalized dose of Provenge. The nurse should talk the patient through the procedure step-by-step prior to the first appointment. The apheresis procedure takes place about three days prior to the Provenge infusion date. Within 30 days prior to the first apheresis procedure, a complete blood count confirms that the patient is not severely anemic and therefore can safely undergo blood extraction.20
Apheresis involves inserting a large-bore intravenous needle (16- or 18-gauge) into each arm. Blood is taken from one site and separated, and the desired immune cells are stored. The remaining blood product is returned to the patient through the second site. This process also may be successfully completed through a double-lumen central line. Apheresis takes approximately three to four hours to complete. Because most patients with metastatic CRPC have not undergone this procedure before, they will need to be informed about what to anticipate and how they can best prepare themselves. See Figure 2 for patient instructions about apheresis.
Once the immune cells are collected, they are immediately shipped to a Dendreon facility to be manufactured into Provenge. The transport of the biologic material is organized and tracked by Dendreon. About three days after the apheresis procedure, the patient will have an appointment at his physician’s office or clinic for the infusion of Provenge.
The infusions are administered on an outpatient basis, about once every two weeks for a total of three doses (in clinical trials, the dosing interval ranged from 1—15 weeks). Each dose of Provenge contains a minimum of 50 million autologous cells, suspended in 250 mL of Lactated Ringer’s solution, and each bag is labeled with a unique patient identifier, as well as expiration dates and times.18 The product is not routinely tested for transmissible infectious diseases because it is intended for autologous use; therefore, healthcare professionals must observe universal precautions when handling it.18 Provenge is slightly cloudy and pale pink in color. It may arrive with visible, small clumps of cellular material; however, the clumps generally disperse with very gentle massage or mixing. If the clumps do not disperse, the product should not be used and the nurse should call Dendreon ON Call, which will arrange for the product to be returned to Dendreon. Provenge should not be left at room temperature for more than three hours.20 This is an important consideration in cases when a patient has an infusion reaction and the infusion is interrupted.
Prior to the actual Provenge infusion, the nurse instructs the patient about the risk of infusion reactions. To help minimize infusion reactions such as chills and fever, the healthcare team premedicates the patient with oral acetaminophen and an antihistamine, such as diphenhydramine, about 30 minutes prior to the administration of Provenge.20 Central venous catheters are not required; however, if a patient has one, the infusion may be given through that catheter. If not, a large-bore intravenous needle suitable for blood transfusions is placed (18- or 20-gauge). If the patient does indeed have a central line in place, the lumens should be flushed, the site cleaned, and the dressing changed prior to the initiation of the infusion. This is a prime teachable moment regarding catheter care at home, as well as the signs and symptoms of infection and blood clots. During Provenge infusion, a cell filter should not be used. The infusion is given over 60 minutes.20
Patients should be instructed in advance to bring a companion or driver to Provenge infusions. If an infusion reaction occurs, patients may be treated with medications that would preclude them from driving themselves home. Additional diphenhydramine may be administered, or meperidine for chills, which were reported in 53% of patients treated in clinical trials.20 Patients are kept for at least 30 minutes after infusion for observation and checks of vital signs. If any deviation occurs from the pre-arranged schedule or any issues arise with the apheresis or product delivery or viability, the entire process must be repeated. Of note, Dendreon will only charge for products that have been infused successfully. As previously mentioned, this process is repeated three times, about once every two weeks, for a complete course of therapy.
In immunotherapy for prostate cancer, the tumor is an indirect target; the primary goal is stimulation of the immune system, which subsequently targets the tumor.26 Once infused into the body, Provenge activates immune cells called T cells. The activated T cells are able to specifically recognize and attack prostate cancer cells. Consequently, patient educational points include the expectations of immunotherapy and how they differ from other therapies used in the treatment of prostate cancer. Although a benefit in overall survival was demonstrated in clinical trials, no significant impact was seen on progression-free survival.19,27 Because patients tend to focus on those tangible milestones, they need education about the basic mechanisms of immunotherapy, with an emphasis on the fact that generating an effective immune response takes time and that the therapy may potentiate an antitumor response that persists after the course of immunotherapy is completed.26
Don successfully initiates the apheresis process. During his first Provenge infusion, he experiences moderate chills. The infusion is rate is slowed, and he responds. In the first day after his infusion, Don notifies the nurse that he is having mild generalized arthralgias. The nurse instructs him to use acetaminophen or ibuprofen as needed for comfort. Don’s remaining infusions are completed without incident, and the course of therapy is complete within a month of initiation.
Significant support is available to assist patients being treated with Provenge and their healthcare providers. Patients and healthcare teams can access the assistance through Dendreon ON Call, a call center staffed by a team of coordinators who serve as the primary contact about patient assistance programs, reimbursement support, and patient logistical support. Upon receipt of a completed Patient Enrollment Form, a dedicated coordinator will provide benefits verification, typically within 48 hours. If a prior authorization is needed, the coordinator will research, collect information about, and track the progress of the prior authorization. Dendreon ON Call agents also will assist with coding and billing support and will provide local payer policy expertise.
Provenge is covered by all Medicare Administrative Contractors, if used for the indication approved by the U.S. Food and Drug Administration. For about three-quarters of patients, there will be minimal to no out-of pocket expense for the therapy. The remaining patients will typically have up to a 20% co-insurance.28 For patients who need financial help, assistance is available. Dendreon is committed to helping patients get treatment when they need it. Several patient-assistance programs are available to help patients gain access to Provenge. If a patient has a significant co-pay, co-insurance, or deductible, a reimbursement coordinator may refer him to an independent foundation for financial help. Independent foundations also may be able to provide funding to cover travel-related expenses that a patient may incur for treatment with Provenge. If a patient has no health insurance at all, or if a claim for coverage is denied by an insurance company after all appeals, the patient may be able to get Provenge at no cost through a program sponsored by Dendreon.
In addition to providing reimbursement support, Dendreon ON Call will provide product support. A scheduling coordinator will develop individualized schedules for apheresis appointments and infusion appointments, complete with appointment dates, times, locations, and product treatment windows with expiration information. Dendreon ON Call will call patients with reminders of upcoming apheresis appointments (patients may opt out of this service if they choose), and agents will assist and coordinate product deliveries and returns as necessary. For additional information, patients or healthcare providers may call Dendreon ON Call at 1-877-336-373, call Dendreon Medical Information at 1-877-768-3643, or visit www.PROVENGEreimbursement.com.
Don lives about one hour from the nearest apheresis and infusion centers. He is on a fixed income and is having difficulty covering the travel expenses to and from his appointments. The nurse notifies a Dendreon ON Call coordinator, who facilitates Don’s receipt of travel assistance through an independent foundation.
Provenge is the first and only immunotherapy approved by the US Food and Drug Administration for men with asymptomatic or minimally symptomatic metastatic castration- resistant prostate cancer. The use of this immunotherapy in the treatment of metastatic CRPC broadens treatment options by providing a clinical benefit with a safety profile you and your patients can manage. The role of nurses is critical, and they must be proactive with appropriate patient identification, education, and symptom management to achieve the maximum benefit for patients.
Historically, the only therapy available for patients with metastatic CRPC proven to provide a survival benefit has been chemotherapy. Over the past several years, new agents have been developed and approved for use in patients with advanced prostate cancer. After treatment with Provenge, those new agents may still be used as indicated, offering a multitude of treatment options for patients, where there once were few.
This white paper was developed by ONS:Edge and Dendreon Corporation. All content belongs to and is copyrighted by Dendreon Corporation. ONS:Edge provided editorial assistance, distribution, and promotion. ONS:Edge participation in this project does not imply product endorsement.
For more information about this paper or to download copies, visit www.onsedge.com. ONS:Edge can be contacted by email at firstname.lastname@example.org or by telephone at 877-588- EDGE (3433) or 412-859-6108.
Reprinted with permission from Dendreon Corporation.