US Pharm. 2007;32(7)(Oncology suppl):11-24.
ABSTRACT: Therapeutic cancer vaccines differ from traditional vaccines in that they are only given to patients who already have cancer, with the goal of decreasing the spread of the disease and prolonging survival. Such vaccines are designed to stimulate the immune system to selectively kill tumor cells. While therapeutic prostate cancer vaccines have not yet received FDA approval, many have shown promising activity in clinical trials. This article reviews the etiology, pathophysiology, diagnosis, and treatment of prostate cancer and explores the potential roles of three therapeutic prostate cancer vaccines: PROSTVAC-VF, Provenge, and GVAX.
Over the last decade, significant progress has been made in the diagnosis and treatment of prostate cancer.1 Today, prostate cancer can be detected earlier with the use of routine prostate-specific antigen (PSA) screenings.1,2 As a result, curative modalities offer better success rates. Treatment options for advanced disease are also better; hormonal therapy is commonly initiated earlier in the course of the disease, and more effective chemotherapeutic regimens that prolong survival are now being used.2,3 According to the American Cancer Society (ACS), these factors have contributed to a decrease in the mortality rate of prostate cancer of 3.5% annually in recent years.4 Despite these positive trends, prostate cancer still ranks as the second leading cause of cancer-related deaths in American men.1,2,4
Recent advances in understanding the pathophysiology of prostate cancer have led to the discovery of numerous potential therapeutic prostate cancer vaccines.5,6 While these products have not yet been approved for use in the United States, many have demonstrated promising activity in phase II and III clinical trials. 2,5,7
Prostate Anatomy and Physiology
The prostate, a walnut-sized gland located in the pelvis, is surrounded by the rectum, bladder, urinary sphincter, and penile innervation.8-12 The prostate is composed of three different cell types: stromal cells, glandular cells, and smooth muscle cells. The glandular cells within the prostate produce a milky fluid, and during sexual intercourse, the smooth muscles contract to squeeze this fluid into the urethra. At this point, the fluid mixes with sperm and other fluids to make semen. The prostate gland also contains an enzyme called 5 alpha-reductase, which is responsible for converting testosterone to dihydrotestosterone.4,8,9
Prostate cancer is the most common cancer in American males and the fourth most common cancer worldwide.1,4,10,11 About 1 in 6 men will be diagnosed with prostate cancer during his lifetime, but only 1 in 34 will die from it. The ACS estimates that in 2007, approximately 210,000 new cases of prostate cancer will be diagnosed, and 27,000 men will die from the disease. More than 99% of prostate cancers develop in glandular cells and are termed adenocarcinomas .4 Generally speaking, the survival rate for prostate cancer is excellent when the cancer is detected early.9
Causes and Risk Factors: While the exact cause of prostate cancer is unknown, data suggest that several factors may contribute to the development of the disease. Prostate cancer is more common in older men, with 75% of new prostate cancers diagnosed after age 65. African-Americans are 1.7 times more likely to develop prostate cancer than white Americans.10 In addition, prostate cancer occurs less often in Asian men than in white men, and Hispanic men develop prostate cancer at rates similar to those of white men; the exact reasons for these racial differences are not clear.4 Family history also appears to have a role. Men who have a first-degree relative (i.e., a father, brother, or son) with prostate cancer are twice as likely to develop the disease, compared with men who have no family history of prostate cancer. Other factors that may increase the risk of prostate cancer include exposure to industrial chemicals, high-fat diets, and high testosterone levels.10
Prevention: Limited data suggest that certain lifestyle changes and medications can prevent some cases of prostate cancer. Prostate cancer rates are lower in populations that have low-fat, plant-based diets. Furthermore, higher fat intake is associated with an increased risk of prostate cancer.12 Products such as tomatoes, pink grapefruit, and watermelon, which are rich in lycopenes--antioxidants that help prevent damage to DNA--may also lower prostate cancer risk slightly.4 Likewise, data suggest that certain vitamin and mineral supplements (e.g., selenium and vitamin E) may decrease prostate cancer risks. Perhaps the most convincing piece of evidence on this topic comes from the Prostate Cancer Prevention Trial. In this study, men who took finasteride (Proscar) were about 25% less likely to develop prostate cancer than those who took placebo.4,8
Symptoms: Prostate cancer usually does not cause symptoms in the early stages of the disease.9 However, as the malignancy spreads, it may constrict the urethra and cause urinary problems similar to those seen in benign prostatic hyperplasia.4,9,12 Locally advanced disease can invade adjacent tissues, including the seminal vesicles and bladder. Urinary dysfunction--decreased urine stream, inability to urinate, blood in the urine, interruption in the urine stream, frequent urination (especially at night), and pain and burning during urination--and new-onset impotence are symptoms of locally advanced prostate cancer.12 The primary symptoms associated with late-stage prostate cancer usually include significant pain in one or more bones. This chronic pain occurs most often in the spine and sometimes flares in the pelvis, lower back, hips, or bones of the upper legs. In many cases, the chronic pain may also be accompanied by significant weight loss. 9
Detection: Since the early 1900s, digital rectal exams have been the primary tool for detection of prostate cancer.12 Although about 90% of all prostate cancers arise in the outer part of the prostate near the rectum, only a small portion can be detected by digital rectal exams. The exam is quick and painless, but many men find it to be extremely embarrassing.9 Although digital rectal exams carry a specificity for prostate disease of greater than 85%, they should not be used alone as a screening tool.12
Screening for prostate cancer was enhanced in the late 1980s with the introduction of an immunoassay for PSA. 9,12 Prostate cancer cells appear to release PSA into the bloodstream in elevated quantities.9 Levels of PSA greater than 4 ng/mL are more likely associated with prostate cancer.4 Since the introduction of PSA screening in the 1980s, there has been a dramatic increase in the incidence of prostate cancer in the U.S. Before the availability of PSA testing, only a minority (25%) of cancers detected were confined to the prostate gland. Because of the widespread use of PSA screening, the majority (75%) of prostate cancers now discovered are confined to the prostate gland. 12 However, the PSA test is far from foolproof. Nonmalignant causes of an elevated PSA level include presence of benign prostatic hyperplasia or prostatitis, increasing age, ejaculation within two days of the blood test, recent digital rectal exams or prostate biopsies, and use of finasteride. The PSA test is not accurate enough to completely rule out or confirm the presence of cancer. Relying too heavily on the test may lead to unnecessary biopsies, while not relying on it carries the risk of the cancer being undetected.9 Recommendations from the ACS with regard to PSA screenings and digital rectal exams are discussed in Table 1.9,12
Diagnosis: A prostate biopsy is necessary to confirm a diagnosis of prostate cancer and to grade the tumor specimen. Ten to 12 samples are usually taken during a prostate needle biopsy using a transrectal approach with ultrasound guidance. 4,11
Prostate cancers are most commonly graded according to the Gleason system. This system assigns a Gleason grade, using numbers from 1 to 5, based on how much the cells in the cancerous tissue resemble normal prostate tissues. Grade 1 tumors resemble normal prostate cells, whereas grade 5 tumors have cells that seem to be poorly organized. Grade 2, 3, and 4 tumors have features between these extremes. Because prostate cancers often have areas with different grades, the two most predominant grades are added together to yield a Gleason score between 2 and 10. The higher the Gleason score, the more likely the cancer will grow and spread quickly.4
The tumor-node-metastasis (TNM) classification system (Table 2),13 the preferred staging system developed by the American Joint Committee on Cancer, is updated every five years to include new pathologic findings. Staging in the TNM system is based on tumor size (T), nodal status (N), and presence or absence of metastasis (M). Similar TNM staging systems have been developed for most other cancers.12 The prognosis for patients with prostate cancer depends on many factors, including the TNM grade, Gleason score, tumor volume, PSA, and patient age.11
Conventional Treatments of
Conventional treatment options for prostate cancer require assessing patients' individual needs with respect to life expectancy, comorbidities, likelihood of a cure, and personal choice based on the potential adverse effects of each treatment. The initial treatment for prostate cancer depends on several factors, including the TNMgrade, the Gleason score, PSA, presence of distant disease, and presence of symptoms.11,12 Treatments for men with localized prostate cancer include watchful waiting (also known as expectant management ), surgical prostate removal, radiotherapy, and other ablation. Androgen deprivation may be used for men who wish to receive some therapy but are not candidates for or do not wish to receive surgery or radiation. Androgen deprivation therapy is considered the mainstay of treatment for men with advanced prostate cancer; improvement in symptoms and disease regression in over 80% of patients has been noted. For hormone-refractory prostate cancer, other treatments, such as chemotherapy, are warranted.14
Expectant management is often used for slow-growing tumors that are
asymptomatic, especially in older men. Watchful waiting incorporates routine
follow-up monitoring with intervention if the disease progresses or symptoms
develop. Patients usually receive digital rectal exams and PSA screenings
every six months during the observation. This treatment option allows patients
to avoid unnecessary surgery or treatments that may affect quality of life.
Surgery and Radiotherapy: Surgery or radiotherapy may be recommended for low-risk, early stage prostate cancer (T1 or T2) who have a life expectancy of more than 10 years and no significant comorbidities.12,14 Radical prostatectomy and radiotherapy are considered therapeutic equivalents for treatment of low-risk prostate cancer. Radical prostatectomy consists of removing the prostate gland and seminal vesicles.12 This surgery can be done as the standard "open" procedure or by the newer laparoscopic or robotic techniques. Advantages to laparoscopic or robotic radical prostatectomy include shorter hospital stays, smaller incisions, decreased postoperative pain, and a potential decreased risk of both incontinence and erectile dysfunction.15
External beam radiotherapy is used with either conventional technology or three-dimensional conformal radiotherapy or intensity-modulated radiotherapy. The newer techniques allow higher doses to reach target tissue with less toxicity.12,14,16 Brachytherapy is another option for treatment of localized prostate cancer. It involves the insertion of permanent or temporary radioactive seeds directly into the gland to deliver focused radiation and minimize toxicity to normal tissues.12,14 Ultrasound and computed tomography scans can be used to provide more accurate positioning of the seeds.16 Brachytherapy can also be combined with external beam radiation for treatment of more advanced disease.14 Patients should avoid contact with pregnant women and children while the seeds are implanted to avoid unnecessary radiation exposure. Adverse effects associated with radiotherapy can include impotence, incontinence, diarrhea, skin irritation and atrophy, fatigue, urinary frequency, and radiation cystitis. Radiotherapy can also be used after radical prostatectomy to reduce the risk of disease recurrence.12
Cryosurgery: Cryosurgery is another therapeutic option for localized prostate cancer. This technique involves freezing prostate cancer cells using percutaneous probes filled with liquid nitrogen that is compressed and cooled to -206°C. Transrectal ultrasound is used to monitor the freezing process and assist with freezing of the prostate while reducing damage to surrounding normal tissues. 1 Cryosurgery is less established than prostatectomy and long-term outcomes are less known. Adverse effects of cryosurgery include incontinence, impotency, and rectal and bladder injury.17 Cryosurgery can also be used for treatment of patients with more advanced disease, local recurrence, or salvage therapy after radiation.1,12
High-Intensity Focused Ultrasound: High-intensity focused ultrasound is an emerging treatment for localized prostate cancer, as well as a salvage therapy after radiation. The procedure employs transrectal ultrasound of the prostate that is highly focused to create an intense heat that kills prostate cancer tissue. Because the surgeon is able to precisely ablate the gland with pinpoint accuracy, the adjacent structures are less likely to be affected. The most common side effects of high-intensity focused ultrasound are obstruction and radiation necrosis of the urethra. Incontinence is rare, and impotence rates seem to be low, compared to those seen with other therapies. This procedure is currently used in Europe, China, Japan, Mexico, Latin America, and the Caribbean and is undergoing approval by the FDA in the U.S.18
Androgen Deprivation Therapy: In men with early stage prostate cancer, androgen deprivation can be used as primary therapy or as an adjunct to other local treatments. 19 Both local and metastatic prostate cancer are under the control of androgenic hormones.12 Androgen deprivation therapy can be accomplished by removing the testes, which produce most of the body's circulating testosterone, or by drug therapy. Effective agents include luteinizing hormone-releasing hormone (LHRH) agonists, antiandrogens, and estrogens.12,20
Surgical removal of the testes, known as bilateral orchiectomy, reduces circulating testosterone to less than 50 ng/dL. Many patients with prostate cancer are not surgical candidates due to advanced age, and some may find this treatment unacceptable. Bilateral orchiectomy is the preferred initial therapy in patients with spinal cord compression or ureteral obstruction.11,12
LHRH agonists work by stimulating the anterior pituitary gland to release luteinizing hormone (LH) and follicle-stimulating hormone. These drugs include leuprolide, goserelin, histrelin, and triptorelin (Table 3).11,21 High levels of LHRH agonists inhibit the release of gonadotropins by causing down-regulation of receptors and a negative feedback loop in the pituitary gland. Levels of testosterone initially increase and then rapidly decrease to very low levels. The initial rise in testosterone levels can cause hot flashes, bone pain, and spinal cord compression during the first week of therapy. This reaction is known as the flare effect and may be attenuated by using combined androgen blockage.11,12 The response rate for LHRH agonists is approximately 80% for advanced prostate cancer. Patients with inadequate responses may be treated with palliative radiation, additional hormone therapy, or systemic chemotherapy.12 The LHRH agonists have similar adverse effects, including erectile dysfunction, hot flashes, loss of libido, and gynecomastia. Prolonged therapy may cause muscle wasting and osteoporosis, which can lead to bone fractures. Patients should have baseline and periodic bone mineral density checks and should receive calcium and vitamin D supplementation. Bisphosphonates can be used for osteoporosis treatment as well as for treatment of metastatic bone lesions associated with prostate cancer.11,12,19,22,23
Antiandrogens, including flutamide, bicalutamide, and nilutamide (Table 4), block androgen receptors and prevent the body from responding to its own hormones. 11,12,21 Possible adverse effects with the antiandrogens include hot flashes, gastrointestinal disturbances, abnormal liver function tests, breast tenderness, and gynecomastia. These agents are associated with less sexual dysfunction, fewer hot flashes, and less osteoporosis but more gynecomastia than the LHRH agonists. Antiandrogens can be used as monotherapy but are usually combined with LHRH agonists.12,19,20
Combined androgen blockade utilizes LHRH agonists in conjunction with antiandrogen therapy. The antiandrogens should be initiated one to two weeks prior to the LHRH agonist to prevent the disease flare caused by the LHRH agonist. The two drugs can be given together for one to two months or until the prostate cancer progresses. Combined androgen blockade has been shown to increase progression-free survival and overall survival in patients with advanced prostate cancer who are newly diagnosed.12
Estrogen therapy with diethylstilbestrol was once a mainstay of treatment for advanced prostate cancer. However, diethylstilbestrol was removed from the market in 1997 due to increased cardiovascular risk.11 Estrogen therapy is now rarely used for the treatment of prostate cancer.20
Chemotherapy: In the past, chemotherapy has been considered to be relatively ineffective for treatment of hormone-refractory prostate cancer or androgen-independent disease. The standard of care changed in 2004 with the publication of the TAX-327 trial, which showed that patients with metastatic hormone-refractory prostate cancer who received docetaxel every three weeks with prednisone had longer survival, higher response rates, and better pain control than those who received mitoxantrone and prednisone.20 In general, the type of chemotherapy that is chosen for a particular patient is based on concomitant disease states and physician or patient preference. Mitoxantrone should be avoided in patients with cardiovascular problems, due to its potential to cause heart failure and arrhythmias. Docetaxel should be avoided in patients with neurologic problems. Systemic chemotherapy is probably best for patients with no liver metastases and with mild-to-moderate bone pain.12
Therapeutic Vaccines for Prostate Cancer
Immunotherapy for prostate cancer is an active field of investigation using a wide variety of approaches.22,23 Currently, clinical trials are underway to test prostate cancer vaccines that are based on genetically modified viruses (e.g., PROSTVAC-VF), protein- or peptide-pulsed dendritic cells (e.g, Provenge), or tumor cells that are modified to secrete proinflammatory cytokines (e.g., GVAX). While each of these approaches has unique advantages and disadvantages, they all endeavor to stimulate the immune system to actively reject prostate cancer cells.24
PROSTVAC-VF: PROSTVAC-VF (recombinant vaccinia virus expressing human PSA), a viral vector vaccine, stimulates the immune system to destroy PSA-expressing cancer cells by mimicking the natural infection and thereby inducing a potent immune response.7,25 With this technology, genes that are overexpressed in a tumor, contain tumor-associated antigens of interest, or express costimulatory proteins are inserted into viral vectors. These viral vectors then stimulate antigen-presenting cells. Early clinical data suggest that viral vaccines have a favorable safety profile and induce a specific T-cell response.25
PROSTVAC-VF consists of two genetically engineered vaccines, a partially attenuated version of the virus used for the smallpox immunization (PROSTVAC-V) and fowlpox virus (PROSTVAC-F) administered in a sequential regimen.25 Interestingly enough, the poxviruses are among the most commonly studied vectors for gene delivery. 26 In particular, fowlpox, which is unable to replicate in human cells, has been shown to be an effective means of boosting cellular immune responses initiated with vaccinia.25
Further attempts at improving the PROSTVAC-VF vaccine have included the addition of three costimulatory molecules (B7-1, ICAM-1, and LFA-3) called TRICOM and granulocyte-macrophage colony-stimulating factor (GM-CSF).24-26 Data suggest that TRICOM enhances T-cell stimulation, whereas GM-CSF helps increase tumor-specific immunity and may have some cytotoxic effects.7,24
Numerous phase II and III studies conducted by the National Cancer Institute have demonstrated the safety and potential activity of PROSTVAC-VF in patients with different stages of prostate cancer, including patients with newly diagnosed, localized disease, patients with biochemical recurrence after hormone therapy without metastatic disease, and patients with metastatic prostate cancer.22,24 In these studies, injection site reactions and fatigue were the most commonly reported adverse events.23,24
Researchers are currently recruiting participants for a phase III trial (known as the PARADIGM study) that will further examine the safety and potential activity of PROSTVAC-VF. The PARADIGM study is a randomized, double-blind, controlled phase III study involving men with prostate cancer who have elevated PSA levels and no measurable metastatic disease.24,27 The study will utilize the vaccinia virus, followed by fowlpox schedule in combination with TRICOM and GM-CSF, administered as a subcutaneous injection on days 1 to 4. 24 The primary efficacy end point will be time to overt metastatic disease. The FDA recently awarded PROSTVAC-VF with Fast Track designation in conjunction with the design of the PARADIGM study.27
Provenge: Sipuleucel-T (Provenge) is also being studied in advanced prostate cancer. With this therapy, dendritic cells of the immune system are removed from a patient by leukophoresis. These cells are shipped to a central location where they are combined with a fusion protein, consisting of prostatic acid phosphatase and GM-CSF. These cells are matured and activated in vitro and then sent back for injection into the patient. Sipuleucel-T stimulates the immune system (specifically T-cell immunity) against prostatic acid phosphatase, which is present in approximately 95% of prostate cancers. 28-30
Several phase II and III clinical trials have demonstrated the safety and efficacy of sipuleucel-T. In a combined phase I/II trial, 31 men with hormone-refractory prostate cancer received sipuleucel-T. Six patients had significant PSA decreases. No significant adverse effects were seen.22,31 In a phase II trial with 21 patients who had metastatic hormone-refractory prostate cancer, one patient demonstrated a complete response, with a PSA that declined to undetectable levels. The PSA has remained undetectable for four years. Two additional patients had transient reductions in PSA levels.31 A phase III trial examined 127 men with asymptomatic hormone-refractory prostate cancer who received sipuleucel-T or placebo every two weeks for a total of three doses. Overall survival was prolonged to a significant degree in patients who received sipuleucel-T. After three years, 34% of patients who received sipuleucel-T were alive, compared with 11% of those who received placebo. The vaccine was generally well tolerated. Side effects more commonly associated with sipuleucel-T included rigors, pyrexia, tremor, and a "cold" feeling.31,32 A phase III trial is now underway to evaluate sipuleucel-T versus placebo in patients with prostatic acid phosphatase–expressing prostate cancer who have disease-related pain and disease progression.31 In November 2005, the FDA granted Fast Track status to sipuleucel-T for the treatment of metastatic hormone-refractory prostate cancer.5,33
One possible disadvantage to this vaccine is the great cost and effort involved with its production. Large amounts of peripheral blood mononuclear cells obtained by leukapheresis must be cultured for several days in the presence of costly cytokines (e.g., GM-CSF, interleukin-4, or tumor necrosis factor-alpha) and then reinfused into the patient. This labor-intensive approach must be performed for each patient. 22
GVAX: Prostate GVAX is a type of active immunotherapy. This vaccine uses whole-cell allogenic prostate cancer cell lines (PC-3 and LnCap), which are genetically modified to secrete GM-CSF. The tumor cells are irradiated to prevent further cell division (i.e., tumor growth) before they are injected intradermally.7,34 GM-CSF is an ideal vaccine component due to its ability to effectively activate dendritic cell antigen presentation. In addition, GM-CSF assists in the initiation of danger signals that activate the immune system, break the development of tolerance, and facilitate an antitumor immune response.35 The PC-3 and LnCap cell lines were chosen based on complementary antigenic features that represent the spectrum of prostate cancer. The PC-3 cell line is from a prostate cancer bone metastasis and is hormone refractory. This cell line expresses high levels of several proteases and neuroendocrine peptides, which are associated with hormone-refractory prostate cancer. The LnCap line is from a prostate cancer lymph node metastasis expressing antigens such as PSA and a prostate-specific membrane antigen. The LnCap component is hormone sensitive.35 One advantage to GVAX is that the vaccine can be used off-the-shelf in multiple patients.28 In May 2006, the FDA granted Fast Track status to GVAX for the treatment of advanced prostate cancer. 5,36
Like PROSTVAC-VF and sipuleucel-T, GVAX has been studied in several phase II and III clinical trials. The G-9803 trial (phase II) enrolled 34 patients with hormone-refractory prostate cancer who had asymptomatic metastatic disease. These patients received 13 doses of GVAX. The median survival for the patients in the study was 26.2 months--beyond that expected for chemotherapy results or observation alone.3,35 The most common side effect during this study was injection site reactions.7 The G-0010 study (phase II) enrolled 80 patients with asymptomatic metastatic hormone-refractory prostate cancer.37 Patients received three different doses of GVAX. The overall survival of the patients in the trial was more than 24.4 months. The vaccine was well tolerated; common side effects included injection site reactions, fatigue, malaise, myalgias, and arthralgias.28
Two phase III trials, Vital-1 and Vital-2, are currently underway. Vital-1, initiated in July 2004, is enrolling asymptomatic patients who have never received chemotherapy. It compares GVAX to docetaxel plus prednisone. Vital-2 is enrolling patients with symptomatic hormone-refractory prostate cancer who have cancer-related pain. This trial will compare docetaxel plus GVAX with docetaxel plus prednisone. 7,28,34,37,38
Place in Therapy: The vast majority of patients diagnosed with prostate cancer have localized disease, which can be treated successfully with surgery or radiation. Despite treatment, about one third of patients will have advancing disease and require manipulation of hormones with LHRH agonists and antiandrogens.2,4,12,39 As previously discussed, such therapies are commonly associated with sexual dysfunction, bone loss, and other embarrassing adverse effects (e.g., gynecomastia and hot flashes). In addition, once patients become resistant to hormonal therapies, cytotoxic chemotherapy agents (which are associated with nausea and vomiting, myelosuppression, alopecia, and renal toxicities) are often used.12 In contrast, the prostate cancer vaccines that are being studied in the treatment of advanced prostate cancer appear to be extremely efficacious, and few adverse effects have been associated with those studied in clinical trials. Given their favorable toxicity profile, vaccine immunotherapy represents a promising new approach for prostate cancer treatment, either alone or in combination with traditional treatment options. 7,24
Role of the Pharmacist
Pharmacists should continually remind patients of the importance of annual prostate screenings. With annual screening, prostate cancer can usually be detected before it spreads. Patients should be informed that when prostate cancer is detected early, five-year relative survival rates approach 100%.39 Pharmacists should remind patients that the digital rectal exam takes only minutes to perform, and the PSA immunoassay is simply a blood test.4
Erectile dysfunction and/or incontinence are common adverse effects associated with traditional prostate cancer treatments. When prostate cancer vaccines are combined with traditional treatment options, pharmacists should communicate with patients about problems with sexual dysfunction and/or incontinence and discuss both drug and nondrug treatments.12 Finally, pharmacists should encourage eligible patients to participate in clinical trials. Patients should be aware that while these vaccines are still being tested in clinical trials, the preliminary data is very promising.5,12
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