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The New Advancement in Treatment of Prostate Cancer - Term Paper Example

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This paper 'The New Advancement in Treatment of Prostate Cancer' tells us that prostate cancer continues to be the most common solid tumor malignancy in men and the second leading cause of male cancer mortality, accounting for more than 30,000 deaths in the United States alone in 2007…
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The New Advancement in Treatment of Prostate Cancer
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?Introduction Pro cancer continues to be the most common solid tumor malignancy in men and the second leading cause of male cancer mortality, accounting for more than 30,000 deaths in the United States alone in 2007 (CDC, 2007; Sternberg et al., 2007). In fact, in Europe, the incidence rate of prostate cancer has increased to 214 cases per 1000 men, surpassing that of colorectal and lung cancer (Jemal et al., 2008). Although it has been shown that prostate cancer responds well to androgen deprivation therapy, the effect of the treatment appears to be temporary and all patients were reported to eventually develop hormone refractory prostate cancer (HRPC) (Small et al., 2006). Sadly, according to Vogelzang (1996), metastatic HRPC is responsible for almost all prostate cancer deaths. Medical options currently available for the treatment and management of prostate cancer include radical prostatectomy, radiation therapy, mitoxantrone, estramustine, vinca alkaloids, doxurobicin, and taxanes, among others (Middletone, 1996; Goodin et al., 2002). The choice of therapeutic management, however, is greatly determined by how advanced the disease has become. For instance, studies have shown that radiotherapy and radical prostatectomy could increase survival rate of patients with stage 1 and stage 2 prostate cancers by as much as 95% in the next 5 years but were no longer effective in treating the disease in its metastatic stage (Middleton, 1996). On the other hand, for patients with HRPC, taxane-based chemotherapy has demonstrated a modest survival advantage, but median survival after treatment is only 19 months (Small et al., 2006). Moreover, not all cancer patients are candidates for chemotherapy. Hence, more effective treatment regimens for advanced and metastatic prostate cancer are needed. A more recent advancement in the field of prostate cancer management is the use of the patient’s immune system to combat the disease through the administration of a non-prophylactic cancer vaccine (McNeel, 2007; Sonpavde et al., 2007). Sipuleucel-T, the first ever vaccine that works against late-stage, metastatic, and hormone-refractory prostate cancers, is an autologous cellular immunotherapy specifically designed to stimulate the body’s immune responses (FDA, 2010). This paper highlights sipuleucel-T (tradename: PROVENGE®) as a novel, nontoxic modality for the treatment of advanced prostate cancer. Specifically, this paper aims to review what sipuleucel-T (PROVENGE®) is, its components, its side effects, evidences of its effectiveness based on clinical trial studies, and its advantages over some of the existing prostate cancer treatments. Discussion Among the different immunotherapy approaches investigated in the past, the use of dendritic cells (DCs), which are the main antigen-presenting cells (APCs) of the body, was found to be the most efficient way of presenting cancer antigen to the immune system (Bono et al., 2010). Sipuleucel-T, produced by Dendreon Corporation under the tradename of PROVENGE®, is a cancer vaccine that makes use of the patient’s own dendritic cells, hence the term autologous immunotherapy, to improve T-cell response (Harzstark and Small, 2009; FDA, 2010). Specifically, each dose of PROVENGE® contains at least 50 million autologous CD54+ cells activated with a recombinant human protein called PAP-GM-CSF, composed of prostatic acid phosphatase (PAP) and granulocyte-macrophage colony-stimulating factor (GM-CSF) (FDA, 2010). CD54+, a cell surface glycoprotein that functions as a stimulator on APCs, bind to its receptor on the surface of T-cells during the process of antigen presentation (CST, 2010). Meanwhile, PAP is a surface antigen expressed in prostate tumor cells. Studies have shown that PAP antigen is relatively specific to prostate epithelium, making it a good target for vaccines (Oh, 2010; Nabhan et al., 2011). On the other hand, GM-CSF is an immune cell activator (FDA, 2010). The CD54+ cells collected from the patient through a process known as leukapheresis, are treated with PAP-GM-CSF to enhance their response against prostate tumor cells. The resulting vaccine is then infused back to the patient three times over 1 month (Armstrong and George, 2008). According to Dendreon Corporation, the potency of the resulting vaccine is partly determined by how well the expression of CD54+ on the surface of APCs has increased. The more CD54+ molecules there are, the better the immunologic reaction between the APCs and T-cells will be. The use of PROVENGE® has been approved by the U.S. Food and Drug Administration (FDA) only last April 2010, making PROVENGE® the first FDA-approved cancer vaccine specifically indicated for prostate cancer. In an official statement released by the U.S. FDA, PROVENGE® is said to benefit those suffering from asymptomatic or minimally symptomatic prostate cancer that has affected the other parts of the body and has become resistant to hormone treatment (metastatic castrate resistant or hormone refractory prostate cancer) (FDA, 2010). According to Karen Midthun, acting director of FDA’s Center for Biologics Evaluation and Research, “The availability of PROVENGE® provides a new treatment option for men with advanced prostate cancer, who currently have limited effective therapies available,” ( FDA, 2010). Although sipuleucel-T is relatively new in the market, the theories and concept behind it has been concocted many years back. An early Phase I clinical trial to demonstrate the effects of sipuleucel-T on patients with HRPC was conducted by Burch et al. (2000). Burch and his team recruited thirteen (13) patients and were treated with sipuleucel-T in two infusions, 1 month apart. Results revealed that circulating prostate-specific antigen eventually dropped after administration of the complete doses (Burch et al., 2000). Interestingly, sipuleucel-T infusion did not significantly affect the response of T-cells against PAP and GM-CSF. However, it was noted that antibodies to GM-CSF increased to a maximum level after two injections of the vaccine (Burch et al., 2000). This indicates that sipuleucel-T can also stimulate humoral response. A larger placebo-controlled Phase III trial was conducted to further investigate the potential of sipuleucel-T as an immunotherapeutic modality (Small et al., 2006). Specifically, the study was conducted to evaluate the safety and efficacy of sipuleucel-T in HRPC patients. A total of 127 patients with asymptomatic HRPC were randomized in the placebo (n=45) and sipuleucel-T (n=82) group in a 2:1 ratio (Small et al., 2006). The sipuleucel-T group received three infusions of the vaccine once every two weeks. Results indicated that the median for time progression of the disease for sipuleucel-T group was 11.7 weeks in contrast to 10 weeks for the placebo group. In addition, the ratio of T-cell stimulation to baseline values was found to be eight times higher in the group treated with the vaccine. In addition, a preplanned three-year survival analysis predicted that 34% of the patients under sipuleucel-T will survive as compared to the 11% survival rate of patients not treated with the vaccine (Small et al.,2006). With regards to safety of sipuleucel-T, Small and his colleagues (2006) reported that the therapy was well tolerated by all patients. In fact, no patient was reported to have discontinued the treatment or was advised to drop the therapy due to side effects (Small et al., 2006). According to the study, common side effects of sipuleucel-T treatment were rigors (59.8% vs 8.9% in placebo), pyrexia (29.3 % vs 2.2%), tremor (9.8% vs 0%) and feeling cold (8.5% vs 0%) (Small et al., 2006). The results obtained by Small et al. (2006) is consistent with the findings of a more recent and even larger randomized phase III clinical trial sponsored by ImPACT, immunotherapy Prostate Adenocarcinoma Treatment (Kantoff , 2010). Kantoff (2010) recruited 512 patients with minimally symptomatic or asymptomatic metastatic HRPC. The patients were randomly assigned in a 2:1 ratio to either sipuleucel-T treatment or placebo group. Patients under the vaccine therapy were given three infusions of PROVENGE® at two weeks interval. Progression of disease and over-all survival of the patients was monitored. It was found that sipuleucel-T demonstrated a median survival of 25.8 months compared to the 21 months median survival of the placebo group (Kantoff, 2010). Moreover, for a 36 month period, the model predicted a 31.7% chance of survival for those patients receiving sipuleucel-T. The untreated group however, exhibited only an estimated 23% survival rate within a 36 month-period (Kantoff, 2010). An equally important finding is that the effects of the vaccine were upheld with longer follow up (Kantoff, 2010). One of the advantages of sipuleucel-T compared to the existing prostate cancer treatment such as radiation and chemotherapy is that it is non-cytotoxic and its effects are specific to cancer cells. Unlike doxorubicin for instance, which also kills non-cancerous cells, sipuleucel-T only eliminates those cells expressing prostate-specific antigen on their surfaces (Goodin et al., 2002). For instance, in a study conducted by Sella et al. (1994), it was reported that administration of doxorubicin plus ketoconazole resulted to 45% of the patients admitted to the hospital secondary to chemotherapy-associated toxicities such as neuropenia. On the other hand, the use of mitoxantrone as a chemotherapeutic drug was found to exhibit improvement in the palliation of symptoms in patients with HRPC, but treatment outcome in terms of tumor inhibition was not as effective as Doxurubicin (Goodin et al., 2002). Another problem encountered by clinicians with chemotherapeutic drugs despite improved response rate is that the duration of drug response is short (Goodin et al., 2002). Cancer patients apparently develop resistance to chemotherapeutic agents such as paclitaxel, a problem not reported with sipuleucel-T vaccine. Conclusion Sipuleucel-T (PROVENGE® ) is an autologous immunotherapeutic vaccine intended for the treatment of asymptomatic and symptomatic cases of metastatic hormone refractory prostate cancer (HRPC). PROVENGE® , a product of Dendreon Corporation is the first FDA-approved cancer vaccine. Its approval by the U.S. FDA was made public last April 2010. Sipuleucel-T consists of CD54+ cells and a recombinant protein, PAP-GM-CSF. PAP antigen specific to prostate tumor cells serves to increase the expression of CD54+ glycoprotein on the surface of antigen-presenting cells. This increase in CD54+ expression would expectantly stimulate the patient’s immune response, specifically T-cell activity. However, there are also some studies indicating the possibility that humoral response is also activated. Phase III clinical trials revealed that patients with metastatic HRPC treated with sipuleucel-T showed an increase in the over-all survival by 4.1 months. According to Bono et al. (2010), this result led the FDA to approve the use of PROVENGE® as a new treatment approach for metastatic HRPC. In addition, the administration of PROVENGE® was associated with minimal side effects limited to rigors, pyrexia, tremors and feeling cold. Perhaps, if I will have metastatic HRPC, sipuleucel-T will be my choice of therapy because it increases over-all survival without toxic side effects. Literature Cited Armstrong, A., and George, D. 2008. New drug development in metastatic prostate cancer. Urologic Oncology: Seminars and Original Investigations 26:430–437 Bono, J., Bianchini, D., Zivi, A. and Sandhi, S. 2010. Horizon scanning for novel therapeutics for the treatment of prostate cancer. Annals of Oncology 21 (Supplement 7): vii43–vii55 Burch PA, Breen JK, Buckner JC et al. Priming tissue-specific cellular immunity in a phase I trial of autologous dendritic cells for prostate cancer. Clin Cancer Res 6: 2175–2182 Cell Signaling Technology, 2010. CD54 (ICAM-1) antibody. Accessed at: http://www.cellsignal.com/pdf/4915.pdf. Date Accessed: May 3, 2011 Centers for Disease Control and Prevention (CDC). 2007. 1999–2007 Cancer Incidence and Mortality Data. Accessed at : http://apps.nccd.cdc.gov/uscs/. Date Accessed: May 1, 2011 Food and Drug Administration (FDA). 2010. PROVENGE® (sipuleucel-T). Accessed at: http://www.fda.gov/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/ucm210012.htm. Date Accessed: May 2, 2011. Food and Drug Administration (FDA). 2010. FDA news release: FDA Approves a Cellular Immunotherapy for Men with Advanced Prostate Cancer. Accessed at : http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm210174.htm. Date Accessed: May 4, 2011. Goodin, S., Rao, K., and Dipaola, R. 2002. State-of-the-art treatment of metastatic hormone-refractory prostate cancer. The Oncologist. 7:360-370 Harzstark, A., and Small, E. 2009. Immunotherapeutics in development for prostate cancer. The Oncologist.14:391–398 Jemal A, Siegel R, Ward E. 2008. Cancer statistics. CA Cancer J Clin. 58:71–96. Kantoff, P. 2010. Updated results of the IMPACT trial of sipuleucel-T for metastatic, castration-resistant prostate cancer (CRPC). Dana-Farber Cancer Institute. pp 1-23 McNeel, D. 2007. Cellular immunotherapies for prostate cancer. Biomedicine and Pharmacotherapy. 61:315-322 Middleton, R. 1996. The management of clinically localized prostate cancer: guidelines from the American Urological Association. A C a n c e r J C l i n 4 6 : 2 4 9 - 2 5 3 Nabhan, C., Parsons, B., Touloukian, Z., and Stadler, W. 2011. Novel approaches and future directions in castration resistant prostate cancer. Annals of Oncology. In Press. Oh, W. 2010. Immunotherapy for Castration-Resistant Prostate Cancer: A New Era? Journal Watch Oncology and Hematology. 1:1 Sella, A., Kilbour, R., and Amato, R.1994. Phase II study of ketoconazole combined with weekly doxorubicin in patients with androgen- independent prostate cancer. J Clin Oncol 12:683-688 Sternberg, C., Mancuso, A., and Oudard, S. 2007. Effective chemotherapy for hormone-refractory prostate cancer (HRPC): present status and perspectives with taxane-based treatments. Critical Reviews in Oncology/Hematology. 61:176–185 Small, E., Schellhammer, P., Higano, C., Redfern, C., Nemunaitis, J., Valone, F., Verjee, S., Jones, L., and Hershberg, R. 2006. Placebo-controlled phase III trial of immunologic therapy with Sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. Journal of Clinical Oncology. 24(19): 3089-3094 Sonpavde G., Spencer, D., Slawin, K. 2007. Vaccine therapy for prostate cancer. Urologic Oncology: Seminars and Original Investigations 25;451–459 Vogelzang, N. 1996. One hundred thirteen men with prostate cancer died today. J Clin Oncol 14:1753-1755 Read More
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