Radiation therapy for prostate cancer

OBJECTIVES: To review the advances in radiation therapy for prostate cancer and the nursing care of patients with prostate cancer. DATA SOURCES: Peer-reviewed journal articles, including research studies and review articles. CONCLUSIONS: Radiation therapy is used to cure early stage prostate cancer, control locally advanced disease, and effectively palliate symptoms of metastasis. The three forms of treatment used include external beam radiation therapy, brachytherapy; and radiopharmaceutical treatments. IMPLICATIONS FOR NURSING PRACTICE: Nursing care of patients receiving radiation therapy for prostate cancer includes managing the symptoms associated with the disease and treatment, educating patients and families about self-care measures, and providing support throughout the course of the disease.     

Radiation therapy for prostate cancer

The advent of image-guided or CT-based treatment planning, such as 3D-conformal or intensity modulated radiation therapy has allowed safe delivery of high- dose radiation therapy in men with prostate cancer with an acceptable rate of side effects and complications. External-beam radiation therapy designed to decrease exposure of normal tissues using methods such as 3D-conformal treatment planning is under clinical evaluation. Randomized trial shows escalation of radiation dose leads to improved biochemical disease-free survival for a select group of patients. Interstitial brachytherapy has been also employed for patients with selected for favorable characteristics, including low Gleason score, low PSA level, and stage T1 to T2 tumors. Long-term follow-up of patients is necessary to assess treatment efficacy and side effects.     

Adenovirus-mediated lymphotactin gene transfer improves therapeutic efficacy of cytosine deaminase suicide gene therapy in established murine colon carcinoma

Lymphotactin (Ltn) is the sole member of C chemokines which attracts T cells and NK cells specially. Ltn gene was transferred in vivo to improve the antitumor efficacy of cytosine deaminase (CD) gene therapy. Upregulation of CD80 and CD54 on murine CT26 colon carcinoma cells was observed after combined transfection with adenovirus encoding CD (AdCD) and adenovirus encoding murine Ltn (AdLtn) followed by administration of 5-fluorocytosine (5FC) in vitro. AdCD/5FC treatment also increased the expression of CD95 and induced obvious apoptosis of CT26 cells. After combined treatment with AdLtn and AdCD/5FC, the pre-established murine model with subcutaneous CT26 colon carcinoma exhibited most significant tumor growth inhibition, and four of eight tumor-bearing mice were tumor free, while tumors in other mice grew more progressively. Examination of lymphocyte infiltration and cytokine gene expression in tumor tissue revealed that tumors from AdLtn/AdCD/5FC-or AdLtn-treated mice were heavily infiltrated with CD4+, CD8+ T cells and NK cells, and IL-2 and IFN-gamma mRNA expression were present in parallel with T cell and NK cell infiltration. Splenic NK and CTL activities increased significantly after the combination therapy. In vivo depletion analysis showed that NK cells, CD4+ T cells and CD8+T cells participated in the antitumor effect of the host with CD8+T cells being the main T cell subset responsible for the enhanced antitumor immune response. These findings suggested that increased immunogenicity and induction of apoptosis of the tumor cells, and efficient induction of local and systemic antitumor immunity of the host might contribute to the enhanced antitumor effects of the combined Ltn and CD suicide therapy. Gene Therapy (2000) 7, 329-338.     

Adeno-associated virus 2-mediated intratumoral prostate cancer gene therapy: long-term maspin expression efficiently suppresses tumor growth

Maspin is a member of the serine protease inhibitors and the maspin gene, a tumor suppressor gene, is down-regulated in a large fraction of prostate cancers. We evaluated the use of adeno-associated virus (AAV, serotype 2) vector encoding maspin as a means for in vivo gene therapy for human prostate cancer. TUNEL assay of subcutaneously formed LNCaP or DU145 tumors in nude mice showed that intratumoral AAV-mediated maspin expression significantly upregulated the number of apoptotic cells compared with AAV-LacZ treatment. Immunofluorescence double staining for maspin protein and apoptosis in LNCaP tumors showed that the percentage of apoptotic cells in AAV-maspin-mediated maspin-expressing cells was significantly high compared with that in AAV-GFP-mediated GFP-expressing cells. Moreover, significantly fewer CD31-positive microvessels were observed in AAV-maspin-treated tumors compared with the control tumors. These therapeutic responses were highly correlated to persistent maspin expression in tumors, confirmed by Western blot analysis until at least day 56 after treatment. Finally, intratumoral delivery of AAV-maspin significantly suppressed growth of LNCaP and DU145 tumors and improved survival of mice. We conclude that AAV-mediated prolonged maspin expression efficiently suppresses human prostate tumor growth in vivo by apoptosis induction and inhibition of angiogenesis.     

Adenovirus-mediated interleukin-12 gene therapy for prostate cancer

As a human prostate cancer gene therapy trial, we have performed Herpes Simplex Virus-thymidine kinase gene transduction and ganciclovir therapy in locally advanced prostate cancer after radiation therapy(USA) or endocrine therapy(Japan). Safety and clinical efficacy were confirmed. In our current studies, we demonstrated the efficacy and safety of gene therapy approaches using recombinant adenoviral vector that transduce interleukin-12 in an orthotopic mouse model of prostate cancer. These preclinical studies will soon be resulted in the initiation of clinical trials using this approach(USA: FDA approved, Japan: Under IRB review) in advanced prostate cancer patients with or without metastasis after endocrine therapy. In this chapter, preclinical data and clinical protocol are introduced.     

Peptide-based cancer vaccine therapy for prostate cancer, bladder cancer, and malignant glioma

Currently, peptide-based cancer vaccines are developed in many different groups, however, no sufficient clinical outcomes have been obtained. We have developed personalized peptide vaccine for advanced cancer patients with different types of HLA-A locus. Personalization of the vaccination peptides from the candidate peptide pool was conducted by considering the HLA types of patient and pre-existing levels of IgG to the candidate peptides. The personalized peptide vaccine for patients with hormone-refractory prostate cancer has been approved as innovative therapy by the Ministry of Health, Labour and Welfare, Japan. Here, we describe the recent progress of the personalized peptide vaccine particularly for patients with prostate cancer, bladder cancer, and malignant glioma.     

Adenoviral vector-mediated mRTVP-1 gene therapy for prostate cancer

We previously identified the mouse RTVP-1 (mRTVP-1; related to testes-specific, vespid, and pathogenesis proteins) gene as a direct target of p53 with proapoptotic activities in various cancer cell lines, including prostate cancer. To test the therapeutic potential of mRTVP-1 we constructed an adenoviral vector capable of efficient transduction and expression of mRTVP-1 (AdmRTVP-1) and used this vector in an orthotopic, metastatic mouse model of prostate cancer. A single intratumoral administration of AdmRTVP-1 gene therapy significantly reduced primary tumor wet weight compared with control Adbetagal-injected tumors at two time points after injection with two different vector doses (p < or = 0.01 at 7 and 14 days). Spontaneous metastasis to lung was also significantly reduced (p < or = 0.02). Evaluation of treated tumors revealed increased apoptosis and lower microvessel density counts. In a rat aortic ring sprouting assay, AdmRTVP-1 inhibited endothelial cell sprouting compared with Adbetagal, confirming its antiangiogenic activity. These therapeutic activities were associated with a significant increase in survival from 22.9 to 26.8 days (p = 0.003) in this aggressive model of prostate cancer. Interestingly, there were significant increases in the infiltration of tumor-associated macrophages, dendritic cells, and CD8+ T cells, which persisted at 14 days posttreatment in the AdmRTVP-1-treated tumors compared with Adbetagal control-treated tumors. In addition, significantly increased natural killer and cytotoxic T lymphocyte activities were demonstrated in the mice with AdmRTVP-1-treated tumors. The unique therapeutic properties of AdmRTVP-1 gene therapy demonstrated in this study provide new opportunities for gene and immunotherapy of prostate cancer and potentially other malignancies.     

In situ gene therapy for prostate cancer: immunomodulatory approaches

The development of effective treatments for prostate cancer is thwarted by the natural history of the disease. The biological and clinical potential of most individual cancers is uncertain. In many cases the disease will not progress to clinical significance but experimental and clinical studies indicate that prostate cancer can and may metastasise early in the course of the disease from relatively small foci (i.e., not necessarily the largest or index cancer). Localised prostate cancer is potentially curable with localised therapies (radical prostatectomy or irradiation therapy). However, there are no curative therapies for metastatic prostate cancer. Gene therapy, especially those approaches with an immunomodulatory component, may provide additional therapeutic options with the potential to affect both localised and systemic disease. We have pioneered the development and application of in situ gene therapy protocols using adenoviral vectors to transduce specific genes that generate cytotoxic activity and/or a systemic antitumour immune response. In addition we have completed initial studies that demonstrate the therapeutic potential of adenoviral vector-mediated gene modified cell-based vaccines. Our review discusses preclinical studies focused on the development of immunostimulatory in situ gene therapy approaches that hopefully will provide novel and effective treatments for localised and metastatic prostate cancer.     

Combination of MIG (CXCL9) chemokine gene therapy with low-dose cisplatin improves therapeutic efficacy against murine carcinoma

MIG (monokine induced by interferon-gamma) is a CXC chemokine ligand (CXCL9) that can potently inhibit angiogenesis, and displays thymus-dependent antitumor effects. The effectiveness of a treatment combining gene therapy with plasmid-borne MIG (pORF-MIG) and low-dose cisplatin chemotherapy was determined using colon carcinoma (CT26) and Lewis lung carcinoma (LL/2c) murine models. The program was carried out via intramuscular delivery of pORF-MIG at 100 mug/mouse twice a week for 4 weeks, and/or intraperitoneal delivery of cisplatin at 0.6 mg/kg/mouse every 3 days for 48 days. Tumor volume and survival time were evaluated after treatment. CD31 immunohistochemical staining in tumor tissues and alginate capsule models in vivo was used to evaluate angiogenesis. Induction of apoptosis and cytotoxic T-lymphocyte (CTL) activity were also assessed. The combination of pORF-MIG and low-dose cisplatin produced significant antitumor activity, with complete tumor regression in 4/10 of CT26 colon carcinomas and 3/10 of LL/2c lung carcinomas, low vascularity, in alginate capsules, apparently degraded tumor microvessel density, and increased induction of apoptotic and CTL activities compared with either treatment alone. This study suggests that the combination of pORF-MIG plus cisplatin augments the inhibition of angiogenesis and the induction of apoptosis or CTL activity, all of which enhance antitumor activity. These findings may prove useful in further explorations of the application of combinatorial approaches to the treatment of solid tumors.     

Advances in preclinical investigation of prostate cancer gene therapy.

Treating recurrent prostate cancer poses a great challenge to clinicians. Research efforts in the last decade have shown that adenoviral vector-based gene therapy is a promising approach that could expand the arsenal against prostate cancer. This maturing field is at the stage of being able to translate many preclinical discoveries into clinical practices. At this juncture, it is important to highlight the promising strategies including prostate-targeted gene expression, the use of oncolytic vectors, therapy coupled to reporter gene imaging, and combined treatment modalities. In fact, the early stages of clinical investigation employing combined, multimodal gene therapy focused on loco-regional tumor eradication and showed promising results. Clinicians and scientists should seize the momentum of progress to push forward to improve the therapeutic outcome for the patients.     

Development of a prostate-specific promoter for gene therapy against androgen-independent prostate cancer

Androgen ablation has been the standard treatment for metastasized prostate cancer. In most cases, however, prostate cancer cells eventually lose androgen dependency and become refractory to the conventional endocrine therapy. Androgen-independent prostate cancer is characterized by a heterogeneous loss of androgen receptor (AR) expression among tumor cells. Prostate-specific promoters such as prostate-specific antigen and rat probasin (rPB) promoters have been examined in the development of gene therapy targeted to prostate cancer. However, those promoters require binding of the androgen–AR complex to the androgen-response element and are active only in the androgen-dependent prostate cancer cell lines and not in the androgen-independent cell lines. To target transgene expression in androgen-independent prostate cancer, we designed a prostate-specific promoter that is activated by the retinoids–retinoid receptor complex instead of the androgen–AR complex. The modified rPB promoters expressed transgenes in response to retinoid in both androgen-dependent and androgen-independent prostate cancer cells and not in other cancer cell lines or in human normal cells, in vitro and in vivo. Furthermore, the combination of retinoid treatment and adenovirus-mediated gene transfer of the modified rPB-driven HSV-tk gene resulted in a significant growth suppression of the androgen-independent prostate cancer cells in the presence of the prodrug ganciclovir. This study suggests that tailoring of the hormone-responsive elements may offer a new therapeutic opportunity against the hormone-refractory stage of prostate cancer.     

Collaboration between hepatic and intratumoral prodrug activation in a P450 prodrug-activation gene therapy model for cancer treatment

Presently, we investigate the mechanisms whereby intratumoral expression of a cyclophosphamide-activating hepatic cytochrome P450 gene enhances therapeutic activity when cyclophosphamide is given on an every 6-day (metronomic) schedule. In P450-deficient 9L gliosarcomas grown in severe combined immunodeficient mice, metronomic cyclophosphamide substantially decreased tumor microvessel density and induced a approximately 70% loss of endothelial cells that began after the second cyclophosphamide treatment. These responses were accompanied by increased expression of the endogenous angiogenesis inhibitor thrombospondin-1 in tumor-associated host cells but by decreased expression in 9L tumor cells. These antiangiogenic responses preceded tumor regression and are likely key to the therapeutic activity of metronomic cyclophosphamide. Unexpectedly, 9L/2B11 tumors, grown from 9L cells infected with retrovirus encoding the cyclophosphamide-activating P450 2B11, exhibited antiangiogenic responses very similar to 9L tumors. This indicates that the tumor endothelial cell population is well exposed to liver-activated cyclophosphamide metabolites and that intratumoral P450 confers limited additional anti-endothelial cell bystander activity. In contrast, an increase in apoptosis, which preceded the antiangiogenic response, was substantially enhanced by intratumoral P450 2B11 expression. 9L/2B11 tumor regression was accompanied by an overall loss of tumor cellularity and by substantial enlargement of remaining P450-immunoreactive tumor cells as the number of P450-positive tumor cell decreased and the P450 protein content declined with cyclophosphamide treatment. We conclude that metronomic cyclophosphamide regresses P450-expressing tumors by two independent but complementary mechanisms: increased tumor cell killing via intratumoral P450-catalyzed prodrug activation, coupled with strong antiangiogenic activity, which is primarily associated with hepatic prodrug activation.     

L-BLP25: a MUC1-targeted peptide vaccine therapy in prostate cancer

Renewed interest in cancer vaccine strategies has occurred with the identification of tumour-associated antigens and a further understanding of the immunoregulatory pathways involved in cancer development and progression. MUC1 is a mucinous glycoprotein that is overexpressed and aberrantly glycosylated in many human malignancies, including prostate cancer. BLP25 is a synthetic, liposomal cancer vaccine that targets the extracellular tandem repeat sequences of the MUC1 tumour-associated antigen. Preclinical L-BLP25 studies have shown the induction of a cell-mediated response and subsequent Phase I and II studies have established the vaccine dose, schedule and excellent safety profile. A Phase II study in advanced non-small cell lung cancer demonstrated a strong survival trend in favour of L-BLP25 in a subgroup of patients with locoregional stage IIIB disease. L-BLP25 also shows promise in prostate cancer. A pilot Phase II study in hormone naive patients with prostate-specific antigen failure after radical prostatectomy demonstrated a prolongation of prostate-specific antigen doubling time with little morbidity. These encouraging results suggest the potential of L-BLP25 in the management of cancer.     

Biological response determinants in HSV-tk + ganciclovir gene therapy for prostate cancer.

The limitations of current forms of prostate cancer therapy have driven researchers to search for new alternatives. Previously we showed cytopathic effect related to HSV-tk in prostate cancer. In this study we present initial results of a neoadjuvant HSV-tk gene therapy trial and address some of the potential mechanistic aspects of its effect in human tissues. We enrolled 23 men with clinically localized prostate cancer but high risk for recurrence in this Phase I-II trial. Intraprostatic viral injections (one to four) were followed by 2 weeks of ganciclovir and prostatectomy 2-4 weeks later. Toxicity was modest. Surgical specimens were embedded fully and whole-mount slides were imaged and analyzed for areas of cytopathic effect. The larger the tumor the greater the cytopathic effect. The effect also seems to be related to areas of high CAR expression. However, the number of injection sites did not influence effect. Local (CD8+ cells and macrophages) and systemic immune response (CD8+ and activated CD8+, IL-12) was increased in patients treated with HSV-tk. Increased apoptosis and decreased microvessel density were also noted in these patients. The results suggest a tumor-specific effect mediated by systemic and local immune response, antiangiogenic effect, and modulation of apoptosis.     

L-BLP25: a MUC1-targeted peptide vaccine therapy in prostate cancer

Renewed interest in cancer vaccine strategies has occurred with the identification of tumour-associated antigens and a further understanding of the immunoregulatory pathways involved in cancer development and progression. MUC1 is a mucinous glycoprotein that is overexpressed and aberrantly glycosylated in many human malignancies, including prostate cancer. BLP25 is a synthetic, liposomal cancer vaccine that targets the extracellular tandem repeat sequences of the MUC1 tumour-associated antigen. Preclinical L-BLP25 studies have shown the induction of a cell-mediated response and subsequent Phase I and II studies have established the vaccine dose, schedule and excellent safety profile. A Phase II study in advanced non-small cell lung cancer demonstrated a strong survival trend in favour of L-BLP25 in a subgroup of patients with locoregional stage IIIB disease. L-BLP25 also shows promise in prostate cancer. A pilot Phase II study in hormone naive patients with prostate-specific antigen failure after radical prostatectomy demonstrated a prolongation of prostate-specific antigen doubling time with little morbidity. These encouraging results suggest the potential of L-BLP25 in the management of cancer.     

Cytokine gene transfer enhances herpes oncolytic therapy in murine squamous cell carcinoma

Replication-competent, attenuated herpes simplex viruses (HSV) have been demonstrated to be effective oncolytic agents in a variety of malignant tumors. Cytokine gene transfer has also been used as immunomodulatory therapy for cancer. To test the utility of combining these two approaches, two oncolytic HSV vectors (NV1034 and NV1042) were designed to express the murine GM-CSF and murine IL-12 genes, respectively. These cytokine-carrying variants were compared with the analogous non-cytokine-carrying control virus (NV1023) in the treatment of murine SCC VII squamous cell carcinoma. All three viruses demonstrated similar infection efficiency, viral replication, and cytotoxicity in vitro. SCC VII cells infected by NV1034 and NV1042 effectively produced GM-CSF and IL-12, respectively. In an SCC VII subcutaneous flank tumor model in immunocompetent C3H/HeJ mice, intratumoral injection with each virus caused a significant reduction in tumor volume compared with saline injections. The NV1042-treated tumors showed a striking reduction in tumor volume compared with the NV1023- and NV1034-treated tumors. On subsequent rechallenge in the contralateral flank with SCC VII cells, 57% of animals treated with NV1042 failed to develop tumors, in comparison with 14% of animals treated with NV1023 or NV1034, and 0% of naive animals. The increased antitumor efficacy seen with NV1042 in comparison with NV1023 and NV1034 was abrogated by CD4(+) and CD8(+) lymphocyte depletion. NV1042 is a novel, attenuated, oncolytic herpesvirus that effectively expresses IL-12 and elicits a T lymphocyte-mediated antitumor immune response against murine squamous cell carcinoma. Such combined oncolytic and immunomodulatory strategies hold promise in the treatment of cancer.     

Anti-idiotype antibody vaccine therapy for cancer

The use of anti-idiotype (Id) antibodies as vaccines to stimulate antitumour immunity is one of several promising immunologic approaches to the therapy of cancer. Extensive studies in animal tumour models have demonstrated the efficacy of anti-Id vaccines in preventing tumour growth and curing mice with established tumours. A number of monoclonal anti-Id antibodies that mimic distinct human tumour-associated antigens (TAAs) have been developed and tested in the clinic, and demonstrate encouraging results. In general, the antigen mimicry by anti-Id antibodies has reflected structural homology in the majority of the cases, and amino acid sequence homology in a few of them. The greatest challenge of immunotherapy by means of anti-Id vaccines is to identify the optimal anti-Id antibody that will function as a true surrogate antigen for a TAA system, and ideally will generate both humoral and cellular immune responses. Although several clinical studies have shown enhanced survival of patients receiving anti-Id vaccines, the efficacy of these vaccines will depend on the results of several randomised Phase III clinical trials that are currently planned or ongoing.