A phase II study of high-dose calcitriol combined with mitoxantrone and prednisone for androgen-independent prostate cancer

OBJECTIVE

To evaluate the preliminary efficacy, safety, and impact on quality of life (QoL) of high‐dose calcitriol (DN‐101) combined with mitoxantrone and glucocorticoids in androgen‐independent prostate cancer (AIPC).

PATIENTS AND METHODS

Nineteen patients with metastatic AIPC and no previous chemotherapy received DN‐101 180 µg orally on day 1 and mitoxantrone 12 mg/m² intravenously on day 2 every 21 days with continuous daily prednisone 10 mg orally for a maximum of 12 cycles. A confirmed decline in prostate‐specific antigen (PSA) levels by half was the primary endpoint. QoL was evaluated using the European Organization for Research and Treatment of Cancer QLQ‐C30 questionnaire, and pain and analgesic use were evaluated.

RESULTS

Five of 19 patients (26%; 95% confidence interval, CI, 9–51) achieved a ≥50% decline in PSA level. The median (95% CI) time to PSA progression was 16 (6–26) weeks. The overall median (95% CI) survival was 16 (6–26) months; 47 (21–73)% of patients achieved an analgesic response. Toxicity was similar to that expected with mitoxantrone and prednisone alone. The QoL analysis suggested a decrease in physical functioning and increase in fatigue, insomnia, and diarrhoea.

CONCLUSIONS

DN‐101 given every 3 weeks does not add significant activity to mitoxantrone and prednisone in AIPC, as measured by the PSA decline. The high rate of analgesic response is encouraging. The addition of DN‐101 does not appear to increase the toxicity of mitoxantrone.     

Gene therapy for prostate cancer

The treatment options for the patient with advanced prostate cancer are limited. Due to the recent advances in the understanding of the molecular biology of prostate cancer, the easy accessibility of the gland for injection, and the availability of gene promoters that can provide tissue specific expression of therapeutic gene sequences, gene therapy for prostate cancer is rapidly advancing. Many potential approaches for prostate cancer gene therapy have been identified, with a few of these already entering Phase I clinical trials. This review will discuss the basis of prostate cancer gene therapy, look at the potential approaches, and will compare the different vectors that can be used to deliver the therapeutic genes to the prostate tumor.     

Focal therapy for prostate cancer

PURPOSE OF REVIEW: Nowadays the treatment paradigm for localized prostate cancer is to distinguish patients with clinically relevant cancers who may benefit from radical treatment, or perhaps an organ-sparing approach, from the remainder who may not need intervention at the time of diagnosis. We review new concepts of parenchymal preservation as possible new frontiers in the treatment armamentarium for this malignancy. RECENT FINDINGS: For a select cohort of patients with low-risk unifocal or unilateral prostate cancer lesions, a number of ablative treatment options for focal therapy are available with cryotherapy having the most clinical experience. Technologies that have the ability to be utilized for focal therapy include high-intensity focused ultrasound, brachytherapy, interstitial laser thermotherapy, stereotactic radio surgery, and vascular-targeted photodynamic therapy. Further basic and animal research along with the conduction of large-scale randomized clinical trials demonstrating long-term disease-free survival and quality of life outcomes are necessary. SUMMARY: The concept of focal therapy is evolving with the understanding of the biologic variability (clinically aggressive, significant or insignificant) of various prostate cancer lesions that may require different treatment approaches. Minimally invasive, parenchyma-preserving therapies can assume a greater role in the treatment of unilateral or unifocal lesions, representing an alternative approach to the current treatment extremes of whole-gland treatment and watchful waiting.     

Gene therapy for prostate cancer

The substantial advances made in recent years in the molecular biology of malignant urological tumors and the associated progressive analysis of these conditions at a molecular level have spurred research aimed at gene-based treatment. In the field of prostate cancer, while there have been many ground-breaking studies particularly in the United States, none has yet led to a revolutionary treatment for recurrent prostate cancer. Gene-based treatment is being applied seriously in clinical settings, especially in the United States, but so far without significant effect. Many researchers worldwide are devoting energy to the development of effective vectors. By adjusting the promoter, which has the function of directing the vector, we have developed organ-specific vectors for the treatment of prostate cancer. In the present study, which targeted prostate cancer with bone metastasis, we developed a suicide-gene therapy using an adenovirus vector with an organ-specific osteocalcin promoter. Clinical trials of this vector have already been conducted at the University of Virginia in the United States and have so far confirmed the safety of the therapy. In the present paper we present the results of this gene-therapy research from the basic to the clinical phase alongside an outline of related research at our institution. Gene therapy for cancer is now being targeted not only against the primary tumor but systemic cancers including distant metastases; systemic administration of adenovirus vectors with organ-specific promoters may become one of the most promising systemic anti-tumor therapies of the next-generation.     

Vaccine therapy for prostate cancer

Immunotherapy with vaccines represents a novel, targeted nontoxic modality for the therapy of prostate cancer. Systemic immune responses to candidate prostate cancer antigens have been induced in a tumor that has been conventionally viewed as refractory to immunotherapy. Autologous dendritic cell vaccines expressing prostate-specific antigens have shown promising clinical outcomes in a randomized trial in metastatic androgen independent prostate cancer. Other vaccine approaches include granulocyte-macrophage colony-stimulating factor modified tumor cell vaccines and poxvirus vaccines. A combination of vaccines with chemotherapy, radiotherapy, and other biologic agents is also being evaluated. Efforts to optimize vaccine approaches and select ideal patient populations need to continue because there is no evidence supporting a single superior approach.     

Gene therapy for prostate cancer

In this section there are, as usual, four papers of general interest. The use of gene therapy has become topical, but is in need of further development. Its current status in prostate cancer is updated by the authors from London. In a mini‐review on what is termed ‘hypospadiology’, David Thomas reports on a topic that is one of the most commonly written about in paediatric urology. The authors from Israel review abdominal compartment syndrome, an important complication seen in critically ill patients. Finally, Jim Gillespie introduces us to his interesting views on the origin of the overactive bladder and sensory urgency.     

Gene therapy for prostate cancer

Basic research continues to unravel the molecular complexity of normal and abnormal biologic processes. The development of means to affect the expression level of genes that promote or contribute to cellular transformation, invasion, and metastasis has spawned the concept of gene therapy. This relatively new field seeks to reverse or suspend the pathologic progression of a variety of diseases including the malignant transfor-mation of prostatic epithelial cells. Initial clinical trials for prostate cancer have thus far shown gene therapy to be relatively safe, although definitive evidence of durable therapeutic efficacy remains to be demonstrated. In this article, recent preclinical research, current therapeutic strategies, and recent results of gene therapy clinical trials for the treatment of prostate cancer are reviewed.     

Rationale for the development and current status of calcitriol in androgen-independent prostate cancer

Calcitriol, the principal active metabolite of vitamin D, has significant antineoplastic activity in pre-clinical models of prostate cancer and many other tumor types. Reported mechanisms of activity include inhibition of proliferation and cell cycle arrest, induction of apoptosis, and reduction of invasiveness and angiogenesis. Different mechanisms may be responsible in different tumor types and under different experimental conditions. Importantly, preclinical data suggest that calcitriol acts in a synergistic and/or additive manner when combined with antineoplastic agents that are relevant to prostate cancer, including dexamethasone and several classes of cytotoxic agents. The antineoplastic effects of calcitriol occur at concentrations that substantially exceed the normal physiologic range and cannot be safely achieved with conventional daily dosing. Intermittent administration of calcitriol has allowed significant dose escalation. In combination with weekly docetaxel, the agent produced encouraging results in a single-institution phase II study. An international placebo-controlled randomized trial that is currently under way will provide more robust information about the safety and efficacy of this combination.     

ASCENT: the androgen-independent prostate cancer study of calcitriol enhancing taxotere

ASCENT, the Androgen-Independent Prostate Cancer (AIPC) Study of Calcitriol Enhancing Taxotere, is a double-blind, placebo-controlled randomized clinical trial designed to determine if DN-101, a high-dose oral formulation of calcitriol designed for cancer therapy, significantly increases the proportion of patients who have > 50% reduction in serum prostate-specific antigen (PSA) levels in response to docetaxel. The secondary goals of ASCENT are to evaluate the effect of DN-101 combined with docetaxel on PSA progression-free survival, tumour response rate in measurable disease, tumour progression-free survival, skeletal morbidity-free survival, clinical progression-free survival, and overall survival, and to examine the safety and tolerability of DN-101 combined with docetaxel. ASCENT builds on phase I work showing that weekly dosing allows substantial dose-escalation of calcitriol, the natural ligand for the vitamin D receptor, and on phase II work that suggested that adding weekly high-dose 'pulse' calcitriol may enhance the activity of weekly docetaxel in patients with AIPC. The preclinical rationale for calcitriol and its combination with docetaxel for prostate cancer therapy is reviewed, as are the key clinical trials that led to the development of ASCENT. The ASCENT design and its strengths and limitations are presented.     

Hormone therapy for radiorecurrent prostate cancer

Background

The management of patients who relapse after radical radiotherapy is a challenging problem for the multidisciplinary team. This group of men may have been considered ineligible or chosen not to be treated with an initial surgical approach as a result of high-risk features or significant comorbid conditions. It is important not to miss the opportunity for definitive local salvage therapies at this stage, and eligible patients should undergo careful restaging to determine their suitability for these approaches. For those men not suitable for local treatment, androgen deprivation therapy (ADT) remains an option.

Methods

Literature review of the evidence relating to the management of hormone therapy for radiorecurrent prostate cancer.

Results

Results from retrospective studies have shown that not all men with biochemical relapse will experience distant metastasis or a reduction in survival due to prostate cancer progression. Therefore, the timing of ADT commencement remains controversial. However, it would seem appropriate to offer immediate therapy to men with advanced disease or unfavourable prostate-specific antigen (PSA) kinetics at relapse. Patients with more favourable risk factors and PSA kinetics may be considered for watchful waiting and deferred ADT to avoid or delay the associated toxicities. Patients with non-metastatic disease can be given the option of castration-based therapy or an antiandrogen such as bicalutamide which may have potential advantages in maintenance of sexual function, physical capacity and bone mineral density but at the expense of an increase in gynaecomastia and mastalgia. Recent data suggest the burden of toxicity from ADT may be reduced by the use of intermittent hormone therapy without compromising survival in this group of patients with radiorecurrence.

Conclusions

Hormone therapy remains an option for men with radiorecurrent prostate cancer.     

Intermittent hormone therapy for prostate cancer

Intermittent hormone therapy in prostate cancer consists in disrupting treatment after the nadir PSA has been reached, and reinitiating treatment when the PSA increases over a certain threshold. Theoretical advantages of intermittent hormone therapy are to delay the occurrence of hormone-independence and to decrease treatment-related side effects. Some phase II trials have demonstrated the feasibility of intermittent hormone therapy. The percent time without treatment varies between 40 and 50%. Oncologic results of intermittent hormone therapy are, at least, equivalent to those of continuous therapy. Moreover, the side effects of treatment are decreased and the quality of life is improved during off treatment phases. Due to the lack of comparative studies, the superiority of intermittent upon continuous treatment has not been established at long-term follow-up. Prospective comparative trials are ongoing; they will determine the true benefit of intermittent hormone therapy in prostate cancer.     

Molecular targeted therapy for prostate cancer

Once, prostate cancer becomes hormone-refractory, there are only a few effective therapies such as docetaxel-based chemotherapies. Several molecular targeted therapeutic drugs have been tested for prostate cancer such as endothelin-A receptor antagonist, endothelial growth factor receptor or platelet derived growth factor receptor inhibitor. Nuclear factor kappa B (NFkappaB) is a key molecule for the growth of prostate cancer. Therefore, NFkappaB can be a good target for the therapy. In fact, a couple of NFkappaB inhibitors have been clinically or pre-clinically tested. Among them, Bortezomib and thalidomide showed little clinical efficacy as a single therapeutic agent. However, these drugs exerted clinical benefits to some extent when used with other chemotherapeutic drugs. Dexamethasone is also an NFkappaB inhibitor. Its clinical efficacy is through suppressing the adrenal androgen level. Besides adrenal androgen blockade, dexamethasone suppresses the growth of prostate cancer via NFkappaB inactivation, and also via the inhibition of interleukin-6 production which is reportedly important for the growth of prostate cancer. One of the clinical benefits of dexamethasone treatment is the improvement in anemia.     

Oncolytic virus therapy for prostate cancer

The use of replication-competent viruses that can selectively replicate in and destroy neoplastic cells is an attractive strategy for treating cancer. Various oncolytic viruses have been taken to clinical trials since a recombinant virus was first applied to cancer patients a decade ago. The concept of the therapy is simple: infectious virus kills the host cancer cells in the course of viral replication. It is important, however, that the virus does not harm the surrounding normal tissue. Oncolytic viruses can be classified largely into two groups: DNA viruses genetically engineered to achieve cancer specificity (e.g. adenovirus, herpes simplex virus and vaccinia) and RNA viruses of which human is not the natural host (e.g. Newcastle disease virus and reovirus). Prostate cancer has always been one of the major targets of oncolytic virus therapy development. The result of six clinical trials for prostate cancer has been published and several trials are now going on. Forty-eight of 83 (58%) patients evaluated in the phase I studies demonstrated a >25% decrease in serum prostate-specific antigen level without evidence of severe toxicities. The result shows the oncolytic virus therapy is promising toward clinical application. Here, we review the recent advances in the field and summarize the results from clinical trials.     

Molecular-targeted therapy for hormone-refractory prostate cancer

Molecular-targeted therapy is to treat pathologic pathways specifically in tumor cell or tumor microenvironment. Specific molecular-targeted therapeutic agents for hormone-refractory prostate cancer (HRPC) include endothelin-A receptor antagonist, EGF receptor (EGFR) inhibitor, platelet derived growth factor receptor (PDGFR) inhibitor, nuclear factor of kappaB (NF-kappaB) inhibitor, cyclooxygenase-2 (COX2) inhibitor, and active form of Vitamin D. These agents have been investigated in clinical trials. So far, none of the above-mentioned agent has shown a sufficient clinical efficacy alone. However, docetaxel-based combinations with thalidomide or calcitriol have promising clinical activities. Further investigations are needed to optimize the molecular-targeted agents in the combinations with chemotherapeutic agents for the treatment of HRPC.     

Initiation of salvage therapy for prostate cancer

Physicians and patients have variable and individual levels of comfort regarding when to begin salvage therapy for rising prostate specific antigen (PSA) after definitive treatment of prostate cancer. The decision to start salvage therapy is a multifactorial process for which few rigorous data or guidelines exist. A questionnaire survey of urologists of the Department of Defense (DoD) Center for Prostate Disease Research (CPDR) was undertaken to obtain current perspectives on when to begin salvage therapy for biochemical failure after definitive therapy. Variables of age, grade, T-stage, nodal status, performance status, latency since prior therapy, PSA velocity, and ploidy were prioritized in four clinical situations; subsequent questions assessed consensus PSA cut-offs for beginning adjuvant therapy in 84 clinical scenarios. Consensus on PSA cut-off points was limited to postoperative radiotherapy (RT), where values of 1.0-1.5 were the mean cut-off points. CPDR urologists consider salvage prostatectomy post-RT only for patients <70-y-old with node negative, grade 2-7 disease and excellent performance status. Ploidy was not generally considered useful in any scenario. Many variables in addition to PSA level are involved in the decision of when to commence adjuvant therapy for initial biochemical failure. These are strikingly interdependent, and few clear absolutes are evident from this questionnaire. This is a point of necessary further research and continued discussion among physicians caring for these patients.     

Salvage therapy for prostate cancer recurrence after radiation therapy

Radiotherapy has been successful in treating localized prostate cancer; however, a subset of patients will experience disease recurrence. Determination of the recurrence location must be made using pretreatment and posttreatment clinical variables, imaging, and postradiotherapy biopsy. Patients presumed to have local-only recurrence, optimal clinical risk factors, and an extended life expectancy may be considered for salvage local treatment. Current options include salvage surgery, cryoablation, and brachytherapy. Although they are associated with higher morbidity than primary therapy, salvage treatments can be effective and can still provide patients with a good oncologic and functional outcome. As these modalities continue to improve and patient selection is optimized, better results will evolve.