Abstract
Several presentations by attendees of the 11th International Prostate Cancer Update addressed recent advances in prostate cancer treatment. A study that examined whether a relationship exists between neuroendocrine (NE) cell differentiation and hormone-refractory prostate cancer (HRPC) concluded that the appearance of NE cells in prostatic carcinoma is an important phenomenon in the development of HRPC. Exisuland, a selective apoptotic antineoplastic drug, was compared to placebo in a recent study and was found to significantly inhibit the increase of prostate-specific antigen in patients who had undergone radical prostatectomy. A new dosing regimen for flutamide (500 mg daily) was found to have no significant differences from the currently recommended dose (250 mg every 8 hours); the new, single daily dose could meet with greater compliance and would reduce drug cost by 30%. The antiproliferative effect of vitamin D on prostatic carcinoma cells was discussed, along with the possible role of vitamin D supplementation during prostate cancer treatment. Finally, a presentation on hospice care acknowledged that referral for such care is unfortunately at times delayed by physicians, patients, and patients’ families, leaving insufficient time for all the benefits of that stage of care to be realized.
Key words: Neuroendocrine cells, Hormone-refractory prostate cancer, Exisuland, Flutamide, Compliance, Cost of treatment, Vitamin D, Hospice care
This article will summarize a number of recent approaches to treatment of prostate cancer, ranging from novel methods of local control to the decisions surrounding hospice care. The individual studies and topics are reflective of the diversity of methods being brought to bear on different stages of this disease.
Neuroendocrine Differentiation in Hormone Refractory Prostate Cancer
Recently, neuroendocrine (NE) differentiation in areas of malignant transformation has been proposed to have major impact on prostate cancer progression and constitute part of the mechanism by which prostate cancer progresses toward androgen independence. Prostatic NE cells are distributed throughout the prostatic urethra, prostatic ducts, and peripheral prostatic acini, with the largest concentration of cells being in the prostatic ducts. Morphologically, there are two types of prostatic NE cells: 1) open, flask-shaped cells with long, slender extensions reaching the lumen, and 2) closed cells without luminal extension. Both cell types have a complex appearance, with irregular dendrite-like processes extending underneath and between adjacent epithelial cells.1 Ultrastructurally, prostatic NE cells contain numerous electron-dense granules in the cytoplasm.2
NE cells produce a number of bioactive hormone-related substances, including chromogranin A, serotonin, neuron-specific enolase, calcitonin, somatostatin, and bombesin-like peptides.3–7 These bioactive products in the NE cells can be functionally considered to act as an autocrine or paracrine regulatory agent in the secretory process, and also have growth factor activity. Although initial androgen deprivation therapy is useful for most patients with prostate cancers, the majority of these patients relapse within 3 to 6 years and are resistant to hormone therapy.
To determine whether a relationship exists between NE differentiation status and hormone-refractory prostate cancer (HRPC), an immunohistochemical analysis has been performed. Fifty-nine prostate cancer specimens obtained at radical prostatectomy and 25 prostate cancer specimens obtained from autopsy cases of HRPC were examined for NE differentiation using a labeled strept-avidin-biotin (LSAB) technique with a polyclonal antichromogranin (CgA) from Dako Corporation. These specimens were classified into 3 arms: 19 specimens from patients without hormone therapy (Group 1), 40 specimens from patients responsive to androgen deprivation therapy for 3 to 6 months before radical prostatectomy (Group 2), and 25 autopsy specimens from patients with HRPC (Group 3).
Staining of prostatic carcinoma was scored according to the following schema: 0 = no staining, 1 = stained cells lt; 10% (Figure 1), 2 = stained cells 10% to 20% (Figure 2), 3 = stained cells > 20% (Figure 3). The mean staining score in malignant cells and standard deviation was 0.5 ± 0.8 in Group 1, 0.7 ± 0.7 in Group 2, and 1.7 ± 0.8 in Group 3. A statistical difference among these arms was evident (P < .001). NE differentiation status was increased in the patients with HRPC. The biological features of malignant NE cells include lack of androgen receptors.8 From these findings, it can be concluded that NE cells in areas of prostate cancer are not suppressed by androgen ablation, and following long-term antiandrogen therapy, tumor cell populations contain greater numbers of NE cells. Thus, the appearance of NE cells in prostatic carcinoma is an important phenomenon in the development of HRPC. Although there are limited approaches to the therapy of HRPC, elucidation of the underlying mechanisms of NE differentiation could be useful in developing new strategies for this stage of disease.
Figure 1.
CgA staining score grade 1 (stained cells < 10%). Immunoreactive neoplastic cells are scattered. This case was obtained from a patient without hormone therapy.
Figure 2.
CgA staining score grade 2 (stained cells 10–20%). Immunoreactive cancer cells are dispersed. This case was obtained from a patient response to androgen deprivation therapy.
Figure 3.
CgA staining score grade 3 (stained cells > 20%). Numerous cancer cells with immunoreactivity in a patient with HRPC.
Use of Exisulind in the Treatment of Recurrent Prostate Cancer Following Radical Prostatectomy
Localized prostate cancer is effectively treated in most patients with radical prostatectomy (RP) as evidenced by the reduction of prostate-specific antigen (PSA) to undetectable levels following surgery. However, because of undetected metastatic disease, up to 50% of men experience disease recurrence within 10 to 15 years.9
PSA is widely accepted as a marker of disease progression in prostate cancer and is the most effective means of monitoring for disease progression following RP.10 The risk of developing metastatic disease following RP can be estimated based on the pathological Gleason score, time to initial biochemical recurrence, and postoperative PSA doubling time (PSADT).11 Treatment options for men whose PSA levels rise following RP are limited to radiation therapy and hormone ablation, both of which are associated with significant morbidity.
Exisulind is a selective apoptotic antineoplastic drug, which has antineoplastic activity in a broad range of cancer cell lines including androgen-sensitive (LNCaP) and androgen insensitive (PC3) prostate cancer cells.12–16 Exisulind induces apoptosis selectively in cancer cells by inhibiting cyclic guanosine monophosphate phosphodiesterase (cGMP-PDE), resulting in increased cGMP, protein kinase G activation, and phosphorylation of β-catenin.17 In a nude mouse xenograft model of human prostate cancer, exisulind significantly induced apoptosis and inhibited tumor growth compared to controls.18
Based on preclinical data, a controlled clinical study was conducted using PSA as a marker to evaluate the effect of exisulind on the rate of prostate cancer progression in men following RP. In this 12-month, multicenter, double-blind, placebo-controlled, parallel study, men who had undergone RP were randomized to receive exisulind 250 mg orally twice daily or placebo. Entry criteria included a PSA level of 0.4 to 15 ng/mL, an increase in PSA ≥ 10% during the 4 months prior to entering the study, and no evidence of metastasis based on bone scan, computed tomography scan, and chest x-ray. Patients were prospectively stratified into groups by risk (high, intermediate, low) of developing metastatic disease using pre-study data if available. PSA levels were measured monthly. Efficacy was determined based on median change in PSA from baseline. The median change in PSA levels and median PSADT were analyzed nonparametrically using the Wilcoxon Rank Sum Test.
Of the 96 patients enrolled and randomized, 92 were considered evaluable. The total risk group analysis included 82 patients who were stratified into 3 risk groups: low-risk (16 placebo, 17 exisulind), intermediate-risk (21 placebo, 14 exisulind), and high-risk (6 placebo, 8 exisulind). Sixty-nine patients (36 placebo, 33 exisulind) remained on treatment for 12 months. There were no significant differences between the treatment groups with respect to age, race, or disease parameters.
Exisulind significantly inhibited the increase in PSA compared to placebo (P = .0166) in all patients and in the high-risk group (P = .0003). In the intermediate-risk group, there was a trend toward significance with exisulind (P = .126). No significant differences were seen in the low-risk group, probably owing to the small PSA change in both treatment groups over 12 months. Mean changes in PSA from baseline for the overall population and risk groups are shown in Figure 4.
Figure 4.
Mean change in PSA from baseline (ng/mL).
The mean and median PSADTs of the treatment groups were compared pre-study and on-study. A statistically significant increase in PSADT was seen in the high-risk patients receiving exisulind (P = .048). The median PSADT increased from 5.63 to 8.84 months in patients receiving exisulind versus a decrease from 4.9 to 2.39 months in placebo-treated patients (Figure 5). An increase in PSADT was also observed in the intermediate-risk patients receiving exisulind compared with placebo; however, this change was not statistically significant. The low-risk patients, whose pre-study PSA doubling times exceeded 20 months, did not show a significant change in this 12-month study.
Figure 5.
Median and mean PSA doubling times in high-risk patients.
Because of the small numbers of patients and events, there was no statistical comparison for adverse events (AEs) between the two treatment groups. However, exisulind was well tolerated, with the most commonly reported adverse event being mild to moderate elevations of alanine aminotransferase (ALT) in 15 of 47 patients. The elevation of liver enzymes was reversible in all patients upon dose reduction or temporary discontinuation of drug. Other events that occurred in the exisulind group included the following: asthenia, dyspepsia, nausea, abdominal and back pain, and viral infection. Serious AEs occurred in 10 patients (2 placebo, 8 exisulind); none of these events were considered related to study drug.
The results of this study suggest that exisulind may slow the progression of prostate cancer following RP, as measured by the disease marker PSA. The effect was evident within 2 to 3 months after initiation of therapy, and continued through the 12 months of the study. At the end of study, all patients were given the opportunity to receive exisulind for an additional 12 months. Sixty patients (33 placebo, 27 exisulind) entered the open-label extension. The results of the extension study are not yet available. Additional studies of exisulind in prostate cancer are underway and others are planned.
Studies Comparing Dosing Regimens of Flutamide
The original pharmacokinetics studies performed in humans on oral flutamide and its active metabolite 2-hydroxyflutamide suggested that the elimination half-life of 2-hydroxyflutamide was 4 to 6.6 hours and 8 to 22 hours after a single oral dose of 250 and 500 mg of flutamide, respectively, in patients with prostate cancer.19 Although this early study suggested that a single 500-mg dose of flutamide may result in a longer half-life of the drug, comparative dosing studies have not been performed. More recent data from animal studies suggest that the biological half-life of flutamide and its active metabolite 2-hydroxyflutamide may be quite different than the serum half-life of these agents. In rats, the prostate continues to respond to a dose of flutamide for up to 96 hours (Labrie animal data, personal communication). Furthermore, data from geriatric volunteers suggests that patients are only 40% compliant with a thrice-daily dosing schedule of any drug but are 83% compliant with twice daily and 90% compliant with single daily dosing (data on file, Schering Corporation).
These data led to the development of a prospective randomized trial comparing the efficacy and toxicity of a new dose (500 mg daily [QD]) of flutamide to the currently recommended dose, 250 mg every 8 hours (q8h), in the treatment of advanced prostate cancer. The objective of this trial was to compare two doses of flutamide based on PSA response with secondary endpoints of quality-of-life and toxicity differences.
From July 1995 to October 1999, 440 men aged 46 to 94 years (mean 71 years) were randomized to receive either 500 QD of flutamide or 250 mg q8h plus medical or surgical castration for 3 months. Patients were required to be <40 years of age with de novo M+ or N+ prostate cancer or stage T1–T4 with biochemical evidence of progression defined as a PSA < 0.5 ng/mL (for baseline PSA < 2 ng/mL, three serial PSA elevations a minimum of 2 weeks apart after nadir had been reached; for baseline PSA < 2 ng/mL, two serial PSA elevations a minimum of 2 weeks apart after nadir had been reached) following definitive therapy (radical prostatectomy or radiation therapy). All patients were required to have a life expectancy of at least 1 year, an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, no prior treatment for metastatic prostate cancer, able to read and understand English, and able to give informed consent. Patients with hepatic or renal disease were excluded from the trial, as well as those with known hypersensitivity to study drugs, metastatic prostate cancer to the central nervous system or evidence of spinal cord compression, liver function tests > 1.5 × normal, creatinine > 2x × normal, white blood cell count < 3000 cells/mm3, hematocrit < 30%, platelet count < 100,000 mm3, any other active malignancy except nonmelanomatous skin cancer, any other investigational drug used within 30 days of the screening visit, or finasteride within 2 weeks of the screening visit. Follow-up visits were performed at weeks 0, 4, 8, and 12 (Table 1).
Table 1.
Study Calendar
| Screening* | Time 0† | Wk 4 | Wk 8 | Wk 12 | |
|---|---|---|---|---|---|
| Physical | |||||
| History/physical/neurologic exam | X | X | |||
| Weight, vital signs | X | X | X | X | X |
| ECOG performance rating | X | X | X | X | X |
| Bone pain scale | X | X | X | X | |
| Toxicity notation | X | X | X | X | |
| Laboratory/Tests | |||||
| CBC | X | X | X | X | X |
| Creatinine | X | X | X | X | X |
| SGOT/SGPT/bilirubin | X | X | X | X | X |
| Alkaline phosphatase | X | X | |||
| PSA | X | X | X | X | X |
| Serum testosterone | X | X | |||
| Bone scans | X | X | |||
| Quality of Life‡ | |||||
| Patient | X | X | X | X |
Pre-study.
Point at which treatment is initiated is considered (Time 0).
HR-QOL questionnaire - EORTC instrument.
The statistical methodology used in this study was as follows: All between-group comparisons used two-tailed test procedures, with a 0.05 level of significance (α = 0.05) to test a null hypothesis of no difference between the treatment groups (QD, q8h). The groups were compared with respect to age, baseline PSA, and baseline quality of life measurements using analysis of variance and with respect to race (percent Caucasian patients) and baseline PSA (percent of patients with normal PSA) using Cochran-Mantel-Haenszel tests.
The following efficacy endpoints were measured at weeks 4, 8, and 12:
Percent of patients with normal PSA
Change from baseline PSA
Percent change from baseline PSA
General quality of life
Urinary quality of life
Cochran-Mantel-Haenszel tests were used for the analyses of percent of patients with normal PSA. Wilcoxon rank sum tests were used for the analyses of change and percent change from baseline PSA. Analysis of variance was used to compare the treatment groups with respect to quality-of-life measurements.
The results of this study included 225 patients who were randomized to the 500-mg-QD arm and 215 to the 250-mg-q8h arm. One hundred and ninety-one patients in the 500-mg-QD arm and 197 in the 250-mg-q8h arm had complete information and were available for comparison at the end of the study. The list of reasons for patients who were excluded from the analysis (including patients who withdrew from the trial with no PSA information and patients who had missing PSA information at baseline) is outlined in Table 2. The majority of laboratory abnormalities were mild elevation of transaminases, whereas the toxicities were primarily diarrhea. No differences were noted in the mean age, race, ECOG performance status, severity of disease, or baseline PSA levels between the two groups (Table 3).
Table 2.
List of Reasons for Discontinuation and Missing PSA Values at Baseline
| Flutamide | Flutamide | |
|---|---|---|
| Reason | 500 QD | 250 q8h |
| (n = 34) | (n = 18) | |
| Discontinuation | 26 | 8 |
| AE: lab abnormality | 4 | 3 |
| AE: toxicity | 3 | 1 |
| AE: other | 9 | 1 |
| Disease progression | 1 | 0 |
| Fail to return | 2 | 0 |
| Protocol violation | 2 | 2 |
| Other | 5 | 1 |
| Missing PSA information | 8 | 10 |
| at baseline |
Table 3.
Demographic and Disease Characteristics
| Flutamide | Flutamide | ||
|---|---|---|---|
| 500 QD | 250 q8h | ||
| Characteristic | (n = 225) | (n = 215) | P value |
| Age | .342 | ||
| Mean ± SD | 71.5 ± 8.14 | 70.7 ± 7.94 | |
| Median | 72 | 71 | |
| Range | 48–89 | 46–94 | |
| Race | .512 | ||
| Caucasian | 156 (69.3%) | 154 (71.6%) | |
| Black | 54 (24.0%) | 50 (23.3%) | |
| Asian | 6 (2.7%) | 3 (1.4%) | |
| Hispanic | 8 (3.6%) | 5 (2.3%) | |
| Other | 1 (0.4%) | 3 (1.4%) | |
| ECOG Performance Status | .938 | ||
| Missing | 0 (0.0%) | 1 (0.5%) | |
| Normal activity | 139 (61.8%) | 132 (61.4%) | |
| Light work | 65 (28.9%) | 62 (28.8%) | |
| No work | 21 (9.3%) | 20 (9.3 %) |
PSA changes were not significantly different: 71% of the 500-mg-QD patients and 75% of the 250-mg-q8h patients normalized their PSA by week 12 and percent change was 89% and 96%, respectively (Table 4). The treatment groups were not significantly different with respect to the incidence of adverse events, which were categorized as possibly, probably, or definitely related to study drug, with 71% reporting at least one event in the 500-mg-QD arm and 68% reporting at least one event in the 250-mg-q8h arm (P = .337) (Table 5). No significant differences were noted between the two groups with regard to any of the quality of life domains.
Table 4.
Percent Change from Baseline PSA
| Flutamide | Flutamide | ||
|---|---|---|---|
| Week | 500 QD | 250 q8h | P value |
| Week 4 | (n = 203) | (n = 197) | |
| Mean ± SD | −85.3 ± 26.3 | −86.9 ± 25.4 | .278 |
| Median | −93.0 | −94.0 | |
| Range | (−100, 89) | (−100, 134) | |
| Week 8 | (n = 191) | (n = 189) | |
| Mean ± SD | −91.1 ± 26.7 | −94.5 ± 15.4 | .200 |
| Median | −98.0 | −98.0 | |
| Range | (−100, 129) | (−100, 44) | |
| Week 12 | (n = 191) | (n = 197) | |
| Mean ± SD | −88.9 ± 40.6 | −95.7 ± 13.1 | .092 |
| Median | −99.0 | −99.0 | |
| Range | (−100, 219) | (−100, 35) |
Table 5.
Incidence of Adverse Events
| Flutamide | Flutamide | ||
|---|---|---|---|
| 500 QD | 250 q8h | ||
| Adverse Event | (n = 225) | (n = 215) | P value |
| Hot flushes | 78 (34.7%) | 78 (36.3%) | .737 |
| Diarrhea | 41 (18.2%) | 31 (14.4%) | .245 |
| Anemia | 20 (8.9%) | 20 (9.3%) | .949 |
| Nausea | 17 (7.6%) | 21 (9.8%) | .444 |
| SGOT increased | 20 (8.9%) | 17 (7.9%) | .772 |
| Fatigue | 11 (4.9%) | 18 (8.4%). | .108 |
| Constipation | 10 (4.4%) | 7 (3.3%). | .494 |
| Vomiting | 8 (3.6%) | 9 (4.2%) | .614 |
| Pain | 10 (4.4%) | 3 (1.4%) | .053 |
| Urinary tract infection | 5 (2.2%) | 8 (3.7%) | .353 |
| Bone pain | 7 (3.1%) | 6 (2.8%) | .848 |
| Insomnia | 4 (1.8%) | 7 (3.3%) | .380 |
| Dizziness | 7 (3.1%) | 3 (1.4%) | .206 |
Heretofore, there have been no studies comparing variable doses of flutamide for advanced prostate cancer (personal communication, F. Labrie, December 1995). Recent animal data suggesting the biological half-life of the drug may be quite different than the serum half-life led to the development of this trial. The data suggest that 500 mg QD of flutamide combined with castration is equally effective in lowering serum PSA when compared to conventional flutamide dosing. Previous studies have brought into question the use of PSA as a surrogate endpoint, primarily because PSA differences were noted between comparison arms early in the trial, but this did not equate to differences in survival.20 The data presented here revealed no significant differences between comparison groups in PSA changes and, thus, differences in survival after long-term follow-up would not be expected. However, only long-term follow-up will definitely answer the question.
Equally important in this trial was the question of differences in toxicities with 500 mg QD flutamide compared to conventional dosing. The researchers found no significant differences between the two groups relative to toxicities. Diarrhea was slightly more common in the 500-mg-QD arm at 18%, compared with 14% in the 250-mg-q8h arm, although the difference was not significant. However, these data may shed some light on the etiology of diarrhea in patients receiving flutamide. This study suggests the diarrhea is due to peak serum levels of the drug, because the 500-mg-QD patients experienced a higher incidence of the side effect.
Finally, a significant benefit of 500 mg QD dosing versus 250 mg q8h is a reduction in cost. The use of 4 capsules per day versus 6 capsules reduces the cost by 30%. This would make flutamide used in combination therapy the least expensive nonsteroidal antiandrogen presently available in the United States.
Vitamin D and Carboplatin in the Treatment of Advanced Disease
Although it is recognized that prostate cancer is an androgen-dependent disease, it is now very apparent that a variety of other steroid and peptide hormones are capable of regulating the growth and differentiation of prostate cancer cells. Early epidemiologic studies have indicated that the clinical emergence of prostate cancer may be at least partially explained by vitamin D deficiency. In addition to age and race, these studies linked geographic location to prostate cancer mortality through potential actions on vitamin D levels. The link between latitude and vitamin D action was clear, because ultraviolet light is required for the initial conversion of the vitamin D precursor 7-dehydrocholesterol to vitamin D3. What remained to be shown was that there was a biologic basis for the remainder of this hypothesis.
Vitamin D is known to act through both nuclear receptors (the genomic pathway) and cell membrane receptors (the nongenomic pathway). Vitamin D receptors had been found in various non-prostate benign and malignant epithelial cells. The Miller laboratory was the first to show that specific, high-affinity binding sites for the active metabolite of vitamin D (1α,25-dihydroxyvitamin D3) are present in prostate cancer cells. The receptor number varies widely between different cell lines.21–24
It had also been shown that vitamin D could have a marked antiproliferative effect on various non-prostate malignant cell lines in vitro. Miller et al have confirmed that this is also the fact in prostatic carcinoma cells. However, it is interesting to note that the degree of antiproliferative effect varies widely between cell lines. This suggests that whereas some cells remain sensitive to the effects of vitamin D, others may have become resistant. The mechanisms through which cells become vitamin D resistant are currently under study in the Miller laboratory and may provide critical insights into the use of vitamin D in the therapy of prostate cancer.
Studies with vitamin D and its analogues have also made it clear that effects on differentiation accompany the antiproliferative effects. Using the well-characterized prostate cancer cell line LNCaP, we have found that vitamin D and its analogues increase the synthesis and release of both PSA and prostate-specific acid phosphatase into the culture medium. This finding is of great clinical importance, because it indicates that in clinical trials, an early increase in a patient’s serum PSA levels might indicate success rather than failure.
The mechanisms through which vitamin D induces a decrease in proliferation are now becoming clear. The Miller laboratory has found that an increase in the cell cycle mediator p21 appears to be necessary for the antiproliferative effects. This increase occurs within days and could be caused by indirect actions on other genes. In line with this possibility, the laboratory has found that in some cells, but not others, p21 induction by vitamin D appears to require a prior induction of transforming growth factor beta.25 Again, the mechanisms of this induction and alternate pathways will probably offer clues to methods for the appropriate use of these compounds in the management of clinical disease.
Finally, it has been found in studies on prediagnostic sera levels that decreased levels of vitamin D metabolites accompany both the presence of prostate cancer and its biologic aggression. Of more interest, it is now known that as many as 37% of hospitalized patients whose vitamin D intake is greater than the current recommended daily allowance can be vitamin D deficient. It also appears that vitamin D deficiency may be particularly common among men with hormone-refractory or advanced-stage prostate cancer. It would seem reasonable, therefore, to include vitamin D supplementation into treatment strategies for these patients. To this end, ongoing studies will examine the ability of vitamin D to potentiate the effects of chemotherapeutic agents not otherwise found to be of great value in the treatment of prostate cancer. Moffatt et al have shown that vitamin D can have a synergistic effect on growth arrest of prostate cancer cells induced by cisplatin or carboplatin.26 These findings have led to a clinical trial in which patients are supplemented with vitamin D prior to receiving carboplatin therapy. Patients are also given dexamethasone prior to receiving either of these agents. The dexamethasone potentially has both direct antiproliferative effects as well as the effect of protecting patients from vitamin D-induced hypercalcemia. Preliminary findings indicate that as many as 70% of men will respond to such therapy with decreases > 50% in their PSA over prolonged periods of time. These findings indicate the potential for vitamin D and perhaps other forms of differentiation therapy to contribute to our armamentarium for the treatment of this lethal disease.27
Making the Decision for Hospice Referral
When novel treatments fail or patients reach a point that they no longer wish to pursue active treatment of their disease, it is incumbent upon the health care providers to assist in the consideration of hospice care. All physicians are in a position to implement palliative care and are trained in the basic principles of palliative care. These principles are a basic part of medical training. The physician can play a key role in helping patients and families at the end of life. Patient quality of life is better when relief of suffering is the primary goal of therapy and when the therapy is adapted to fit the patient’s priorities and views about life. Whenever possible, the patient and physician should reach consensus as to the options and outcomes that are achievable. Expectations of all parties should be realistic in regard to the natural history of the disease process. There is a balance between curative therapy and palliative therapy that is dynamic through the course of treatment of an illness, with palliative therapy becoming more and more dominant as the disease progresses toward hospice care.
Both physician and patient barriers contribute to delayed hospice referral. Misunderstandings about hospice, interpretation of hospice referral as failure, false patient expectations about their illness, and physician training that views death as the enemy instead of an expected outcome at some point all contribute. Hospice care has rigorous standards, not dissimilar in intensity to acute care. Hospice care is aggressive care that attempts to treat the patient and family and acknowledges psychosocial and spiritual needs as well as medical interventions, particularly with regard to pain control. There are many “tasks” at the end of life for patients to complete so that they can die with a sense of closure to their lives. The same is true for survivors to go on with their lives in a healthy fashion following the death of a loved one. This takes time, and hospice referral often occurs too late to take full advantage of these opportunities. Physicians and other care providers have limited ability to accurately predict when patients will die. However, the goal is to move “seamlessly” along a gradually increasing palliative approach to end of life care. There is no therapeutic penalty for early referral to hospice. Patients can receive ongoing treatments of any type as long as the goal is to improve the quality of life, and this should be paramount in the consideration of care options for advanced prostate cancer patients.
Main Points.
A study to determine whether a relationship exists between neuroendocrine (NE) cell differentiation and hormone-refractory prostate cancer (HRPC) concluded that NE cells in areas of prostate cancer are not suppressed by androgen ablation, and thus, the appearance of NE cells in prostatic carcinoma is an important phenomenon in the development of HRPC.
Treatment options for men whose PSA levels rise following radical prostatectomy (RP) are limited to radiation therapy and hormone ablation; but a recent study found that exisulind, a selective apoptotic antineoplastic drug, compared to placebo, significantly inhibited the increase of PSA in patients with RP.
Results from a prospective, randomized trial comparing the efficacy and toxicity of a new dose of flutamide (500 mg daily) to the currently recommended dose, 250 mg every 8 hours, in the treatment of advanced prostate cancer, found no significant differences between the two dosing regimens. The new, single daily dose could meet with greater compliance and would reduce drug cost by 30%.
Studies have confirmed that vitamin D could have a marked antiproliferative effect on prostatic carcinoma cells; the possible role of vitamin D supplementation in the treatment of hormone-refractory or advanced-stage prostate cancer is currently being explored.
Because it is may be viewed as “failure,” referral to hospice care can sometimes be unduly delayed; this results in the patient not having enough time to complete the tasks that will bring a sense of “closure” to their lives.
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