Highlights of contemporary issues in the medical management of prostate cancer

2.1. Adjuvant hormonal therapy 

Once prostate cancer recurs after radical prostatectomy, the prognosis is ultimately poor. The median time from PSA failure to metastases is 8 years, and from metastases to death is 5 years [11].

Recurrence after local prostate cancer treatment detectable only by a rise in PSA is a difficult problem for physicians and patients. The majority of patients are relatively young and otherwise healthy, treatment of PSA-only recurrence requires approaches that not only improve survival but also preserve quality of life. For radical prostatectomy patients, a PSA-only recurrence is defined as persistent or rising PSA in the postoperative period. For radiation-treated patients, the 1997 American Society for Therapeutic Radiology and Oncology guidelines specify three consecutive elevations of PSA after the post-treatment nadir PSA is achieved [12].

PSA relapse following localized therapy usually heralds systemic disease. Whether or not to treat at this initial stage with androgen suppression therapy is controversial, due to its toxicities which include impotence, hot-flashes fatigue, anemia, decrease in cognitive function, reduction of muscle mass and psychological changes [13].

Traditional hormonal therapy is the mainstay of systemic treatment for PSA-only recurrence, although non-traditional approaches have become more popular. Asymptomatic biochemical progression prior to clinical progression has created a window of opportunity to test new non-toxic approaches such as the use of Exisulind, biphosphonates and Vitamin D.

A major unresolved issue concerning the optimal timing of hormonal therapy is the optimal time to initiate treatment [14].

Studies of adjuvant hormonal therapy after radical prostatectomy in locally advanced prostate cancer, have suggested some improvement in disease-free survival [15], but are not conclusive.

In a frequently quoted American study, adjuvant hormonal therapy appeared to benefit patients whose tumor was controlled by surgery. Ninety-eight node positive patients after radical prostatectomy were randomized to intermediate versus delayed hormonal therapy. At a median follow-up of 7.1 years, only 14.8% of men who received immediate anti-androgen treatment died, compared with 35% of men treated at the time of progression (P=0.02) [16]. It appeared from this study that immediate anti-androgen therapy after radical prostatectomy and pelvic lymphadenectomy improved survival and reduced the risk of recurrence in patients with node-positive prostate cancer.

The study, however, had several important drawbacks. The most important of which was that in this trial, it was initially planned to randomize 204 patients, but closed early due to lack of accrual. The other flaw is that there was no reference pathologist in this study. This means that if there was an appreciable difference in the Gleason score of those receiving immediate as opposed to delayed therapy, then the difference in favor of immediate therapy may not have been found [17].

In an EORTC study, 302 patients with node positive prostate cancer who did not undergo prostatectomy were assigned to early or delayed therapy. At a median follow-up of 6 years, the effect of adjuvant hormonal therapy in node positive patients, who did not undergo prostatectomy, was not beneficial [14], [17], [18]. The final analysis of 234 randomized and 86 registered patients will not be available, however, until the end of 2002.

The Rochester group has also sustained that adjuvant hormonal therapy is beneficial in patients at risk for disease progression, especially when administered after radical prostatectomy. They have retrospectively reviewed the clinical information on stage pT3b cancer from their institution to evaluate adjuvant hormonal therapy after radical prostatectomy. They sustain that adjuvant hormonal therapy after prostatectomy has an impact on PSA progression and in decreasing systemic progression and cause specific death in patients with stage pT3b and lymph node positive disease [19].

In a randomized trial from the MD Anderson Hospital, 255 patients with lymphadenectomy-proven pelvic nodal metastases were treated by early androgen ablation with or without prostatic radiation. Disease control and survival were better in patients treated with early combined hormones and radiation [20].

Further prospective studies with longer follow-up are required to confirm the results for patients with stage pT2 and pT3a disease with unfavorable pathological variables.

For surgically treated node-negative high-risk patients, a trial from the MD Anderson Cancer Center and the Eastern Cooperative Group (ECOG) is investigating adjuvant hormonal therapy compared with observation. The endpoints are an increase in relapse-free survival, disease-specific and overall survival and quality of life. This study is designed to detect a 15% decrease in the recurrence rate at 5 years from 50 to 65% in 496 patients (90% power).

There has been a lot of discussion and controversy surrounding the preliminary results of the Early Prostate Cancer program, composed of three separate industry sponsored randomized trials. These studies have included 8113 patients and were designed to be combined in a final analysis. Patients were randomized between 150 mg of daily bicalutamide (Casodex™) and placebo following standard therapy. The majority of patients with early prostate cancer had node-negative disease. In the American study most patients underwent radical prostatectomy. In the European study radiation was largely employed and in the Scandinavian study, watchful waiting was the primary intervention. The median follow-up in the three pooled trials is 3 years. The investigators reported that Casodex delayed progression by 42%. These studies must be interpreted with caution, as there were few events, follow-up is short and survival data are immature. In addition, toxicities included partial gynecomastia in 63%, impotence, diarrhea, and liver function abnormalities [21]. Costs should also be a consideration before recommending such treatment to all patients with early prostate cancer.

2.2. Neo-adjuvant hormonal therapy 

Neo-adjuvant, as opposed to adjuvant hormonal therapy, prior to radical prostatectomy has also been evaluated in numerous randomized trials [7]. Most studies have consistently found that this approach decreased the rate of positive margins, but did not impact on disease-free or overall survival [22], [23].

After RT, hormonal therapy has shown to improve local control and survival in locally advanced prostate cancer [6]. Patients selected for RT tend to be older and have higher-grade, higher stage tumors and higher PSA levels. Younger, healthier men with smaller, localized tumors have historically tended to undergo surgery. For example, in a study of 287 patients with locally advanced prostate cancer, treated with conventional external beam and RT followed for 15 years, overall survival was only 23% [24]. Investigators have, therefore, tried to add hormonal therapy to these poor risk patients.

Neo-adjuvant and adjuvant hormonal therapy when started simultaneously with RT improves local control and survival. This has been confirmed in two studies [25], [26]. The exact length of hormonal therapy remains controversial. An EORTC trial is evaluated 6 months of hormonal therapy versus 3 years. This trial should be closed to accrual at the end of 2001. Another Canadian trial has analyzed 3 versus 8 months of therapy. An interim analysis looked at secondary end points of differences in biochemistry, pathology and adverse events between the two groups. Ongoing biochemical and pathological regression occurred between 3 and 8 months of neoadjuvant hormonal therapy, suggesting that the optimal duration of neoadjuvant hormonal therapy should be longer than 3 months. Further follow-up is required to determine whether longer therapy alters PSA recurrence rates [27].

2.3. Chemotherapy in localized prostate cancer 

The prognosis of localized prostate cancer is related to Gleason grade, PSA level, and TNM staging. Poor risk locally advanced prostate cancer is defined by the parameters of PSA>20 ng/ml, Stage≥T3-4, and Gleason score 8–10 [28]. Poor risk locally advanced prostate cancer has a mortality rate of 75%. Since long term local control is essential, an important requirement for improvement of this poor outcome is the achievement of local control of the primary tumor.

New approaches aimed at better local control are essential. Investigators have increasingly acknowledged that systemic therapy may be necessary, since locally advanced prostate cancer is often associated with systemic disease at the time of diagnosis.

For poor risk patients, combined neoadjuvant chemotherapy and hormonal therapy prior to radical prostatectomy or radical radiotherapy is a new strategy that has already gained momentum. Phase II and III trials in locally advanced prostate cancer are found in Table 1.

Table 1. Phase II and phase III studies of neoadjuvant and adjuvant chemotherapy in locally advanced prostate cancer

	Author	Year	Therapy	N	Results
	Pettaway [29]	2000	K+A Alternating with E+V+RP+CAB	30	Did not achieve 20% pT0
	Clark [30]	2001	E+VP-16+RP	18	Well tolerated
	Zelefsky [31]	2000	E+V+3D RT	27	Increased late G2 GI and GU toxicity
	Ben-Josef [32]	2001	E+VP-16+ RT	18	Well tolerated
	SWOG 9921	Ongoing	CAB+RP vs. CAB+RP+M+Prednisone	1360	Phase III
	RTOG 99-02	Ongoing	Taxol+E+VP-16 +RT+AS vs. RT +AS	1440	Phase III

K, Ketoconazole; A, doxorubicin (Adriamycin™); E, Estracyt™; V, vinblastine; VP-16, etoposide; M, mitoxantrone; P, prednisone; RP, radical prostatectomy; 3D RT, 3 dimensional radiotherapy; AS, androgen suppression; CAB, combined androgen blockade.

Neoadjuvant chemohormonal therapy with CAB combined with ketoconazole and doxorubicin (Adriamycin™) alternating with Estracyt™ and vinblastine was evaluated at the MD Anderson Cancer Center [29]. In one study, this approach was feasible, although the goal of achieving a 20% pT0 status was not achieved.

In another Phase II trial of neoadjuvant Estracyt™ and etoposide, acceptable surgical morbidity was confirmed in 18 patients who underwent radical prostatectomy after chemotherapy [30]. The regimen was associated with estramustine-induced thromboembolic toxicity. Pathologic analysis suggested a higher than expected rate of organ-confined and specimen-confined disease, but little evidence of antitumor effect beyond that associated with androgen deprivation. Additional study of this paradigm, of chemohormonal therapy followed by radical prostatectomy, with other drug regimens is warranted.

This concept is being evaluated by the SWOG (study 9921). Patients who are to undergo radical prostatectomy undergo either radical prostatectomy and CAB or prostatectomy with chemohormonal therapy (CAB plus mitoxantrone and prednisone). Patients with Gleason score ≥8, pT3b-T4 and/or N1 or Gleason score seven with extraprostatic extension or positive surgical margins are eligible. The end points are survival, relapse-free survival and toxicity. The study is designed to detect a 30% increase in median survival at 10–13 years in 1360 patients (90% power).

Chemohormonal therapy associated with RT in high-risk patients has also been evaluated in unfavorable-risk prostate cancer. Neoadjuvant and concomitant Estracyt™ and vinblastine were combined with high-dose three-dimensional conformal radiotherapy (3D-CRT) [31]. Therapy consisted of three 8-week cycles of Estracyt™ and vinblastine and 8 weeks of 3D-CRT, with Estracyt™ given orally and continued until the completion of 3D-CRT to a dose of 75.6 Gy. Although modest GI and GU toxicities were increased, no severe toxicities were encountered with this regimen.

In a similar study, concurrent Estracyt™ and definitive RT followed neoadjuvant Estracyt and etoposide (VP-16). Actuarial 3-year overall survival and disease-free survival were 88 and 73%, respectively. Local control rate, assessed by repeated prostate biopsies at 18 months after therapy, was 71% [32].

A phase III Radiation Therapy Oncology Group (RTOG) trial 99-02 is evaluating androgen suppression and RT with or without Taxol™, Estracyt, and etoposide (TEE) in localized high risk prostate cancer patients. Eligibility criteria include PSA 20-100 and Gleason Score>7 (any T stage) or clinical stage>T2 and Gleason Score>8 (PSA<100) (M0). The endpoints are survival, biochemical control, relapse-free survival, freedom from distant metastases, and toxicity. The study is designed to detect a 6% increase in survival from 79 to 85% at 5 years. Accrual of 1440 patients to this study is expected to take 6 years.

3.1. Hormone-naive disease 

Palliative androgen ablation produces objective tumor regression in soft tissue sites in approximately 80% of patients, normalization of an abnormal PSA in 70%, and an improvement in the bone scan in 30–50% of cases [34].

Orchiectomy has been the gold standard endocrine therapy. However, in most parts of Europe medical therapy is considered to be more acceptable to patients for psychological and cultural reasons than surgical castration. Luteinizing hormone releasing hormone (LHRH) agonists such as goserelin, leuprolide and triptorelin are the most popular androgen ablation therapies. LHRH agonists are often combined with an anti-androgen to prevent flare related to a temporary surge of luteinizing hormone and testosterone.

Anti-androgens competitively inhibit ligand binding to the androgen receptor (AR). The AR functions as a ligand dependent transcription factor that transduces androgen binding into increased transcription of androgen dependent genes. AR blockade induces programmed cell death in the majority of malignant and benign prostate cancer cells that have not been previously exposed to androgen ablation.

The anti-androgens are divided into steroidal and non steroidal agents, with differences in their effect on serum testosterone levels, and their activity at receptors other than the AR. Flutamide, bicalutamide, and nilutamide are non-steroidal anti-androgens which block the AR, and act directly on prostatic cells.

There is vast experience in the palliative and curative therapy of prostate cancer using anti-androgens as monotherapy or in combination with LHRH analogues or surgical castration. Treatment with anti-androgens alone may avoid the loss of sexual potency.

Combined androgen blockade (CAB) refers to the combination of an LHRH analogue and AR blockade. This is a means of also blocking the adrenal androgens. The main advantage to the combination of a LHRH analogue and an anti-androgen is blockade of the LHRH agonist flare at the initiation of therapy.

Whether or not CAB is really necessary has been the subject of intense investigation. Three studies demonstrated an advantage to CAB. In the NCI Intergroup trial, androgen blockade with leuprolide and flutamide resulted in longer progression-free survival and over-all survival than leuprolide alone in patients with minimal disease and good performance status [35]. In a subsequent EORTC trial, goserelin and flutamide were associated with a longer time to objective progression and longer survival than orchiectomy alone [36]. In a third trial, Nilutamide plus orchiectomy was more effective than orchiectomy alone for metastatic prostate cancer [37]. In all of these studies, patients with widespread bone or soft tissue metastases and a poor performance status, had characteristically short responses, and CAB did not appear to provide a significant advantage over LHRH agonists or orchiectomy alone.

When a systematic meta-analysis in 8275 metastatic and locally advanced patients from 27 randomized trials was carried out, 5-year survival for CAB and monotherapy was very similar. Survival was 25.4% in patients treated with CAB and 23.6% with androgen ablation alone. This was a non-significant gain of only 1.8% (logrank 2p=0.11) for CAB, with addition of an antiandrogen to androgen suppression. Five-year survival was improved by 2–3% (depending on whether the analysis includes or excludes the cyproterone acetate trials) with a true benefit from 0 to 5% [38].

CAB is associated with higher toxicity and decreased quality of life. An additional disadvantage is that LHRH analogues and pure anti-androgens are both very expensive. For these reasons, the routine use of antiandrogens in combination with medical or surgical castration as first line hormonal therapy in all patients with metastatic prostate cancer can not be recommended [39].

Research that may affect the future use of anti-androgens include the ongoing evaluation of anti-androgens in combination with five alpha reductase inhibitors to achieve AR blockade without inducing castrate testosterone levels [40].

4.1. Second-line hormonal therapy 

Second-line hormonal treatment works by diminishing circulating adrenal androgens. This may cause tumor regression by suppressing any remaining hormone dependent prostatic cancer cells. Relief of symptoms may occur rapidly, suggesting a mechanism other than adrenal suppression [58].

Following disease progression, remaining androgen sensitive cells may respond to second line hormonal therapy. A variety of hormonal therapies, such as flutamide or bicalutamide have been used as second line therapy. Modest results that have been documented [33].

One of the most important observations is the ‘flutamide withdrawal syndrome’ [59]. Up to 40% of patients failing CAB may respond when the antiandrogen is discontinued. This paradoxical response was first documented with flutamide withdrawal, but was subsequently shown to occur with other nonsteroidal and steroidal anti-androgens. Prolonged therapy with anti-androgens selects for mutations in the AR that change the AR ligand specificity and permits stimulation by ligands that are usually inhibitory. These mutations give insight into the means by which prostate cancer progresses on anti-androgen therapy, and also help to explain the mechanism of the anti-androgen withdrawal syndrome. Mutated ARs can be found in 50% of metastatic prostate cancers. Long term androgen ablation with anti-androgens may lead to increased expression and activity of the AR [60].

Nonetheless, high doses of bicalutamide (150 mg daily) may be effective in some patients [61]. Megace or dexamethasone are other second-line hormonal therapies, which may produce symptomatic improvement and disease regression. Objective responses (OR) vary anywhere from 10 to 30% [33].

Ketoconazole is an oral imidazole derivative with antifungal properties that functions through a hormonal–adrenal mechanism and by inhibiting the cytochrome P 450 enzyme system. Ketoconazole may act by modulation of retinoic acid breakdown. In combination with hydrocortisone, a>50% decrease in PSA in 30 (63%) patients was reported for a median duration of 3.5 months. Toxicities included mild Grade 1 or 2 nausea, fatigue, edema, hepatotoxicity and rash in 4–10% of patients [62].

As part of a larger Cancer and Leukemia Group B (CALGB) study, 260 patients were treated with antiandrogen withdrawal followed by ketoconazole and hydrocortisone at progression. The PSA response to anti-androgen withdrawal in this large multicenter study was modest; 13%. Response to anti-androgen withdrawal and ketoconazole was higher; 27%. There was no difference in survival with early versus delayed use of ketoconazole [63].

When ketoconazole was combined with doxorubicin (Adriamycin™) at the MD Anderson Hospital, a>50% decrease in PSA was seen in 57% of patients. In this study, cardiac and mucocutaneous toxicities were reported, which suggested another mechanism of action of ketoconazole, perhaps related to an increase in retinoic acid levels, rather than only a hormonal mechanism [64].

4.2. Complementary and alternative medicine 

Alternative methods have become increasing popular, although often not always supported by clinical trials. PC-SPES (Prostate Cancer-Hope), a combination of eight Chinese herbs may act through a hormonal mechanism [65], [66]. An extract of PC-SPES induces apoptosis of hormone sensitive and insensitive prostate cancer cells in vitro, and suppresses growth of a hormone insensitive prostate cancer cell line in vivo.

PC-SPES was evaluated in 33 patients with HRPC and 37 patients with androgen-dependent prostate cancer. All patients with hormone dependent prostate cancer had a PSA decline of >80%, with a median duration of 57+ weeks, and 97% had testosterone declines to the anorchid range. About 19 (54%) of 35 HRPC patients had a PSA decline of >50%, including eight (50%) of 16 patients who had received prior ketoconazole therapy. Toxicities included thromboembolic events, allergic reactions and gynecomastia [67].

Further trials are needed to determine whether its effects exceed those expected with estrogen therapy, but PC-SPES seems to have activity in both hormone dependent and HRPC. Its use can be considered in patients in whom chemotherapy is not desired.

4.3. Chemohormonal therapy 

Estramustine (Estracyt™), is the combination of a chemotherapeutic agent, Nornitrogen mustard, and a hormone, Estradiol. Overall response rates have varied from 0 to 40% [68].

Estracyt is synergistic with the vinca alkaloids, epidophyllotoxins, and taxanes and inhibits microtubules by a different mechanism than the vinca alkaloids. It is not cross-resistant with these agents, and bypasses the multi-drug-resistance phenotype. It also has primarily gastrointestinal toxicity which doesn't overlap with many other cytotoxic agents. The main advantages are the ease of its oral administration and its lack of myelosuppression. In EORTC protocol 30 865 gastrointestinal events and myelosuppression were the major problems. In other studies, thromboembolic events have been the most significant disadvantage. Recent efforts have also concentrated on IV weekly administration [69].

When Estracyt was combined with vinblastine in three separate phase II trials, cumulative data revealed a>50% decrease in PSA in 46–61% of patients, with measurable disease regression in 24% [70], [71]. Two phase III randomized studies of the combination were published. An American study revealed a benefit with the combination as compared with vinblastine alone [72], while an EORTC study comparing the combination to Estracyt alone was discontinued due to toxicity, and found no overall difference [73].

4.4. Chemotherapy 

There has been a wide disparity in results obtained with chemotherapy in HRPC [33]. Objective tumor regression in older studies was reported in <10–20% [74]. Median survival from study to study had been similar, 30–40 weeks. No agent or regimen has shown a consistent impact on survival, and because of this today there is no standard chemotherapy regimen for HRPC. Newer agents and combinations, using PSA to evaluate activity, seem to show promise.

Low dose weekly doxorubicin (Adriamycin) 20 mg/m2 was considered as first-line chemotherapy for HRPC in the USA for many years. In Europe, an Adriamycin analogue, epirubicin, was often substituted. Response rates for Adriamycin range from 0 to more than 50%, depending upon the response criteria used.

Mitoxantrone, another anthracycline, has become increasingly popular. Mitoxantrone inhibits topoisomerase II, creates double-stranded DNA breaks, and subsequently leads to apoptosis in sensitive cells. Single agent mitoxantrone has a modest response rate of 20–30% in HRPC [75], [76], [77].

Two large randomized trials showed that mitoxantrone in combination with steroids is more effective in improving pain and quality of life than steroids alone [78], [79]. Both studies confirmed a reduction in pain measures and narcotic analgesic use. In the Canadian study, OR were not measured, but 29% versus 12% had palliation of pain for 43 versus 18 weeks, respectively. There was no difference in PSA decline or survival [78]. In the second study by the CALGB, mitoxantrone and hydrocortisone were more active than hydrocortisone alone in terns of PSA responses and time to treatment failure. The difference did not result in an improvement in survival [79]. Approximately, 40% of patients demonstrate progressive disease with this therapy. Median survival is between 9 and 12 months and no overall survival benefit has been demonstrated. Based on its palliative effects, mitoxantrone is now a FDA approved chemotherapeutic agent for the treatment of HRPC in the USA [79].

The taxanes have gained increasing usage in the treatment of HRPC. Both paclitaxel (Taxol™) and docetaxel (Taxotere™) work by promoting microtubuar assembly and inhibiting disassembly [80], [81]. Encouraging data have also been reported with Taxotere™ monotherapy. As a single agent, Taxotere has been evaluated in two phase II studies with a 50% decrease in PSA 42–45%. Overall responses are always calculated in small numbers of patients of 28–42% [80], [82]. Several phase II trials of weekly Taxotere have been reported with PSA responses rates between 34 and 60% [83], [84], [85], [86]. Most studies do not report overall objective responses (OR). Only two of the studies reported information on pain relief in 33–46% [84], [85]. Results appear similar to the every 3 week schedule, with perhaps less toxicity.

Based on the assumption that agents that inhibit microtubules may work well together, the combination of Estracyt and either Taxol or Taxotere has garnered interest and been evaluated in varying schedules. The combination of Estracyt plus a 96-h infusion of Taxol produced a 50% decrease in PSA in 17 of 32 (53%) patients. The median time to progression, based on increasing PSA level and other clinical criteria, was 22.5 weeks. The estimated median overall survival time was 69 weeks [87]. There have been a flurry of trials containing taxanes and Estracyt (Table 2). Weekly Taxotere and Estracyt has been evaluated in at least four contemporary trials [88], [89], [90], [91].

Table 2. Phase II studies of Taxol™ and Taxotere™ in HRPC

	Author	Year	Therapy	N	>50 PSA response (%)	Objective RR (%)
	Roth [141]	1993	Taxol	23	0	4
	Hudes [87]	1997	E+Taxol	34	53	44
	Savarese [99]	1999	E+Taxotere	40	69	23
	Petrylak [96]	1999	E+Taxotere	33	63	28
	Kelly [103]	2001	E+Taxol+C	56	67	45
	Smith [142]	1999	E+VP-16+Taxol	37	65	45
	Kreis* [97]	1999	E+Taxotere	17	82	17
	Sinibaldi [98]	2000	E+Taxotere	29	45	23
	Picus [80]	1999	Taxotere	35	46	28
	Friedland [82]	1999	Taxotere	21	38	42
	Trivedi [81]	2000	Taxol QW	18	39	50
	Hudes [101]	2001	E+Taxol QW	63	58	27
	Berry [102]	2001	E+Taxol vs Taxol	166	48% vs 25% in favor of E+T	–
	Kosty [88]	2001	E+Taxotere QW	21	14	71
	Rajasenan [89]	2001	E+Taxotere QW	10	NR	70
	Natale [90]	1999	E+Taxotere QW	18	86	78
	Copur [91]	2000	E+Taxotere QW	20	70	70

E, Estracyt; C, Carboplatin; * Phase I/II study; QW, administered weekly.

Estracyt and Taxol have also been combined with etoposide (VP-16), a podophyllotoxin derivative, known to inhibit topoisomerase II at the nuclear matrix level [92]. Although Estracyt is best known as an antimicrotubule agent, it also acts synergistically with etoposide [92], [93], [94], [95]. The mechanism of action may be different from that in combination with vinblastine, and the results are of interest in view of the lack of activity of any one of the single agents.

Taxotere and Estracyt combinations include PSA response in the range of 39–82%, and OR in approximately 25%, improvement in Karnofsky performance status or pain symptoms control in the range of 53–88% [96], [97], [98], [99]. Survival data are usually not reported with the exception of one phase I trial in which median survival of 22.8 months was observed in patients mostly previously treated with prior chemotherapy [96]. The safety profile of the combination appears acceptable.

Most recently, efforts have been made to optimize the schedule of Taxol and Taxotere by using lower does of Estracyt and weekly taxanes. [81], [84], [100], [101]. In an ECOG study, Estracyt 280 BID on the day before, day of and day after Taxol 90 mg2 weekly was given to 63 metastatic HRPC patients. They showed that this regimen was active and less toxic than other taxane-Estracyt combinations [101]. Furthermore, in the only randomized trial of 166 patients treated with weekly Taxol and Estracyt compared with Taxol alone, the response rate with the combination was twice that of Taxol; 48 versus 25% [102]. These data are extremely interesting and require further confirmation.

In this context, an international industry sponsored trial will randomized 804 patients with HRPC between mitoxantrone and prednisone or Taxotere and prednisone. Taxotere will be administered either every 3 weeks or on a weekly schedule. The primary end point is survival, while the secondary end points are response rate and quality of life.

At the same time, another randomized trial by the Southwest Oncology Group (SWOG) is focusing upon the combination of Estracyt and Taxotere compared with mitoxantrone and prednisone in HRPC in 620 patients. The results of this study should be of extreme interest as many investigators continue to study the taxanes in phase II trials and are really unsure as to which combination will be better.

Other groups have concentrated on putting platinum compounds into the therapeutic arsenal of HRPC. The combination of Estracyt, a taxane, and carboplatin has been evaluated in several trials in HRPC. At Sloan–Kettering and other centers, 56 patients with HRPC were treated with Estracyt, Taxol and carboplatin [103]. A >50% decrease in PSA was seen in 67% and in 33 patients with measurable disease, 6% had a CR and 39% a PR. The median time to progression was 21 weeks, and median survival was 19.9 months. Major grade 3 or 4 adverse effects were thromboembolic events in 25%, hyperglycemia in 38%, and hypophosphatemia in 42%. The regimen was thought to be active and the toxicity well tolerated. Newer platinum analogues with an extended spectrum of anti-tumor activity in overcoming platinum resistance such as ZD0473 (cis-amminedichloro(2-methylpyridine) platinum [II]) may also be of interest in the future [104].

Decrease in PSA and palliation of symptoms has also been described with suramin, a growth factor inhibitor, in combination with hydrocortisone. There have been many trials, with a huge variability in the response rates, and in the reported incidence of neurotoxicity. In a large cooperative group trial of suramin plus hydrocortisone versus hydrocortisone and placebo, pain relief and anti-tumor effect may have been dissociated. No survival benefit was seen in this trial conducted with a crossover design [105]. The mechanisms of suramin mediated anti-tumor activity still need to be defined.

What does this all mean? It means that we do not know what the standard of chemotherapy is for HRPC. The use of taxanes with cortisone or in combination with Estracyt has largely been evaluated in small phase II trials. These combinations may or may not prove to be more effective than other regimens used in the past. We must keep in mind the prognostic factors for survival in patients with HRPC [52] in analyzing the results of contemporary trials and await the results of phase III trials.

4.5. Small cell carcinoma of the prostate 

A neuroendocrine component of cells in the prostate has been recognized. Cells with neuroendocrine features may produce a variety of neuropeptides such as serotonin, bombesin, and others that regulate tumor growth and metastatic potential. Small cell carcinoma of the prostate is a subtype of prostate cancer, which may present with advanced disease and doesn't respond to hormones. It is also the most frequent acquired phenomenon in patients who initially present with prostatic adenocarcinoma. This entity must be considered in patients who have rapidly progressive disease, visceral metastases and a disproportionately low PSA. Patients may be treated with chemotherapy, using regimens for small cell carcinoma of other sites, such as etoposide and cisplatin [106], or other newer chemotherapeutic regimens with radiotherapy.

5.1. Gene therapy—molecularly targeted therapy 

Gene therapy is the use of genetic materials (DNA or RNA) to effect a therapeutic change in the specific genetic process which accounts for prostate cancer that will lead to reversal or amelioration of the pathologic process. There have been a large number of trials initiated in gene therapy for a variety of malignancies including prostate cancer.

Strategies for cancer gene therapy include vaccine therapy using various cytokines such as Il-2 or GM-CSF, suicide cytotoxic therapy such as HSV-thymidine kinase or certain toxins, suppressor genes such as p53 or Rb, oncolytic viruses that have been designed specifically to replicate preferentially in prostate cancer cells such as CV787 or CN-706 and anti-sense therapy such as bcl-2 and C-myc [107], [108], [109]

The two types of gene therapy are ex vivo and in vivo. Ex vivo means that tissue or cells are harvested surgically, genetically engineered and re-introduced back into the host. This is particularly effective for clonally expandable cells. In vivo therapy indicates that gene transfer is performed directly in the host.

As a cell dies and liberates tumor antigens it is infiltrated by monocytes and macrophages and eventually the professional antigen presenting cells such as dendritic cells take up these antigens and present them to T helper cells. In the presence of certain cytokine genes stimulation can occur by different co-stimulatory molecules and in particular the proportions of these can change so that there is an immense stimulation for the T helper cells to activate and come back and eradicate subsequent tumor cells. This is the basis of the early vaccination therapies that were performed ex vivo [107].

One of the first autologous gene therapy Phase I trial trials of GM-CSF vaccination was an ex vivo trial from Johns Hopkins. Both a T cell response and humoral immunity were observed [110].

In vivo gene therapy is more cost efficient and doesn't not necessarily have to be tailored to the individual patient, but rather to a class of patients. The disadvantages are that gene transfer efficiency is extremely poor and stimulation of host immunity may have untoward toxicities. There are many methods for DNA gene transfer including viral, liposomal and other novel methods. Adenoviral and retroviral methodologies have been the major focus of attention [111].

Development of genetically engineered conditionally replication competent adenoviruses via prostate specific promoters has led to trials of CN706 (prostate specific oncolytic virus) [108] and to a preliminary phase I/II dose finding trial in HRPC with CV787 [112].

Direct gene therapy for bone metastases is under development [113]. Suicide gene therapy has used diphtheria toxin [114], and in situ tumor vaccines combine the experience of ex vivo work in cytolytic gene therapy with various different cytokines.

Intense research efforts are now focusing upon the combination of agents such as the taxanes with newer molecularly targeted therapies. Stimulation of the signal transduction pathway of the epidermal growth-factor receptor (EGFR) tyrosine kinase family of receptors in tumor cells enhances cellular proliferation, prevents apoptosis, and promotes tumor-cell mobility, adhesion, and invasion [115].

The medical management of prostate cancer is being revolutionized by experimentation with new molecules. Small molecule, low-molecular-weight inhibitors of EGFR tyrosine kinase such as OSI-774, PD182905, PKI-166, CI-1033, and ZD1839 (Iressa™), monoclonal antibodies such as Erbitux™ (IMC-C225) directed against the extracellular binding domain of the EGFR receptor [116], and immunotoxin conjugates—antibody directed against EGFR joined to a cell toxin are under study. Monoclonal antibodies to Erb-B2, Her-2- neu, trastuzumab (Herceptin™), approved in breast cancer in combination with Taxol have also shown promise in prostate cancer [117]. Encouraging results in patients with prostate cancer have been reported with Iressa in a phase I trial [118], and a phase II trial has been initiated.

Bcl-2 is a negative prognostic indicator in prostate cancer, implicated in the development of androgen independence and treatment resistance, and is overexpressed in HRPC. Bcl-2 has emerged as a critical regulator of apoptosis in many tissues as part of a growing family of apoptosis regulatory gene products. Antisense oligodeoxynucleotides such as Genasense™ are being use to therapeutically target genes that play a role in the progression to androgen independence [119], [120]. Genasense has been combined with Taxotere in two phase I/II studies with interesting preliminary results [121], [122] and with mitoxantrone in a phase I study in HRPC [123].

It is important that biologic agents targeting biologic mechanisms are tested at appropriate times in the natural history of the disease. This will most likely ultimately require earlier, adjuvant administration of these agents perhaps even together with initial androgen ablation, to take maximal advantage of castration-induced cell death [109].

The future holds promise for the development of synthetic viral vectors, modification of targeting and expression, in situ vaccines in combination with immunotherapies and adjuvant and neoadjuvant gene therapy in high risk patients.

The promise of molecular medicine is so immense, that it cannot be ignored. Current molecular biology and gene therapy technologies are still in their infancy and the really effective methodologies are yet to be discovered. Focusing attention into the biology of disease processes will hopefully allow us to develop the technology of gene transfer and delivery [111].

5.2. Exisulind 

Exisulind (Aptosyn™) is the first of a new class of targeted agents that induce apoptosis (programmed cell death) in a broad range of pre-cancerous and cancerous tissues without affecting normal cells [124]. In a randomized, placebo-controlled study of prostate cancer patients, Exisulind, a sulfone metabolite of the nonsteroidal anti-inflammatory drug sulindac, lengthened the median PSA doubling time in men who had increasing PSA levels after radical prostatectomy [125].

Because preclinical studies have suggested synergistic interactions between Taxotere and Exisulind, a phase I/II clinical trial combining these agents has been initiated in patients with HRPC [126].

5.3. Vitamin D 

Clinical activity of Vitamin D [calcitrol (1,25-dihydroxycholecalciferol)] has been reported in HRPC with PSA response rates around 28% [127], [128]. The in-vitro cytotoxic activity of Vitamin D seems to be dose dependent, however, its clinical hypercalcemic effect limits clinical dose-escalation of calcitrol.

Vitamin D deficiency may also develop in patients with advanced HRPC. Supplementation with vitamin D may be a useful adjunct for improving pain, muscle strength and quality of life in this patient population [129].

Several agents such as biphosphonates, cortisone, and some chemotherapeutic agents such as carboplatin and Taxol can block the hypercalemia of Vitamin D.

Bisphosphonates are important in the palliation of pain due to osseous metastases as discussed below. The combination of newer more potent biphosphonates, such as Zolandronate, perhaps in combination with Vitamin D is the subject of ongoing trials [130].

5.4. Endothelin-A antagonists 

Altrasentan™ (ABT-627) is an orally active selective endothelin-A receptor antagonist that inhibits ET-1 stimulated growth. Several phase II studies have shown activity in patents with HRPC [131].

In a randomized study in patients with HRPC, Altrasentan 10 mg demonstrated a significant delay in time to clinical progression (196 days) as compared with 129 days in placebo treated patients (P=0.02, 52% delay). A second randomized study compared HRPC patients treated with placebo (n=104), 2.5 mg Altrasentan (n=95) and 10 mg Altrasentan (n=89). Quality of life weighted time to progression was evaluated employing EORTC QLQ-C-30 and FACT-P instruments. It appeared that both doses of Altrasentan conferred a longer time to clinical disease progression using quality of life parameters [132]. This is an interesting new compound, which deserves further evaluation.

5.5. Palliative systemic therapy 

Bone pain is often a debilitating component of metastatic prostate cancer and should be systematically approached. Radiation to palliate bone pain for solitary painful bone metastases is occasionally supplemented by hemibody irradiation for the palliation of widespread metastases. After allowing for adequate recovery, the alternate half-body can be irradiated. Side effects include nausea, vomiting, diarrhea, hematologic abnormalities and pneumonitis. In one study, 82% receiving upper hemi-body and 67% receiving lower half-body irradiation remained pain free until death [133].

Palliative therapy has most recently focused more upon radionuclides and biphosphonates. Strontium89 is useful in palliating bone pain, with subjective responses in >75–80% of patients. This bone-seeking radionuclide, has high uptake in osteoblastic metastases, and remains in the tumor sites up to 100 days, decaying by beta-particle emission [134]. It may be most useful in combination with RT in delaying development of new lesions [34], [134]. Other radionuclides such as Rhenium186 and Samarium153, conjugated to ligands with affinity to bone emit both gamma energies that provide images and beta energies that are therapeutic [34]. CYT-356, conjugated with yttrium90, a beta-emitter has been used in the USA for diagnosis of occult metastatic disease [135].

Strontium89 has recently been used as consolidation therapy in patients with HRPC. In a study from the MD Anderson Hospital, 103 patients received induction chemotherapy with ketoconazole and Adriamycin alternating with Estracyt and vinblastine. After two to three cycles, 72 clinically stable or responding patients were randomized to Adriamycin with or without strontium89 weekly for 6 weeks. Overall 62 of 103 (60%) of patients had >50% reduction in PSA; 49 (52%) patients with bone pain had complete resolution of pain. For 36 patients assigned to receive strontium89 and Adriamycin, median survival time was 27.7 months compared with 16.8 months in 36 patients treated with Adriamycin alone (P=0.0014); hazard ratio 2.76 (95% CI 1.44–5.29). In this study bone-targeted consolidation therapy after induction chemotherapy in stable or responding HRPC patients, appeared to improve survival [136]. This represents an interesting observation concerning adjuvant Strontium89 that should be verified by other investigators.

The use of biphosphonates in metastatic prostate cancer has lagged behind its use in breast cancer, since most metastases are osteoblastic. Biphosphonates relieve pain caused by bone metastases, prevent treatment-related bone mineral density loss [137], and possibly slow the growth of metastases [138]. The use of biphosphonates is based upon evidence that in prostate cancer the metastatic process is associated with increased bone resorption. Documentation regarding the beneficial effects of biphosphonates in reducing morbidity from metastatic prostate cancer has increased, although the choice of the optimal bisphosphonate, mode of administration, dose, and duration of treatment must still to be resolved [139], [140]. Studies of newer biphosphonates target shorter administration times, patients with established metastatic disease [130], and patients with local disease at high risk for relapse.

Although radionuclides and biphosphonates have not been definitively proven to prolong survival in patients with prostate cancer, the potential of both agents to beneficially alter the metastatic process is extremely intriguing.