Introduction

The initial treatment of advanced, inoperable or metastatic prostate cancer is hormonal manipulation, as discussed in detail by Dorff and Pinski in Chap. 49. In many cases, responsiveness to androgen deprivation wanes after a period of months to years, and it may be necessary to provide further systemic treatment in this setting. Traditionally, after failure of hormonal manipulation, patients have been treated with cytotoxic agents, with variable effectiveness.

One of the important issues in the use of cytotoxic chemotherapy is the timing of treatment. When considering chemotherapy for “castrate resistant” prostate cancer, one must ensure that the cancer is really resistant to the impact of castration. Adrenal androgens contribute to the hormonal environment, so that some tumors that appear to be resistant or refractory to the testosterone-depleted setting, may actually be receiving stimulation from adrenal hormones, dehdroepiandrosterone (DHEA) and its sulphate (DHEAS), and will thus respond to second line adrenal blockers, such as aminoglutethimide, ketoconazole or the newer salvage agents, such as abiraterone and MDV-3100 (enzalutamide). These remissions may sometimes be sustained for months to years.

Thus important factors to consider before consideration of chemotherapy include:

  • Adherence – i.e. is the patient taking the medications or are other medicines interfering with absorption or function of the treatment, thus interfering with the process of medical castration? In the case of surgical castration, was a sub-capsular orchidectomy performed, with traces of residual, functioning testicular tissue left in situ?

  • Is there a late agonist effect from peripheral androgen blockers, such as flutamide, nilutamide or bicalutimide?

  • Is there a significant component of adrenal or other androgenic function that is still stimulating growth of prostate cancer tissues?

  • Is this truly adenocarcinoma, or is there a neuro-endocrine or urothelial cancer outgrowth?

  • Is this a second malignancy?

These issues can be assessed via careful history and physical examination, and appropriate tests, such as measurement of gonadotrophins, testosterone, and adrenal androgens. In some cases, where there is no evidence of rapid, symptomatic tumor progression, a therapeutic trial of second-line hormone therapy with an adrenal blocker may yield another remission, and this should be considered before the initiation of chemotherapy. However, the pace of the disease is a crucial consideration, as second-line hormonal therapy may require a time lag of 6 weeks or more before showing an effect. Dorff and Pinski (Chap. 49), have discussed the new generation of novel second-line therapies, including abiraterone and enzalutamide, which have demonstrated clear anti-cancer efficacy in this clinical setting, and provide additional options for patients with apparently “castration-resistant” disease.

An additional domain of emerging systemic therapy is the group of immunotherapies and vaccines, which is beyond the scope of this chapter. In addition, we have viewed the bone-stabilizing agents as falling within the category of supportive therapy rather than representing active anti-cancer options.

Widening the Goal Posts in Assessment of Success

The utility of chemotherapy for patients with advanced, castrate-resistant prostate cancer has been the subject of controversy [1, 2]. However, it has become clear that there is a defined role for cytotoxics in advanced, symptomatic, hormone refractory or castrate-resistant disease, leading to reduced tumor-related symptoms and/or improved quality of life and a survival benefit [3, 4]. Analogous to the management of breast cancer, it seems that chemotherapy may eventually be introduced earlier into clinical practice, perhaps as neo-adjuvant or adjuvant therapy, and will then realize its most useful impact.

In the early days of chemotherapy in the 1980s, attempts were made to define criteria for the assessment of response, culminating in efforts to identify patient benefit within the broad category of disease stabilization [5]. The National Prostatic Cancer Project documented the variability in response patterns and identified that stable disease (SD) correlates frequently with prolonged survival, leading to its inclusion in their criteria of response. As the category of stable disease included both patients with very indolent or “stable” disease prior to treatment, as well as those with a genuine slowing of tumor growth rate by treatment, the NPCP system was heavily criticized [1] and fell into disrepute. This was unfortunate as the basic system was predicated on sound reasoning, focused on the concept that the slowing of the rate of tumor growth would be beneficial in treating prostate cancer. This problem was compounded by the absence of a reliable biomarker that might have been used to measure the changing amount of tumor.

Surrogate Markers of Response

In recent times, many surrogate markers of response have been studied for the assessment of chemotherapy for prostate cancer, in an attempt to address the heterogeneity of outcome within the category of stable disease. With the introduction of serial measurement of PSA, it was hoped that clinical benefit could be more easily defined. A reduction in circulating PSA of 50 % or more has been used to identify patients who have shown an improvement after chemotherapy [6, 7]. This group includes those with stable clinical disease.

Some years ago, the National Cancer Institute convened an expert panel to attempt to achieve consensus on the use of PSA measurements as a surrogate for tumor response in phase II trials [8]. This panel identified four groups of patients that they believed would be suitable for entry into phase II clinical trials: progressive measurable disease, progressive bone metastases, stable bony disease with rising PSA, and rising PSA-only disease [8]. They also required proof of effective castration (via measurement of serum testosterone) at the time of progression to constitute “hormone refractory” disease.

The inclusion of patients with a minimum PSA level of only 5 ng/ml weakened their approach. This lower limit allowed the presence in these trials of patients with lower volume disease and also of those with predominant neuroendocrine or small cell anaplastic differentiation (which is characterized by lower PSA levels and the presence of other markers). Furthermore, it is difficult to conceive that a treatment that reduces a PSA from 5 to 2.5 ng/ml can really be having the same biological impact as one that causes a 50 % reduction from 5,000 ng/ml.

There have been a series of meetings convened by the Food and Drug Administration and the National Cancer Institute to rationalize and update the use of surrogate markers, but these have failed to identify a reliable or optimal surrogate marker; thus there has been no resulting peer-reviewed publication.

Reporting a study from the Southwest Oncology Group, we demonstrated that maintenance at 3 months of PSA remission may be one of the more powerful surrogate markers for patients with advanced hormone-refractory disease, treated by mitoxantrone- or docetaxel- based regimens [9]. Furthermore, in this study we questioned the utility of the specific criterion of a 50 % PSA reduction as a useful surrogate marker.

Other unvalidated PSA endpoints have included PSA velocity, PSA density, and PSA release phenomena. In fact, the acute release of PSA into the circulation, in response to tumor death induced by treatment, can potentially confound the assessment of rates of circulating tumor marker level declines if not measured and calculated in the algorithm.

Circulating Tumor Cells

An important domain of research has focused on the measurement of circulating tumor cells (CTC) as predictive and prognostic markers of treatment of advanced prostate cancer [10–12]. It has been shown that prostate cancer cells are shed into the circulation by primary tumors, although they are not necessarily predictive of a poor prognosis for all prostate cancers [10].

However, in patients with castrate resistant prostate cancer, we have demonstrated in a non-comparative trial that absolute numbers of circulating tumor cells prior to systemic therapy predict outcome, and that reduction in numbers of these cells after treatment also correlates with response and survival [11, 12]. Although many phase II trials in recent times have recorded CTC levels as if they were validated surrogates of survival, this technology still requires validation in the randomized trial setting.

In addition to biomarkers, investigators have studied quality of life indicators in the hope of reflecting the efficacy of systemic therapy.

Quality of Life Assessments: Adding to Confusion

The tools for the measurement of the quality of life (QOL) of patients with prostate cancer have improved somewhat, but are still imperfect. Some systems confuse symptoms of castration or advanced age with those of the cancer or its treatment; others focus on indirect measures that may be inaccurate (e.g. weight gain that is interpreted to suggest improvement, when it may reflect fluid retention). Yet QOL is being incorporated more often into the assessment of new treatments, despite the current flaws in methodology. In inexperienced hands, this may constitute a much less robust surrogate endpoint, leading to artificially high response rates. It is important that validated purpose-designed instruments be employed for prostate chemotherapy trials [13].

It should not be forgotten that many patients who receive chemotherapy for prostate cancer have already been castrated, have intercurrent diseases and are elderly. Symptoms associated with these states may easily confound the assessment of the side effects of chemotherapy or of tumor-related quality of life. For example, castration per se can cause fatigue, depression, lassitude, and even occasional nausea. Symptoms of arthritis in the elderly patient may be mistaken for bone pain associated with progressive tumor.

Nonetheless, with the broader acceptance of structured QOL assessment tools in the field of oncology, the Food and Drug Administration approved the use of mitoxantrone for the indication of advanced prostate cancer, based largely on QOL comparisons in a large Canadian randomized trial [14]. In this study, mitoxantrone plus prednisone was compared to prednisone alone [14]. The primary index of clinical benefit was improved QOL, based on a validated model [13].

This trial represented an important paradigm shift, but there are still substantial problems in the methodology of QOL assessment [15]. We believe that the primary index for the assessment of novel compounds in the management of advanced, hormone refractory prostate cancer should still be objective tumor regression or survival.

Stage Migration: Less Tumor Burden at the Outset

Stage migration is a phenomenon in clinical trials where the amount of tumor in patients presenting for treatment changes over time because of improved staging technology or changes in treatment patterns. In the past 10–15 years, stage migration has contributed prostate cancer study populations with less tumor burden and thus a better inherent prognosis (Table 49.1). This has confounded interpretation of these studies over prolonged time periods, and in particular has confused the assessment of the impact of novel treatments on median survival.

Table 49.1 Comparable series with stage migration
Full size table

For example, the availability of PSA monitoring after primary therapy or hormonal manipulation has now led to the identification of harbingers of clinical relapse much earlier, often many months before the onset of clinical symptoms. By contrast, in the 1980s, prior to the routine use of PSA or high resolution CAT scan or bone scan monitoring, the first evidence of clinical relapse or metastasis was often pain, a pathological fracture, a palpable mass, or some other indication of more advanced cancer.

This change has resulted in the inclusion of patients with lower pre-treatment tumor mass in the current era than in the chemotherapy studies conducted three decades ago. This, in turn, has led to a potential artifact of interpretation where new drugs appear to yield better outcomes than old drugs. For example, the median survival of patients treated with mitoxantrone/prednisone for hormone refractory prostate cancer has increased 50 % in the past 30 years, potentially due to stage migration and better supportive care [9, 16–20]. Therefore we believe that randomized trials are still required to show definitively that a survival benefit can be achieved by the use of a novel systemic therapy, and that historical comparisons are likely to be flawed for such analyses [1, 2].

Importance of Randomized Clinical Trials in Assessment of Chemotherapy

In view of all these variables in the assessment of new treatments, one must ensure that there is rigor and structure in the assessment of progress in this field, which is best done through the use of randomized trials. Non-comparative phase I-II trials have been essential in identifying the potential role of the conventional and novel cytotoxic agents and combination regimens for advanced prostate cancer [1, 2, 21–26]. The following conventional drugs have been shown to have anti-cancer effect against bone-dominant, hormone refractory prostate adenocarcinoma when used as single agents: doxorubicin, cyclophosphamide, cisplatin, carboplatin, mitoxantrone, paclitaxel, docetaxel and mitomycin C [1, 2, 21]. Each produces objective response rates of about 15–20 %, sometimes with reduction of tumor-related symptoms and/or improvement in measured quality of life.

The problem is that the newer endpoints of assessment could easily lead to misinterpretation of the benefit from novel agents, as compared to the utility of some of the older drugs studied in the trials of the 1980s and 1990s. Softer end points (PSA response, reduction in circulating tumor cell numbers, application of waterfall plots, and a new emphasis on progression-free survival) or changes in the population of patients treated may have led us into the trap of making it too easy to attribute “patient benefit” to novel agents. There is a relatively new fashion of expressing tumor reduction through the vehicle of “waterfall plots”. In a waterfall plot, reductions of tumor mass are graphically expressed as a bar below the baseline, and reductions as small as 5 % can be interpreted to indicate treatment benefit, a much lower bar than the 50 % mass reductions required in earlier classification systems. We may thus have begun to over-emphasize the utility of some novel agents [27].

Ultimately the most reliable way to prove that novel agents are achieving more than older compounds is through randomized clinical trials. Through this vehicle, direct comparison has shown that mitoxantrone improves QOL compared to non-cytotoxic treatment [13, 14], and that docetaxel is more active against prostate cancer than is mitoxantrone (at the expense of more toxicity) [3, 4]. This paradigm will continue to be essential to the accurate evaluation of novel agents for prostate cancer.

Evolving Role of Cytotoxic Chemotherapy

Although single agent chemotherapy has been shown to improve QOL and yield a modest survival benefit, randomized trials have not yet proven the superiority of combination chemotherapy over single agents. Some promising combination regimens were reported in non-randomized trials in the past decade, suggesting that combination chemotherapy may increase patient benefit, despite the problems of stage migration and altered endpoints. However, few confirmatory randomized trials have proven this benefit.

The combination of paclitaxel or docetaxel plus estramustine has been reported to produce subjective response in approximately 50–60 % and PSA response in 40–75 %. Objective tumor responses occurred in up to 30 %, depending on whether patients with soft tissue disease dominated the population of patients [22–24]. Others have reported that the addition of carboplatin to the paclitaxel-estramustine doublet adds to clinical activity, claiming higher objective and PSA response rates [25, 26]. A meta-analysis of randomized trials comparing chemotherapy versus chemotherapy plus estramustine concluded that there was a survival benefit from the addition of estramustine [28]. However, once again, a decade after initial reporting of estramustine-based combinations, these data seem to remain controversial. There are significant concerns regarding the thrombo-embolic effects of this combined therapy, and many believe that the gold standard remains single-agent chemotherapy for castrate-resistant prostate cancer.

More recently, cabazitaxel, formerly known as XRP6258, a new generation semi-synthetic taxane with low affinity for multidrug resistance protein, was demonstrated in a phase I trial to show efficacy against docetaxel-treated castrate-resistant prostate cancer [29]. In an international randomized trial, known as “TROPIC”, 755 patients were allocated to treatment with mitoxantrone or cabazitaxel after prior failure of docetaxel [30]. A statistically significant median survival benefit of 3.4 months was noted with cabazitaxel. In several eastern European centers, toxic deaths were experienced in patients treated with this novel agent, emphasizing the hazards of myelosuppression in an elderly population with potential renal dysfunction and bone marrow compromise. These outcomes highlight the importance of subspecialty experience when applying novel therapies to an at-risk population [30]. Nonetheless, this agent was approved by the Food and Drug Administration for use in North America for castration-resistant prostate cancer.

Studies are being implemented to test cabazitaxel versus docetaxel in front line therapy for castrate-resistant disease and to assess utility and safety of novel combination regimens that employ this new agent.

Future Directions: Targeted Therapies, New Agents, Need for Precision

Novel compounds that have some functional similarity to the taxanes, the epothilone B analogues, have been tested against prostate cancer. One of these agents, ixabepilone, has recently been shown to induce objective response in up to 30 % of cases, and a 50 % PSA reduction in 48 % of patients [31]. Similar patterns of response have been recorded with a structural analogue, patupilone [32]. This concept will require further testing, with a focus on randomized clinical trials, to compare activity with that of the taxanes, and to evaluate utility in combination regimens. To our knowledge, this class of compounds has not been approved for use in North America by the Food and Drug Administration, and they thus remain investigational.

Novel therapeutic approaches focused on vitamin D metabolism (e.g. Calcitriol), oncogene and growth factor receptor targets, and immunological manipulation have shown promising results in phase II studies. However, some of these findings have been questioned based on the reduced stringency of assessment of outcome, further supported by failures in randomized clinical trials.

The FDA recently licensed sipuleucel-T, an immunological manipulation focused on enhancing targeted T-cells, based on a statistically significant improvement in survival in a randomized trial [33]. This trial focused on the use of sipuleucel-T for patients with minimal-extent, metastatic prostate cancer. However, a more recent, provocative analysis has questioned the utility of such treatment, and proposed that the leukopheresis implicit in the process caused a deficit in outcome in the control population due to the reduction in circulating immunologically active cells [34]. The argument in this analysis focused on the impaired outcome among the elderly in the control population, and the apparently improved outcome in younger patients who did not receive sipuleucel-T [34]. This controversy serves only to emphasize the importance of design and structure in future studies. It was subsequently suggested that the principal author of this latter study had a significant conflict of interest, adding to the controversy.

Another approach has involved the use of targeted therapies. For example, cabozantinib, also known as XL-184, an oral tyrosine kinase inhibitor directed against the c-MET gene and VEGFR, which may also impede tumor invasion, has been shown to be active against medullary carcinoma of the thryoid [35]. Consequent upon the demonstration of c-MET and VEGFR functionality in prostate cancer, surprising anti-cancer efficacy was demonstrated in a randomized, discontinuation placebo-controlled phase II trial that assessed outcomes in 171 patients [36]. Patients showed regression in soft tissue disease and improvement in bone scans, although the majority of responses were in the stable disease category [36], and it is important to note that the study was discontinued early because of the obvious superiority to the placebo arm. Further trials are in progress to define the true role for this targeted therapy.

In view of the clear evidence of anticancer efficacy of cytotoxics in hormone refractory disease, chemotherapy is now being assessed earlier, analogous to the progression of studies in breast cancer 30 years ago. For example, Waxman and his team have suggested that adjuvant mitoxantrone chemotherapy adds to the impact of castration [37]. While the published data were provocative, case selection bias may have influenced the results. This led to formal testing of the concept in a randomized trial by the Southwest Oncology Group (SWOG). SWOG 9921 compared castration versus castration plus mitoxantrone and prednisone in patients who had undergone radical prostatectomy for locally extensive disease. Despite the promising non-randomized data from the United Kingdom, SWOG 9921 was terminated early on the recommendation of the Data Safety Monitoring Committee. There was an apparent excess of cases of iatrogenic leukemia in the chemotherapy arm [38].

Predicated on the results of SWOG 9916, comparing docetaxel and mitoxantrone [3, 4], studies assessing the utility of adjuvant docetaxel have been started, although these may be hard to implement, given the toxicity of docetaxel and the relatively modest potential difference in outcome. For example, NCT00283062, testing this hypothesis, was opened, accrued poorly, and closed without yielding meaningful results. In contrast to some of the studies in adjuvant therapy of breast cancer in women, men have been more reluctant to participate in such studies with only modest gains and significant toxicity (or perhaps their physicians have been more reluctant to involve them).

Another variant of this approach, neoadjuvant chemotherapy, has been to test novel cytotoxics in patients with untreated, locally extensive disease who are about to undergo radical prostatectomy [39]. In preliminary studies of neoadjuvant docetaxel, reductions of PSA have been documented, although major tumor cell kill has not been identified [39], and more extensive phase II-III trials will be required to validate this approach. One such study NCT00430183 is currently accruing patients.

In a variant of this approach, Shepard et al. [40] assessed a nano-engineered taxane, with purportedly improved tumor uptake characteristics, in the neoadjuvant setting prior to radical prostatectomy. Although we demonstrated minor histological changes in the resected prostate specimens, there was no evidence of objective tumor regression, and further studies were not implemented. However, this design may represent a paradigm for assessment of other novel therapeutic compounds.

Promising new data will require validation in carefully structured comparative clinical trials to ensure that real progress is being made in the use of chemotherapy for prostate cancer, and that improved results are not just a reflection of improved supportive care, earlier diagnosis and stage migration, or altered clinical trial endpoints or surrogates of outcome [27]. For example, our initial clinical experience with enzastaurin appeared to suggest clinical benefit in castrate-resistant disease, but formal testing in a double-blind, placebo-controlled fashion, failed to confirm this observation [41]. Rigor in clinical testing will be essential, especially as several new concepts are being tested in early phase trials, including biochemical modulation, application of nano-technology, and the use of targeted therapies that are directed to the determinants of cellular turnover.