Nontargeting Treatments That Improve Survival and/or Palliate Symptoms
The development and use of cytotoxic chemotherapies for the treatment of advanced PCa has lagged behind parallel advances in other common cancers. In the 1990s, mitoxantrone(Drug information on mitoxantrone) (Novantrone) in combination with prednisone(Drug information on prednisone) was approved for the treatment of advanced prostate cancer, based on improvement in palliative and quality of life measures. The paper by Tannock et al, on which the approval was based, noted that at the time, chemotherapy for these patients was controversial given the frequently seen unwanted secondary effects offsetting pain relief. Prior to this study, the coadministration of corticosteroids muddled cause and effect, since their use alone had also been shown to offer palliation of symptoms from metastatic disease. The Tannock study, however, proved that chemotherapy (mitoxantrone) plus prednisone provides better palliation than prednisone alone.
Since that time, however, several cytotoxic agents have been or are being considered for approved use in patients with CRPC with and without metastasis. In general, this class of agents acts systemically, and their direct cytotoxic activity is not specific to metastatic sites and affects healthy tissues. Chemotherapeutic toxicities and natural and acquired drug resistance remain unresolved issues. Furthermore, objective measurement of response to therapy at metastatic sites remains difficult; although it can be performed radiologically, the classification of response requires radiologist knowledge of the criteria (eg, RECIST [Response Evaluation Criteria In Solid Tumors]). Many of the studies simultaneously report on palliation, but as with the beta particle–emitting radionuclide class of compounds, measures of palliation are more subjective and highly variable between studies. Moreover, these symptomatic outcomes do not reliably indicate tumor regression or reduction in overall disease burden.
To date, most clinicians and study investigators have used serum PSA as a marker of outcome; however, there have been numerous reports of the deficiencies of this marker in the case of cancer immunotherapy.[42,43] Namely, although some prostate cancer immunotherapies have been shown to improve overall survival, they have had little or no impact on PSA kinetics, sometimes even increasing PSA levels despite positive therapeutic effect. Some groups have advocated the use of circulating tumor cells (CTCs) as a marker, where a count of ≥ 5 CTCs/7.5 mL of blood has been shown to correlate with worse outcome compared with < 5 CTCs/7.5 mL of blood.
Despite these hurdles with respect to determining outcomes in patients with metastatic disease, the data clearly show that chemotherapies such as docetaxel(Drug information on docetaxel) and cabazitaxel (Jevtana), and immunotherapy with sipuleucel-T (Provenge), improve overall survival—largely the best measure of cytotoxic effect. To date, there has been relatively little focus on responses in patients with bone metastasis or on survival as a function of extent of bony disease. We are, however, beginning to understand which compounds work best as first-, second-, and third-line agents. After the approval of docetaxel, there had been no clear standard of care in the second-line chemotherapy setting. Mitoxantrone was used, but its activity after progression on docetaxel is modest. The development of newer agents that are examined in different patient classes—such as those who are chemotherapy-naive or chemotherapy-resistant—promises to open up advanced PCa to many new forms of treatment.
Docetaxel. In 2004, docetaxel plus estramustine(Drug information on estramustine) (Emcyt) was reported to yield an improvement in survival compared with mitoxantrone and prednisone, in men with metastatic, advanced CRPC. Median time to progression, defined as two consecutive increases in PSA level over baseline or an interval increase in a bidimensionally-measured lesion, was 6.3 months in those receiving docetaxel and estramustine and 3.2 months in the group given mitoxantrone and prednisone (P < .001). Despite an improvement in overall survival (17.5 months vs 15.6 months, P = .02), no significant differences were noted in measurable disease or pain between the two groups.
Tannock et al compared docetaxel and prednisone, given every week or every 3 weeks, to mitoxantrone and prednisone administered every 3 weeks. This study showed a statistically significant improvement in survival (of approximately 3 months), and it demonstrated improvements in reported pain levels. No efficacy with respect to disease progression was reported in this study. Mature follow-up data comparing mitoxantrone to docetaxel given every 3 weeks confirmed the 3-month survival advantage of the earlier study. On the basis of these data, docetaxel chemotherapy has become the standard first-line chemotherapy treatment for advanced CRPC.
Cabazitaxel. This microtubule inhibitor with a mechanism of action similar to that of docetaxel was approved by the FDA in June 2010 for the treatment of metastatic CRPC after the use of docetaxel chemotherapy. In a recently reported, randomized phase III trial, cabazitaxel given every 3 weeks with prednisone improved median overall survival by 2.4 months (15.1 vs 12.7 months) compared with mitoxantrone and prednisone.[51,52] The investigator-assessed tumor response rate was 14.4% for patients in the cabazitaxel group compared with 4.4% in the mitoxantrone group, and median progression-free survival was 2.8 months in the cabazitaxel group vs 1.4 months in the mitoxantrone group (hazard ratio [HR], 0.74; 95% CI, 0.64–0.86; P < .0001). The patients in this study were required to have chemotherapy-resistant, very advanced disease, thus establishing a new standard, second-line therapy for metastatic CRPC. About 80% of patients had bony metastasis, 50% had measurable soft-tissue disease, and 25% had visceral lesions. The authors did not break out results with respect to palliation of bone pain or disease progression as a function of bone metastasis, which would likely have been difficult in this patient population with mixed bony, visceral, and soft-tissue disease; interpretation of the results with respect to specific treatment of bony disease is thus difficult.
Bone marrow suppression was observed in those treated with cabazitaxel, who experienced a 7.5% incidence of febrile neutropenia compared with 1.3% in those treated with mitoxantrone. There was an increased risk of death within 30 days of last dose in the cabazitaxel-treated patients (5%) compared with the risk in the mitoxantrone-treated patients (2%). Bone marrow suppression can be minimized by granulocyte colony–stimulating factor support. Study investigators recommend close monitoring of patients and future investigation into possible single-nucleotide polymorphisms in genes such as CYP3A4 and CYP3A5, which are responsible for the metabolism of cabazitaxel and which may contribute to such toxicities.
Sipuleucel-T. In the late 1990s, researchers began to investigate the concept of tumor-specific immunity, whereby an immune response is stimulated in order to target tumor cells for destruction. This idea was central to the development of sipuleucel-T. In the course of treatment with sipuleucel-T, a patient’s antigen-presenting cells (APCs; specifically dendritic cells) are collected via leukapheresis and then loaded ex vivo with a fusion protein consisting of prostatic acid phosphatase (PAP) and granulocyte-macrophage colony–stimulating factor (GM-CSF). After culturing this fusion protein with the dendritic cells, the product is then reinfused into the patient, activating T-cells via class I and class II HLA molecules and resulting in a beneficial immune response against PAP.
Initial studies found PSA level to be a poor marker of clinical response in the case of sipuleucel-T. To address this potential inadequacy of PSA levels, investigators altered the definition of “progression” from a biochemical change (in PSA level), to objective enlargement of soft tissue disease or the appearance of two or more new lesions on radionuclide bone scan. Using this new definition, median time to progression in a phase II study was 118 days.
A phase III trial enrolled 127 asymptomatic men with metastatic CRPC randomized in a 2:1 ratio to receive either sipuleucel-T or placebo. Interestingly, there was no significant difference in time to progression between the two treatment arms, but there was a 4.5-month improvement (P = .01) in overall survival in the sipuleucel-T arm. However, this study was not originally designed to detect an increase in overall survival.
To bolster proof of clinical efficacy, investigators proceeded with a second phase III, double-blind, placebo-controlled, multicenter trial of sipuleucel-T that was designed to measure its effect on overall survival. In this trial, 512 patients were randomized in a 2:1 ratio to receive either sipuleucel-T or placebo. The study detected a 4.1-month improvement in overall survival compared with placebo, despite allowing 109 of 171 patients in the placebo group to cross over and receive salvage sipuleucel-T (prepared and cryopreserved at the time of placebo preparation). Adverse events in the treated group were primarily limited to fever, chills, and headache at or near the time of the infusion. Similar to previous studies, there were no differences in the time to disease progression (measured radiographically at 6, 14, 26, and 34 weeks, and every 12 weeks thereafter) between the two groups.
Investigators attributed the discordance between the observed survival benefit and the lack of effect on disease progression to a possible class effect, since a similar phenomenon has been reported in a study on poxviral-based PSA-targeted immunotherapy (PROSTVAC-VF). Other studies of metastatic CRPC have also shown a lack of correlation between disease progression and overall survival.[56,58] Sipuleucel-T was approved by the FDA in April 2010 for the treatment of metastatic CRPC that is asymptomatic or minimally symptomatic. Because the focus of this review is palliative treatment of metastatic disease, we point out that there is currently no evidence to support the use of sipuleucel-T in symptomatic patients.