Change in the Standard of Care for Advanced Disease – the Highlight of the Meeting

This year’s American Society of Clinical Oncology (ASCO) annual meeting in New Orleans, Louisiana brought new treatment options for prostate cancer to the forefront. Of the top five abstracts presented at ASCO this year, two were nationally randomized studies that compared Taxotere®-containing chemotherapy to Novantrone® and prednisone in the treatment of prostate cancer. Both studies showed a survival benefit with Taxotere®. This is the first time that a survival benefit for chemotherapy, or any therapy for that matter, has been shown in androgen-independent prostate cancer (AIPC).[1, 2]

Eisenberger, et al. evaluated Novantrone® plus prednisone versus two different schedules of Taxotere® and daily prednisone in a study called TAX327. Taxotere® 75 mg/m² administered every 21 days plus daily prednisone provided a longer survival benefit (24% reduction in the risk of death) as well as better pain reduction. Weekly Taxotere® plus prednisone was not superior to Novantrone® plus prednisone with respect to survival.

SWOG 9916 further established the use of the 21-day schedule of Taxotere®-based chemotherapy as the standard of care for metastatic AIPC. Petrylak, et al. compared Taxotere® 60 mg/m2 plus five days of estramustine to Novantrone® plus prednisone. A 20% reduction in the risk of death was found in the Taxotere® plus estramustine treatment arm. However, a higher frequency of grade 3 or 4 toxicities was found in patients treated in this study, as well as TAX327, when compared to patients who were treated with Novantrone® and prednisone. The results of these studies are likely to have a substantial impact on practice.

Taxotere® dosed every 21 days along with daily prednisone was recently approved by the U.S. Food and Drug Administration for the treatment of AIPC and will likely be viewed as the standard of care for this disease. The weekly schedule of Taxotere®, the most commonly used schedule for the treatment of prostate cancer in the U.S. today, will probably be used less frequently. Although these studies did not directly tackle the question of the importance of estramustine, it is unlikely to be used commonly. This is because estramustine adds to toxicity and a demonstrated benefit of adding this drug to Taxotere® would be required to persuade physicians that it is worth its cost in adverse events.

Risk Reduction and Diagnosis

No known means exist for the prevention of prostate cancer; however, a study of statins used to lower cholesterol suggest the possibility that these agents may lower the risk of prostate cancer.[3] An evaluation of the medical records of VA patients who were referred for prostate biopsy and frequency age-matched controls, adjusted for age and body mass index, found that men who used any statins had a 56% lower risk of being diagnosed with prostate cancer than those who had not used statins. Additional studies will be needed to confirm this initial finding, but the body of evidence that suggests statin use may decrease the risk of several cancers is increasing.

The question of what to recommend to patients who are suspected of harboring prostate cancer, but have a negative biopsy of the prostate remains a vexing problem. Studies suggest that a single negative biopsy is not completely reassuring, but little is known about which patients should have a repeat biopsy. In a retrospective analysis of over 300 patients who underwent at least two, and as many as seven, biopsy procedures, Garzotto, et al.,[4] found that factors such as PSA doubling time (PSADT), PSA density (PSAD), biopsy indication, and the presence of prostatic intraepithelial neoplasia (PIN) can predict the risk of harboring prostate cancer in men with a negative initial biopsy. These factors were then combined to describe clinically meaningful risk groups. As these data are disseminated, they should provide some guidance to physicians who are counseling their patients about the risk of prostate cancer after a negative initial biopsy.

Treatment of localized prostate cancer

Initial therapy

Choosing between surgery and radiation for the treatment of newly diagnosed localized prostate cancer can be reminiscent of reading tealeaves. It may be possible to apply molecular biology techniques to advise patients more effectively. Ritter et al. found that in good-risk patients, abnormal p53 status was associated with a substantially increased risk of recurrence after radiation therapy, but not after surgery.[5] This makes biologic sense because abnormal p53 may mediate resistance to radiation therapy. Because this study involved a small number of patients (81 prostatectomy and 53 radiation), it will need to be confirmed before it is adopted into routine practice, but it may herald an era where treatment selection for prostate cancer will be driven by rational use of molecular markers.

Extent of lymph node dissection

In a study of 311 patients who had a radical pelvic lymphadectomy at the time of radical retropubic prostatectomy, 47% of those who had positive nodes had positive nodes in the internal and common iliac regions. These areas are not commonly part of a standard lymph node dissection.[6] These data suggest that a more extensive lymph node dissection may be appropriate in selected higher-risk patients and that current staging systems may underestimate the incidence of nodal involvement in patients with newly diagnosed prostate cancer.

Adjuvant radiation therapy for high-risk patients

Bolla, et al. randomly assigned 1,005 T2N0 patients who had at least one pathologic risk factor for local recurrence (including capsule invasion, positive surgical margins, or invasion of seminal vesicles) to receive either conventional postoperative radiation to the prostate bed or observation.[7] PSA relapse-free survival was improved from 51.8% to 72.2% (p<0.0001) in those patients who received radiation therapy after five years. Improvement in clinical progression-free survival was 74.4% compared to 83.3% (p=0.004), with the incidence of local-regional failure also improved in the group that received the radiation therapy. Further results of the evaluation of this treatment on distant metastases and overall survival will require additional follow up. A similar trial from SWOG has completed accrual but results are not available yet. In many centers, radiation is given as salvage treatment (for a rising PSA). Encouraging results have been reported with this approach. Thus, there is likely a role for postoperative radiation in selected patients, but the optimal approach (adjuvant vs. salvage) remains to be determined.

Rising PSA following initial therapy with curative intent

Prognosis

Patients with a detectable and rising serum PSA after initial therapy with curative intent represent a heterogeneous population, therefore understanding their prognosis is critical to their optimal management. A nomogram was presented using all known predictors for patients eight years after a rising PSA, or biochemical recurrence, after prostatectomy.[8] Another analysis demonstrated that PSA doubling time (PSADT) less than or equal to 10 months was the most significant predictor of distant metastases and survival.[9]

Treatment

For patients who pursue androgen deprivation therapy (ADT) after radical prostatectomy when they have a rising PSA, the median duration of response was 10.8 years.[10]

The long-term adverse effects of androgen suppression have prompted the evaluation of alternative methods of treatment such as “peripheral androgen blockade.” Finasteride at 5 mg/day and Flutamide at 250 mg TID produced greater than 80% PSA declines in 91 of 94 patients. After three years, the median time to progression has not been achieved.[11] Further study will need to be carried out to evaluate this regimen in a randomized setting.

Bisphosphonates and metastases prevention

In an effort to reduce the incidence of metastases to the bones, the MRC PR04 studied a bisphosphonate called clodronate*. Patients were randomly assigned to either receive 2080 mg daily of clodronate or a placebo. Patients were followed for five years or until the development of symptomatic bone metastases or prostate cancer death. Clodronate was not beneficial.[12] It is possible that more potent bisphosphonates would succeed where clodronate failed, but until a randomized study demonstrates such a benefit, the use of these agents to prevent bone metastases in prostate cancer is not indicated.

Hormonal therapy for prostate cancer

Adverse Effects

An analysis of Medicare non-metastatic prostate cancer patients that had received GnRH agonists and those who had not received GnRH agonist therapy showed that hormonal therapy was associated with a 40% increase in the risk of fractures. Longest duration of therapy was associated with the greatest risk.[13]

In another analysis, risk factors for fracture in men who had received androgen-deprivation therapy were ascertained.[14] Men older than 85 years and with bone metastases had the highest risk of pathologic fractures, while men older than 81 years with cardiovascular disease and longest duration of androgen deprivation therapy had the greatest risk of non-pathologic fractures. Both of these studies highlight the increasingly recognized bone-related morbidity of androgen deprivation therapy (ADT). Recently published guidelines call for periodic examination of bone density in patients who are on ADT and appropriate therapy in patients with osteoporosis.

Another common adverse effect of ADT is hot flashes. A study of venlafaxine*, an antidepressant, was studied in men with prostate cancer after it was found to be effective for women with breast cancer as a treatment for hot flashes. Twelve of seventeen evaluable patients had a response to treatment, with a greater than 50% reduction in the hot flash score. The weekly score average reduction was 58%.[15] Therefore, venlafaxine should be added to the list of agents available to treat male hot flashes.

Cholesterol and lipid profile levels were studied in men with androgen independent prostate cancer on high-dose transdermal estrogen*. These levels were studied while the patients were receiving conventional ADT and after eight weeks on treatment with high-dose transdermal estradiol. Treatment with transdermal estradiol produced important improvements in total cholesterol, LDL cholesterol, and HDL cholesterol.[16] Adverse changes in the lipid profile, which in the long term can lead to cardiovascular complications, are an overlooked adverse effect of androgen deprivation therapy. These results suggest that different forms of ADT may affect lipids quite differently. Additional studies are needed to clarify the impact of these differences on the long-term experience of prostate cancer patients.

Androgen-independent prostate cancer (AIPC)

Surrogates for survival

Timely development of new drugs for prostate cancer will only be feasible if endpoints short of survival can be used to demonstrate a clinical benefit. Thus the search for surrogate endpoint in prostate cancer is essential.

SWOG 9916, described above, was analyzed to determine if PSA changes in response to chemotherapy could be used as such a surrogate. PSA velocity during the first 3 months of therapy met all requirement of a surrogate marker for survival.[17] These analyses will need to be performed for TAX327; however, these data suggest that it maybe possible to detect clinical benefit quickly with a surrogate marker. This would be an important advance for prostate cancer drug development.

Treatment options

Several studies of note focused on new chemotherapy agents for patients with metastatic AIPC. Two phase II studies examined epothilone-B (BMS-247550)* activity in patients with metastatic AIPC who have not previously received chemotherapy. The first study was a multi-institutional trial that looked at the combination of epothilone-B with estramustine phosphate.[18] This study found that this combination provided a 69% PSA response and a 56% PSA response was found in those patients treated with epothilone-B alone. A Southwest Oncology Group cooperative study demonstrated significant single agent activity for epothilone-B in this setting.[19] Forty-one percent had a PSA response, while 30% had measurable disease response. Both of these studies found that neuropathy was common with this agent. The optimal management strategy for neuropathy seen with this agent will need to be developed.

Hormone refractory prostate cancer patients who progress after docetaxel- containing therapy have no established treatment options. Three of four patients treated with docetaxel plus carboplatin after progressing on docetaxel responded to therapy.[20] A phase II study of this combination is underway.          

Chemotherapy plus novel agents

The novel agent bortezomib (Velcade®)*, a proteosome inhibitor, was combined with Taxotere® in a phase II study. Thirty-one patients were enrolled and 22 of them had evaluable disease. Thirty-six percent of these patients had a greater than 50% PSA decline, with five patients having a greater than 90% response rate. Nineteen of the evaluable patients had prior chemotherapy, with 14 of these receiving taxane-based therapy.[21]

Biologic agents alone

Atrasentan*, an oral endothelin A receptor antagonist, was studied in a phase III, randomized, double blinded clinical trial. Eight hundred and nine patients with metastatic AIPC were enrolled. Time to progression was not delayed with atrasentan (HR 1.14, 95% CI 0.98-1.34). In the protocol compliant subset, a modest benefit in clinical progression was noted (HR 1.26, 95% CI 1.06-1.50). Overall, the treatment was well tolerated with few patients discontinuing therapy due to toxicity.[22]

Immunotherapy

Seven of nine evaluable patients treated with GM-CSF* in combination with thalidomide* responded by PSA, [23] however toxicity was substantial. This combination needs further refinement but the level of activity is intriguing.

A larger study of 80 patients on GVAX*, an allogeneic GM-CSF transduced vaccine showed modest PSA reductions in 32% of patients treated at the highest dose level (6 of 19). Phase III studies of GVAX are planned.

*Investigational product or unlabeled use

References

1.         Petrylak, D.P., et al., SWOG 99-16: Randomized phase III trial of docetaxel (D)/estramustine (E) versus mitoxantrone(M)/prednisone(p) in men with androgen-independent prostate cancer (AIPCA). Proc Am Soc Clin Onc, 2004. 23: p. 2.

2.         Eisenberger, M.A., et al., A multicenter phase III comparison of docetaxel (D) + prednisone (P) and mitoxantrone (MTZ) + P in patients with hormone-refractory prostate cancer (HRPC). Proc Am Soc Clin Onc, 2004. 23: p. 2.

3.         Shannon, J., M. Garzotto, and A.J. Palma, Statin use and prostate cancer risk. Proc Amer Soc Clin Onc, 2004. 23: p. 404.

4.         Garzotto, M., et al., Predictors of prostate cancer in men undergoing serial prostate biopsies: Results from 371 patients. Proc Am Assoc Cancer Res, 2004. 23: p. 402.

5.         Ritter, M.A., et al., Integrating biomarkers into clinical predictive and prognostic paradigms for prostate cancer: The role of p53 status. Proc Am Soc Clin Onc, 2004. 23: p. 857.

6.         Heidenreich, A., et al., Extended pelvic lymphadenectomy in men undergoing radical prostatectomy - an update on > 300 cases. Proc Am Soc Clin Onc, 2004. 23: p. 408.

7.         Bolla, M., et al., Does post-operative radiotherapy (P-RXT) after radical prostatectomy (Px) improve progression-free survival (PFS) in pT3N0 prostate cancer (PC)? (EORTC 22911). Proc Am Soc Clin Onc, 2004. 23: p. 382.

8.         Dotan, Z.A., et al., Predicting time to metastatic progression from biochemical recurrence after radical prostatectomy. Proc Am Soc Clin Onc, 2004. 23: p. 416.

9.         Partin, A.W., et al., Prostate specific antigen doubling time (PSADT) predicts for distant failure and prostate cancer specific survival (PCSS) in men with biochemical relapse after radical prostatectomy (RP). Proc Am Soc Clin Onc, 2004. 23: p. 394.

10.       Bianco, F.J., et al., Duration of response to androgen deprivation therapy and survival after subsequent biochemical relapse in men initially treated with radical prostatectomy. Proc Am Soc Clin Onc, 2004. 23: p. 393.

11.       Picus, J., et al., Efficacy of peripheral androgen blockade on prostate cancer: Results of CALGB 9782. Proc Am Soc Clin Onc, 2004. 23: p. 395.

12.       Mason, M.D., Development of bone metastases from prostate cancer: First results of the MRC PR04 trial (ISCRTN 61384873). Proc Am Soc Clin Onc, 2004. 23.

13.       Smith, M.R., et al., Association between androgen deprivation therapy and fracture risk: A population-based cohort study in men with non-metastatic prostate cancer. Proc Am Soc Clin Onc, 2004. 23: p. 382.

14.       Krupski, T.L., et al., Profile of men with prostate cancer on androgen deprivation therapy at greatest risk of bone complications. Proc Am Soc Clin Onc, 2004. 23: p. 726.

15.       Shafqat, A., et al., A phase II study of venlafaxine for the treatment of hot flashes in men undergoing androgen deprivation for prostate cancer. Proc Am Soc Clin Onc, 2004. 23: p. 762.

16.       Purnell, J.Q., et al., Transdermal estrogen therapy improves cholesterol levels and lipid profiles in men with prostate cancer. Proc Am Soc Clin Onc, 2004. 23: p. 734.

17.       Crawford, E.D., et al., Three-month change in PSA as a surrogate endpoint for mortality in advanced hormone-refractory prostate cancer (HRPC): Data from Southwest Oncology Group Study S9916. Proc Am Soc Clin Onc, 2004. 23: p. 382.

18.       Kelly, W.K., et al., Multi-institutional trial of the epothilone B analogue BMS-247550 with or without estramustine phosphate (EMP) in patients with progressive castrate-metastatic prostate cancer (PCMPC): Updated results. Proc Am Soc Clin Onc, 2004. 23: p. 383.

19.       Hussain, M., et al., Epothilone B (Epo-B) analogue BMS-247550 (NSC #710428) administered every 21 days in patients (pts) with hormone refractory prostate cancer (HRPC). A Southwest Oncology Group Study (S0111). Proc Am Soc Clin Onc, 2004. 23: p. 383.

20.       Tay, M.H., et al., Docetaxel plus carboplatin (DC) may have significant activity in hormone refractory prostate cancer (HRPC) patients who have progressed after prior docetaxel-based chemotherapy. Proc Am Soc Clin Onc, 2004. 23: p. 425.

21.       Dreicer, R., et al., Phase I/II trial of bortezomib plus docetaxel in patients with advanced androgen-independent prostate cancer. Proc Am Soc Clin Onc, 2004. 23: p. 418.

22.       Carducci, M., et al., Effects of atrasentan on disease progression and biological markers in men with metastatic hormone-refractory prostate cancer: Phase 3 study. Proc Am Soc Clin Onc, 2004. 23: p. 383.

23.       Lilly, M., et al., Phase I trial of sargramostim and thalidomide for treatment of hormone-refractory prostate cancer. Proc Am Soc Clin Onc, 2004. 23: p. 427.