Prostate Cancer

Prostate cancer is the most common type of cancer, with increasing incidence in older age groups. Prostate cancer has a tendency to metastasize to bone. Earlier detection is now possible with a blood test, prostate-specific antigen (PSA), and simplified biopsy using transrectal ultrasound (TRUS) guides.

One in six American males will be diagnosed with prostate cancer in his lifetime, leading to more than 6,000 new cases in Georgia each year.

Prostate cancer is caused by natural defects in the male prostate brought on by aging, making the disease predictable, but unpreventable. Like all cancers, it can spread through the body and interfere with vital bodily functions. Diagnosed early, however, prostate cancer is virtually 100% curable. That is why advanced screenings for early detection is so imperative.

Beginning at age 50, men should have yearly PSA tests and exams to screen for prostate cancer. Depending on your family history, lifestyle, and medical record, your physician may recommend a variety of screenings.

Prostate Cancer Treatment Summaries

Chemoprevention

A placebo controlled phase III randomized trial studied 5mg q day of Finasteride (5-alpha reductace inhibitor) to prevent prostate cancer. There was a statistically significant reduction of prostate cancer in the study arm (18.4% vs 24.4% at 7 years, which equates to a 25% relative reduction of prostate cancer). Furthermore there was a decrease in cumulative incidence of “for cause” prostate cancer (rising PSA or positive DRE) from 5.5% to 3.5% at 7 years.

However, these positive results were accompanied by a 25% relative increase in high grade tumors (6.4% vs 5.1%).

This has led to clinical uncertainty as to the benefit of Finasteride as a chemopreventive agent as well as impact on patients taking Finasteride for the approved breatment of BPH.

References:

  • Thompson I et al. The influence of finasteride on the development of prostate cancer. N Engl J Med. 2003: 349: 211-220.
  • Scardino P. The prevention of prostate cancer: the dilemma continues. N Engl J Med. 2004: 349: 293-295.
  • Mellon J. The finasteride prostate cancer prevention trial (PCPT): what have we learned? Eur J Cancer. 2005: 41: 2016-2022.
  • Klein E et al. Assessing benefit and risk in the prevention of prostate cancer: the prostate cancer prevention trial revisitied. J Clin Oncol. 2005: 23: 7460-7466.
Chemotherapy of hormone refractory prostate cancer

1. Docetaxel based therapy (55)

Based upon recently presented data, Docetaxel based chemotherapy should be considered standard therapy for patients with HRPC. Mitoxantrone + prednisone is approved for HRPC but results in palliation of symptoms in 30% of HRPC patients without improvement in median survival (8-12 months).

SWOG 9916 studied 770 AIPC patients, 334 randomized to docetaxel + estramustine vs 332 to mitoxantrone + prednisone. Median survival 18 months vs 16 months. TTP 6 months versus 3 months. 20% reduction in risk of death, 27% increase in PFS, 50% PSA response (vs 27%), 17% objective RR (vs 11%). The D + E arm experienced higher rate of GI toxicity but no difference in toxic death.

Reference:

  • (Petrylak DP et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Eng J Med. 2004: 351: 1513-1520.

A second randomized trial TAX 327 randomized patients to Docetaxel q 3 weeks + daily prednisone versus Docetaxel q week + daily prednisone versus M + P (n = 1006). Survival 18.9 months vs 17.4 months vs 16.5 months. The q 3 week Docetaxel arm provides a statistically significant survival advantage compared to the M + P arm.

Reference:

  • Tannock IF et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004: 351: 1502-1512.
Treatment of hormone refractory prostate cancer

1. Anti-Androgen Withdrawal

Anti-androgen withdrawal (AAWD) therapy was reported in a large prospective study to result in a decline of PSA (> or = 50%) in 13% of patients and an objective anti-tumor response in only 2% of patients. Despite this low response, AAWD should be recommended before embarking on further therapy in HRPC.

Reference:

  • Small EHS et al. Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-independent prostate cancer patients: A phase III trial (CALGB 9583). J Clin Oncol 2004: 22: 1025-1033.

2. High Dose Anti-Androgen Therapy

High dose anti-androgen therapy (bicalutamide 200mg/d) has been shown to produce responses in 14% of patients whose disease had progressed on flutamide (irrespective of previous AAWD).

Reference:

  • Sher HI et al. Casodex (200mg) for advanced prostate cancer: the natural vs treated history of disease. J Clin Oncol 1997: 15: 298-2938.

3. Suppression of Adrenal Androgens

After gonadal androgen suppression, adrenal androgens (DHEA, DHEAS, androstendione) are capable of activating both the mutated androgen as well as the wild type receptors. Ketoconazole suppresses adrenal steroid synthesis and has been found to be beneficial in patients as salvage hormonal therapy (in conjunction with corticosteroid replacement). In a randomized trial of HRPC, patients were randomized to anti-androgen withdrawal alone or in combination with high-dose ketoconazole/hydrocortisone. The study arm demonstrated a 30% PSA response (as compared to 13%). However only 2% of patients on the study arm demonstrated an objective response. These data was inferior to previous phase II single center studies which revealed a PSA response rate of 55%. It should be noted that Ketoconazole is best absorbed in the presence of gastric acids (empty stomach and discontinuation of anti-acids), and may influence clinical response.

References:

  • Small EJ et al. Simultaneous antiandrogen withdrawal and treatment with detoconazole and hydrocortisone in patients with advanced prostate cancer. Cancer 1997; 80: 1755-1759.
  • Small EHS et al. Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-independent prostate cancer patients: A phase III trial (CALGB 9583). J Clin Oncol 2004: 22: 1025-1033.
Primary treatment of metastatic prostate cancer

1. Hormone therapy of metastatic prostate cancer

Two large placebo controlled studies of CAB versus LHRH monotherapy reached divergent conclusions in terms of overall survival (both showed improved PFS but were divergent in their conclusions regarding OS).

References:

  • Crawford ED et al. A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N Engl J Med 1989; 321: 419-424.
  • Three meta-analysis (1995, 2000, 2002) including several thousand patients suggest that CAB is slightly better than monotherapy, but also associated with slightly increased toxicity (Group PCTC et al. Maximum androgen blockade in advanced prostate cancer: an overview of 2 randomized trials with 3283 deaths in 5711 patients. Lancet 1995; 346: 265-269).
  • Maximum androgen blockade in advanced prostate cancer; an overview of the randomized trials. Prostate Cancer Trialists’ Collaborative Group. Lancet 2000; 355: 1491-1498).
Adjuvant Combined Modality Therapy

Combining radiation therapy and androgen deprivation in the adjuvant setting has been studied and demonstrates improvement in local control, disease free survival as well as overall survival. The group of patients who best benefit from combined modality therapy as well as the optimal duration of androgen deprivation (2,3,5 years) remains controversial.

References:

  • Pilepich MV et al. Phase III RTOG trial 86-10 of androgen deprivation adjuvant to definitive radiotherapy in locally advanced carcinoma of the prostate. Int J Radiat Oncol Biol Phys 50: 1243-1252, 2001.
  • Lawton CA et al. Updated results of the phase III RTOG trial 85-31 evaluating the potential benefit of androgen suppression following standard radiation therapy for unfavorable carcinoma of the prostate. Int J Radiat Oncol Biol Phys 49: 937-946, 2001.
  • Roach M et al. Predicting long term survival and the need for hormonal therapy: meta-analysis of RTOG prostate cancer trial. Int J Radiat Oncol Phys 47: 617-627, 2000.
Adjuvant Radiation Therapy

To date, improvement in local control following irradiation of high-risk prostate cancer has not translated in a survival advantage in a randomized trial. A SWOG trial addressing this issue recently completed accrual and results are awaited.

References:

  • Syed S et al. Management of high-risk localized prostate cancer: The integration of local and systemic therapy approaches. Urol Oncol 21: 235-254, 2003.
  • Paulson DF et al. Radical prostatectomy for clinical stage T1-2N0M0 prostate adenocarcinoma: Long term results. J Urol 144: 1180-1184, 1990.
  • Ansher MS et al. Adjuvant radiotherapy for pathologic stage T3/T4 adenocarcinoma of the prostate: Ten year update Int J Radiat Oncol Biol phys 33: 37-43, 1995.
Neo-Adjuvant Therapy

Although adjuvant androgen deprivation for node-positive disease has demonstrated a survival benefit in clinical trials testing, neo-adjuvant androgen deprivation prior to radical prostatectomy has not demonstrated any survival benefit. Soloway et al reported extended follow-up of a trial comparing 3 months of neo-adjuvant androgen deprivation for cT2b, NX, M0 disease. While positive margins were reduced (48% versus 18%), the 5 year biochemical recurrence-free survival was not improved in the study arm (68% versus 65%). Therefore, while neo-adjuvant hormonal deprivation may improve surgical respectability and achievement of negative margins, it does not translate in improved recurrence free or overall survival.

Reference:

  • Soloway MS et al. Neoadjuvant androgen ablation before radical prostatectomy in cT2NXM0 prostate cancer: 5 year results. J Urol 167: 112-116, 2002.
Adjunctive treatment of high risk prostate cancer

1. Node Positive Disease – Adjuvant Therapy

Application of adjuvant androgen deprivation therapy has shown to prolong survival in a randomized trial. Messing et al randomized node positive patients to immediate or delayed (at the time of metastatic disease) androgen deprivation therapy after radical prostatectomy. After a median of 7.1 years, disease progression was reduced from 77% to 18% and survival increased from 65% to 85%. These findings combined with the MRC Study and the EORTC trials reported by Bolla provde evidence-based data for early rather than delayed treatment of high-risk patients with androgen deprivation therapy.

References:

  • Messing EM et al: Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. N Engl J Med 341: 1781-1788, 1999.
  • Medical Research Council Prostate Cancer Working Party Investigation Group: Immediate versus deferred treatment for advanced prostate cancer: Initial results of the Medical Research Council Trial. Br J Urol 79: 235-246, 1997.
  • Bolla M et al: Long term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (An EORTC study): A phase II randomized trial. Lancet 360: 103-108, 2002.
  • Bolla M et al: Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med 337: 295-300, 1997.