by Dr. C.D. Buckner M.D. updated 10/2018
Prostate cancer is the most commonly diagnosed cancer in men in the United States. Prostate cancer is stimulated to grow by male hormones, particularly testosterone. Therefore, patients may receive treatment, referred to hormone therapy, to reduce levels of male hormones available to cancer cells. This removes the growth stimulus produced by male hormones and causes the cancer to shrink.
Unfortunately, patients ultimately stop responding to hormone therapy after being on treatment for a period of time, and are referred to as having hormone-refractory or androgen independent prostate cancer.
Chemotherapy, like hormone therapy is a systemic therapy in that the cancer-fighting drugs circulate in the blood to parts of the body where the cancer may have spread and can kill or eliminate cancers cells at sites great distances from the original cancer. Several chemotherapeutic drugs have demonstrated the ability to kill prostate cancer cells in patients with advanced prostate cancer. In particular, the chemotherapy drugs Novantrone® (mitoxantrone) and Taxotere® (docetaxel ) have demonstrated to have effectiveness in treating prostate cancer.
Docetaxel chemotherapy was demonstrated to improve survival of men with advanced HRPC in 2004 and has remained the mainstay of chemotherapy often utilized in combination with other chemotherapy or newer targeted medications. Taxotere® in combination with prednisone replaced Novantrone chemotherapy as initial treatment because it improved symptoms and modestly prolonged survival for men with HRPC. Other combinations have been evaluated.
To improve on these results researchers from France evaluated the combination of Taxotere and estramustine for the treatment of HRPC. in 92 patients with metastatic HRPC. Men were treated with either Taxotere alone or Taxotere plus estramustine.
- Prostate specific antigen levels were reduced in 68% of patients treated with Taxotere/estramustine compared with only 30% of patients treated with Taxotere alone.
- Median time to cancer progression was 5.7 months for patients treated with Taxotere/estramustine compared with 2.9 months for those treated with Taxotere alone.
- Median survival was 19.3 months for patients treated with Taxotere/estramustine compared with only 17.8 months for patients treated with Taxotere alone.
- There were no significant differences in quality of life measurements between the two groups of patients.
A second clinical trial in 674 patients confirmed this beneift.The average duration of survival in patients with HRPC treated with Taxotere®/estramustine was 18 months, compared with 15 months for those treated with mitoxantrone/prednisone. The average time to cancer progression was 6 months for patients treated with Taxotere®/estramustine, compared to only 3 months for those treated with mitoxantrone/prednisone.
Quadramet® with Taxotere®
According to a press release from the Cytogen Corporation, treatment of advanced, hormone refractory prostate cancer with the chemotherapy drug Taxotere® and Quadramet® (samarium sm-153 lexidronam)-an injection that delivers radiation to bone metastases-reduces prostate specific antigen (PSA) levels.
Results from a phase II clinical trial evaluating the combination of the chemotherapy drug Taxotere and Quadramet in 29 men with advanced, HRPC have been reported.
- Within 12 weeks of the start of the first treatment cycle, 34% of men experienced PSA declines of greater than 50%.
- PSA eventually increased in 69% of men, after a median of four months.
- Severe toxic effects of the treatment combination were rare, and included low while blood cell levels.
The researchers conclude that the combination of Taxotere and Quadramet offers promise for the management of advanced hormone refractory prostate cancer. Additional studies are underway to further evaluate Quadramet in combination with Taxotere and other agents.
Intermittent Taxotere® Effective in Hormone-refractory Prostate Cancer
Intermittent administration of Taxotere® (docetaxel) appears to provide as much benefit, with fewer side effects, than continuous administration of Taxotere among patients with hormone-refractory prostate cancer according to a study presented at the 23rd annual meeting of the European Association of Urology.
Because continuous delivery of chemotherapy is associated with side effects, researchers have been evaluating “chemotherapy holidays” or intermittent administration (IA), an approach that allows for a break in delivery of chemotherapy. The concept behind IA is to reduce side effects associated with continuous delivery in order to maintain a good quality of life while gaining the anticancer benefits of chemotherapy. There has also been some data that indicates a potential for IA to delay the development of resistance to chemotherapy (however, these findings require further testing).
Researchers from Turkey recently conducted a small clinical trial to compare continuous administration (CA) of Taxotere with IA of Taxotere in men with AIPC. This trial included 31 men who received CA Taxotere administered once every three weeks or IA Taxotere administered at measurable cancer progression or increase in pain from 2004 to 2006.
Anticancer responses measured by prostate-specific antigen levels, average survival, and survival at one year were all similar between the CA and IA groups.
The researchers concluded that intermittent administration of Taxotere appears to provide the same treatment benefits of continuous administration in men with AIPC.
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Modified Taxotere® Regimen Effective for Advanced Prostate Cancer
Researchers from Greece have reported that the treatment combination consisting of Taxotere® (docetaxel), estramustine (Emcyt®) and Zometa® (zoledronic acid) is an effective and safe therapeutic regimen for men with advanced hormone-refractory prostate cancer.
One common site of cancer spread in men with hormone-refractory prostate cancer is to the bones. Once cancer spreads to the bones, referred to as bone metastasis, men can experience extreme bone pain, which may become debilitating, as well as bone fractures or compression of the spinal cord, which may be life-threatening. Zometa® is an agent that has demonstrated a reduction of bone complications caused by bone metastasis and researchers are continuing to evaluate Zometa® to determine the optimal timing of its use, as well as treatment combinations it may be used with most effectively.
Taxotere® and Novantrone® Sequence Evaluated as Initial Chemotherapy for Hormone-Refractory Prostate Cancer
According to results recently published in the journal Cancer, initial chemotherapy treatment with the agent Taxotere® followed by Novantrone® appears more favorable than treatment with initial Novantrone followed by Taxotere in men with HRPC.
When men progress to a hormone-resistant condition, the chemotherapy agents Novantrone and Taxotere are available as treatment options. However, it has not been determined if treatment with Taxotere first followed by Novantrone, or treatment with Novantrone first followed by Taxotere at signs of a cancer recurrence provides more favorable outcomes. Researchers from Canada recently reviewed data to evaluate whether the sequence of these chemotherapy agents affects outcomes for men with HRPC.
The study included 68 men with HRPC who were treated either with Taxotere followed by Novantrone, or the reverse sequence. Men initially treated with Taxotere had favorable outcomes compared to those who were initially treated with Novantrone:
- Median overall survival was 22 months for men treated with Taxotere first and 15 months for those treated with Novantrone first.
- Progression-free survival was 2-3 months for both groups.
- Both agents, when used as the second agent, resulted in high rates of side effects that affected doses or prompted discontinuation of therapy (64% for Taxotere and 46% for Novantrone).
The researchers concluded that initial treatment with Taxotere followed by Novantrone for the treatment of HRPC appears to trend toward improved survival compared to initial treatment with Novantrone followed by Taxotere in these patients. However, clinical trials (rather than review of data) to directly compare the sequences of these agents in patients with HRPC are necessary to confirm these findings.
The U.S. Food and Drug Administration (FDA) had granted OncoGenex Pharmaceuticals fast-track designation for their investigative agent OGX-011 (custirsen sodium) for the treatment of prostate cancer in combination with Taxotere® for the treatment of progressive, metastatic prostate cancer. OGX-011 is designed to inhibit clusterin, a protein that is associated with resistance to treatment. Phase III trials however were negative and did not lead to the approval of OGX-011.
Provenge®, Activated Cellular Immunotherapy, Shows Promise for Treatment of Androgen Independent Prostate Cancer
Researchers involved in a multicenter trial have demonstrated that Provenge® (Sipuleucel-T) may improve the survival of patients with HRPC when Provenge was followed by Taxotere®.
Provenge is an active cellular immunotherapeutic agent that targets the prostatic acid phosphatase (PAP) antigen. The PAP antigen is present in approximately 95% of all prostate cancers. Published phase I and II studies of Provenge in patients with prostate cancer show the approach using activated cellular immunotherapy with Provenge is safe and provides a potential benefit.
The data presented at the Prostate Cancer Foundation meeting was an update of data published in the July 1, 2006, issue of the Journal of Clinical Oncology. This phase III study (D9901) randomly allocated 127 patients with asymptomatic metastatic AIPC to receive Provenge or placebo every two weeks until death or progression. Randomization was on a 2:1 basis with 82 patients in the treatment group and 45 in the control group. Patients were followed until death or for 36 months from entry on study. Thirty-four patients in the placebo group were treated with Provenge after disease progression.
- Survival at 36 months was 34% for the Provenge arm, compared with only 11% for those who received placebo (p=0.0046).
- Median survival was 25.9 months for the Provenge arm, compared with 21.4 months for those who received placebo (p=0.01)
- Median prostate cancer specific survival was 35.2 months for patients in the Provenge arm, compared with 23.5 months for those who received placebo.
All patients received subsequent treatment with Taxotere (docetaxel). Sixty-eight percent of patients initially randomized to the placebo arm ultimately received Provenge in a crossover salvage strategy.
- Median survival was 34.5 months for patients who received initial Provenge/Taxotere, compared with 25.4 months for those who received placebo/Taxotere.
- Among patients who crossed-over to receive Provenge, the median survival was 25.7 months following treatment with Taxotere, compared to only 20.2 months for patients treated with placebo/Taxotere.
- Eisenberger M, DeWit R, Berry W, et al. A multicenter phase III comparison of docetaxel (D) + lprednisone (P) and mitoxantrone (MTZ) + P in patients with hormone-refractory prostate cancer. Proceedings from the 40th annual meeting of the American Society of Clinical Oncology. June 2004. Abstract #4.
- Petrylak D, Tangen C, Hussain M, 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 (AIPC). Proceedings from the 40th annual meeting of the American Society of Clinical Oncology. June 2004. Abstract #3.
- Michels J, Montemurro T, Murray N, et al. First- and second-line chemotherapy with docetaxel or mitoxantrone in patients with hormone-refractory prostate cancer. Does sequence matter? Cancer. 2006; 106: 1041 – 1046.
- Efstathiou E, Bozas G, Kostakopoulos A, et al. Combination of docetaxel, estramustine phosphate, and zoledronic acid in androgen-independent metastatic prostate cancer: Efficacy, safety, and clinical benefit assessment. Urology. 2005;126-130.
- Oudard S, Banu E, Vannetzel JM, et al. Results of a phase II randomized trial of docetaxel (D), Estramustine (E) and prednisone (P) – two schedules – versus mitoxantrone (M) and prednisone in patients (pts) with hormone refractory prostate cancer (HRPC). Annals of Oncology. 2002;13 (Suppl. 5): page 90. The 27th annual meeting of the European Society of Clinical Oncology, abstract 325O.
- Akdogen B, Ozen H, Kirdal Y. Is intermittent docetaxel chemotherapy reasonable in hormone-refractory prostate cancer? A prospective randomized study. Proceedings from the 23rd annual European Association of Urology meeting. March 2008. Milan, Italy. Abstract #643.
- Cytogen Press Release. Cytogen Announces Presentation of Data from Phase II Study Evaluating Combination of QUADRAMET® with Chemotherapy in Hormone Refractory Prostate Cancer. Ocotober 3, 2005.
- Small EJ, et al. Sipuleucel-T (Provenge) for Advanced Prostate Cancer. Prostate Cancer Foundation’s 13th Annual Scientific Retreat. Scottsdale, Arizona. October 19-21, 2007.
- Petrylak D, et al. Defining the optimal role of immunotherapy and chemotherapy: Advanced prostate cancer patients who receive sipuleucel-T (PROVENGE) followed by docetaxel derive greatest survival benefit. 14th Annual Meeting of the Chemotherapy Foundation Symposium. New York, New York. November 8-11, 2006.
- Small EJ, Schellhammer PF, Higano CS, et al. Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic asymptomatic hormone refractory prostate cancer. Journal of Clinical Oncology 2006;24:3089-3094.
- Eymard J-C, Priou F, Zannetti A, et al. Randomized phase II study of docetaxel plus estramustine and single-agent docetaxel in patients with metastatic hormone-refractory prostate cancer. Annals of Oncology. 2007;18:1064-1070.