By Richard Lam, M.D.
Prostate Oncology Specialists,
Marina del Rey, CA
Edited from PCRI Insights February, 2009 v 12.1
In the last decade, the role of chemotherapy has evolved significantly. The first approved chemotherapy agents, mitoxantrone (Mitoxantrone) and estramustine (Emcyt), were utilized for prostate cancer patients to help control pain and to relieve symptoms associated with their metastatic disease. Because of the drugs’ inherent side effects, doctors were reluctant to prescribe chemotherapy unless patients were experiencing problems from the cancer. Understandably, even in the face of cancer progression, patients who had a good quality of life were not offered chemotherapy. More recently, as a result of two landmark phase 3 trials that demonstrated an overall survival benefit, the FDA approved docetaxel (Taxotere) for the treatment of metastatic prostate cancer. This article reviews the evolution of chemotherapy for prostate cancer, from the early role of mitoxantrone and Taxotere to the most up-to-date research on Taxotere-based regimens. Finally, a brief overview of new drugs and new indications of chemotherapy will be presented.
For prostate cancer, chemotherapy is administered after the development of hormone-refractory (also known as androgen-independent) disease. Hormone- refractory prostate cancer is defined by cancer growth despite castrate testosterone levels. Cancer growth can be demonstrated by (1) a rising PSA level, (2) new changes on radiographic studies, and (3) worsening symptoms such as pain. Oftentimes, physicians will prescribe secondary hormonal medications, such as nilutamide, ketoconazole, or estrogen, prior to starting chemotherapy. However none of these agents have any proven benefit in terms of overall survival.
In 1996, mitoxantrone was cleared by the FDA for the treatment of metastatic prostate cancer because this chemotherapy agent decreased pain and improved the quality of life of men suffering from prostate cancer.1,2 Mitoxantrone is administered intravenously every three weeks and is usually well tolerated. Possible side effects include mild nausea, fatigue, hair loss, and occasionally heart problems. However, because of its lack of benefit in prolonging survival, mitoxantrone was relegated to the palliative setting. Usually, patients were only referred by their urologist to a medical oncologist for mitoxantrone if they were having significant bone pain and were unable to tolerate narcotics.
The Emergence of Taxotere
In 2004, these two important studies ushered in a new role for chemotherapy. For the first time, there was a drug, Taxotere, which actually helped prostate cancer sufferers live longer. The first study3,5, TAX 327, randomized 1006 men with metastatic hormone refractory prostate cancer, to either Taxotere administered every three weeks, Taxotere administered weekly, or mitoxantrone. All three groups received prednisone. The median PSA was 115. Compared to the mitoxantrone group, the two groups that received Taxotere had a higher PSA response rate (45-48% vs. 32%) and better quality of life scores. More importantly, the every three-week Taxotere cohort had a statistically significant improvement in overall survival (19 vs. 16 months).
Of note, at least 30% of patients who were randomized to the mitoxantrone arm also received Taxotere after failure on mitoxantrone. This crossover effect probably decreased the apparent difference in overall survival between the two treatment groups. Despite this confounding effect of second-line treatment with the more effective therapy (Taxotere), a survival benefit associated with Taxotere remained apparent. In other words, if men on the mitoxantrone arm never received Taxotere, then the survival difference would likely have been larger.
The second study4, SWOG 99-16, randomized 679 men with metastatic disease to either Taxotere plus estramustine (an older oral chemotherapy agent) or mitoxantrone plus prednisone. This study essentially confirmed the superiority of Taxotere to mitoxantrone in terms of PSA response, duration of response, and overall survival. However, the addition of estramustine to Taxotere resulted in more nausea/vomiting and cardiovascular side effects, without any apparent survival benefit. Therefore, estramustine is not commonly combined with Taxotere in the first-line setting.
Overall, Taxotere is well tolerated, and its side effects are usually very manageable. Many of the most reviled toxicities associated with chemotherapy (i.e. nausea and vomiting, blood transfusions, and weakening of the immune system) are generally not observed with Taxotere. One can expect to experience mild fatigue, mild loss of appetite, hair loss, skin and fingernail changes. Infections are uncommon. For details, please refer to the PCRI Insights article “Dealing with Taxotere Side Effects” from the May 2007 issue.
Editor note – Also see: Chemotherapy for Prostate Cancer: “Why Bother?”
Improving Taxotere-based Chemotherapy
The next phase of research for chemotherapy is to find ways to make Taxotere-based chemotherapy better. One such promising agent, bevacizumab (Avastin), appears to do just that. Avastin is a monoclonal antibody that targets the VEGF receptor; its main mechanism of action is via anti-angiogenesis. Anti-angiogenesis essentially means shutting down the blood supply, and thereby starving the cancer. For breast, colon and lung cancer, adding Avastin to chemotherapy improves clinical outcomes. As a result, Avastin is FDA-approved for these cancers.
Now, Phase 2 and 3 trials involving Avastin for prostate cancer are underway. One of the most exciting studies7 combines Avastin with Taxotere and thalidomide, an oral anti-angiogenesis agent. Researchers at the National Cancer Institute and the FDA treated 60 men with this combination regimen. All men had metastatic disease. The median PSA was 99, with a PSA doubling time of 1.5 months. These men had widespread, rapidly growing cancers. The preliminary findings appear to be significantly better than single-agent Taxotere. See Figure 1. 90% of the men had a PSA decline of over 50%, and for 76% of the men, their PSA levels declined more than 75%. At the time the data was presented, the median overall survival had not been reached, but the progression-free survival was 19 months, which means the overall survival must be at least that long. The main downside to this combination therapy is its toxicity profile. This combination therapy has side effects not commonly seen with single agent Taxotere; included are severe infections, bleeding and blood clots. To accurately assess whether or not the likely clinical superiority outweighs the extra side effects, further studies are required.
Figure 1: PSA reduction (%) while on Taxotere, Avastin and Thalidomide
Provided to PCRI Insights Courtesy of Yang-min Ning NCI/NIH
Currently a large multinational Phase 3 trial comparing Taxotere to Taxotere plus Avastin is rapidly accruing patients. Other promising compounds that may enhance the clinical benefit of Taxotere are capecitabine (Xeloda), custirsen, sunitinib, and 5,6-dimethylxanthenone-4-acet i c acid (DMXAA).
Approaches When Taxotere Loses its Effects
Another clinical dilemma encountered by physicians and their patients is what to do when first-line Taxotere loses its effect. Few trials have been conducted in the second line setting6. Therefore, there are no standard approaches. Researchers have reported modest response rates with single agent mitoxantrone, cyclophosphamide, ixabepilone, and capecitabine. At Prostate Oncology Specialists, we have observed an encouraging response rate (40%) using the combination of carboplatin, paclitaxel, and estramustine. In some cases, this response has been very durable, lasting over 12 months. Also, PSA responses have been observed by simply adding Avastin or Xeloda to Taxotere, even when single-agent Taxotere fails. Finally, a non-chemotherapy compound, abiraterone has generated a great deal of interest as a second line agent for men who have progressed on Taxotere. In early Phase 1/2 studies, abiraterone resulted in fairly high PSA response rates of 50% or more. The multinational Phase 3 trial comparing abiraterone to placebo is rapidly accruing. Preliminary clinical results should be available in mid-2009.
Commonly Prescribed and Newer Novel Chemotherapy Regimens
Estramustine 140mg-280mg PO, three times daily
Cyclophosphamide 25-50mg PO, twice daily
Mitoxantrone 12mg/m2 IV, every 3 wks + Prednisone 5mg PO, twice daily
Docetaxel 60-75mg/m2 IV, every 3 wks + Prednisone 5mg PO, twice daily
Docetaxel 30mg/m2 IV, weekly x3, then 1 wk off + Thalidomide 200mg PO, daily
Docetaxel 75mg/m2 IV + Bevacizumab 15mg/kg IV every 3 wks + Thalidomide 200mg PO daily
Docetaxel 35mg/m2 IV weekly x3, then 1 wk off + Capecitabine 625mg/m2 PO on day 5-18
Carboplatin AUC 5 IV + Paclitaxel 175mg/m2 IV, every 3 weeks
IV=intravenous; PO=taken by mouth
As in other cancers where chemotherapy was initially approved in the metastatic setting but has subsequently been shown to be beneficial in earlier settings, chemotherapy, mainly Taxotere, is being evaluated in the non-metastatic setting. Patients who may benefit from chemotherapy are men with cancers that have high-risk features, such as a rapid PSA doubling time, a high baseline PSA, a high Gleason grade, and a high tumor volume. For these cases, Taxotere is being studied as part of a multimodality approach, where the drug is combined with surgery, radiation, and hormone therapy8. The goal with such an approach is to increase the cure rate for patients who have a high risk of relapsing. Another clinical setting where Taxotere is being studied is for patients who have relapsed rapidly after local therapy (surgery or radiation) and who may develop hormone resistance soon10. Usually, the goal of using chemotherapy in this setting is to prolong hormone-sensitive disease and possibly allow patients to be off salvage treatment for longer periods of time.
In summary, the role of chemotherapy is gaining acceptance for men with high risk or metastatic prostate cancer. Initially used as a palliative treatment for men who wanted to avoid narcotic medications, chemotherapy is now administered to prolong the duration and quality of life. As newer compounds and newer drug combinations become available, more clinical benefit will be seen. Furthermore, researchers are studying ways to incorporate chemotherapy in early-stage high-risk disease to improve clinical outcomes as well.
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