by Brad Guess, PA-C | Executive Director, PCRI | Edited from PCRI Insights May, 2006 vol. 9 no.2
I recently had the opportunity to sit in on a prostate cancer (PC) journal club meeting attended by PC experts from a multitude of medical specialties. The focus of this meeting was the use of chemotherapy in PC, specifically docetaxel(Taxotere®), a drug recently approved by the Food and Drug Administration (FDA) for metastatic hormone-refractory prostate cancer. One participant at the meeting, an eleven year advanced PC survivor, patient advocate and lay expert, raised an important and challenging question about the results of the two large phase III clinical trials that led the FDA to approve the drug.
“I speak to guys with advanced disease every day,” he said.“They read these studies, and they say to me, ‘You’ve gotta be kidding me; if I do chemotherapy I’m going to live 2 to 2 1/2 months longer. Why bother?’” In this article, I will attempt to answer this question, as well as discuss the use of docetaxel in earlier stages of PC, and introduce some novel drugs in clinical development for advanced PC, many of which are being combined with chemotherapy.
The First Chemotherapy Drug to Increase Survival in Metastatic Hormone-Refractory Prostate Cancer
Prior to the approval of docetaxel in May 2004, the only other FDA-approved chemotherapy for advanced PC was mitoxantrone. Even though mitoxantrone showed no evidence of a survival benefit in two large randomized phase III clinical trials (in 1996 and 1999), the FDA approved it because it demonstrated that approximately one-third of symptomatic patients experienced improvement in pain.1,2
Then in October 2004, the New England Journal of Medicine reported on two studies using docetaxel in advanced PC. The first was TAX 327, which randomized 1006 men to docetaxel plus prednisone or mitoxantrone plus prednisone. After completion of the study, the median survival of all patients treated with docetaxel was 18.2 months compared with 16.4 months for those treated with mitoxantrone.3 The second study was SWOG 9916, which randomized 770 men to docetaxel and estramustine compared with mitoxantrone and prednisone. In this study, overall survival favored docetaxel (18.9 months compared with 16 months for mitoxantrone).4
Mark Twain’s (sometimes attributed to Disraeli) famous quip about the practice of lying, identified three types, each worse than the one before – lies, damned lies, and statistics. “Survival analysis” with the production of “survival curves” (see Figure 1) is the most common statistical method used to determine the effectiveness of a new drug in cancer patients, for the purposes of FDA approval.
This type of analysis compares the “median survival” of one group of patients treated with a new drug or treatment to the median survival of those patients who were treated with a conventional drug (or placebo if no conventional drug exists). Median survival (see Figure 2) is the time at which half of the patients have died, or to say more optimistically, the time at which the percentage surviving is 50%.
In the two previously mentioned docetaxel studies, it was an increase in the median survival of men treated with docetaxel compared to the conventional drug mitoxantrone that led to FDA approval. Considering that docetaxel compared to mitoxantrone (a treatment which offered no improvement in survival) increased median survival by only 2 to 2 1/2 months, it is no surprise that many medical practitioners and informed patients ask the question “Why bother for 2 to 2 1/2 more months?” However, this conclusion should be avoided, since survival analysis is very easily misinterpreted, often in the direction of underestimating hope.
Several points should be made about the survival analysis in these studies. First, both studies crossed over (to docetaxel) men who initially received mitoxantrone and did not respond. In other words, some men who were treated with mitoxantrone eventually received docetaxel (the better treatment), but only after a considerable delay. This cross over skewed the differences in survival between the two treatment groups by improving the survival of some of the mitoxantrone treated men.
Second, survival analysis that is done by comparing median survival of two groups obscures an improvement in survival when less than half the men treated have their lives prolonged. This is because such analysis includes all patients, not only those who respond, but also those that do not respond. Additionally, the survival of any one individual may be much longer (in some cases several years) than that of the median of the study population.
The third point to consider is that median survival analysis says little about patients on the right side of the survival curve (the men who respond to treatment, despite a poor prognosis). In a study of the data of 217,573 patients with breast, colorectal, lung, and prostate cancer, Kato et al analyzed conditional median survival.5 Conditional median survival can be defined as a survival rate conditioned on having survived x years (for example, a 5-year rate for individuals having already survived 2.5-years). To say it another way, the prognosis of people with common cancers who had metastatic disease at the time of their initial diagnosis changed as a result of their continued survival.
The existence of a small group of survivors far past the “median” point, even in cancers with a dire prognosis such as advanced PC, should provide real hope even when the prognosis is bleak.
Lastly, and on a more practical note, when men who are not a part of a clinical trial are treated with chemotherapy and are not responding, their treatment is quickly changed, and they go on to other potentially beneficial treatments, which may also have the potential to extend life. These facts are not taken into consideration in survival analyses. (For a much more comprehensive and articulate handling of the statistics of survival and other related topics, see Steve Dunn’s excellent Web site www.cancerguide.org.)
A Closer Look at the Benefits of Docetaxel for Men with Advanced Prostate Cancer
In addition to survival, two other important benefits (which should not be overlooked) were seen in men treated with docetaxel. The first benefit was that pain was reduced more frequently among men receiving docetaxel compared to those treated with mitoxantrone. Anyone who has experienced or taken care of a man with bone pain from advanced PC understands the significance of this benefit. The second benefit seen with the use of docetaxel compared to mitoxantrone in men with advanced PC, was an improvement in quality of life. The greatest benefit in the docetaxel group with regard to quality of life was in the area of weight loss, appetite, pain, physical comfort, and bowel and genitourinary function. It is well known that if untreated, advancing PC will ruin the quality of life of a man, often for many months or even years, before he succumbs.
What About Chemotherapy in Earlier Stages of PC?
With the benefit of a docetaxel-based therapy in advanced PC now well established, its potential role in earlier-stage PC becomes a much more important question. There are several groups of earlier-stage PC patients to be considered. The first group is men who have been newly diagnosed with “high-risk” PC. Generally speaking, high-risk PC is defined as having a PSA > 20 or a Gleason score of 8 or higher or a Clinical Stage of T3 or higher determined by a digital rectal exam (tumor is already extending outside of the prostate gland). Men with high-risk PC have a high chance (usually > 50%) of disease recurrence even after definitive local therapy such as surgery, radiation or cryotherapy. The primary reason for this is the presence of microscopic disease outside the prostate and beyond the reach of the local prostate treatment. Clinicians and patients are now better able to identify those men at high risk through the use of nomograms (see Dr.Glenn Tisman’s article “Using Nomograms to Predict PC Treatment Outcomes” in PCRI Insights Nov 2005 Vol. 8, No. 4).
The use of chemotherapy in high-risk patients takes place in a “neoadjuvant” or “adjuvant” setting. (Neoadjuvant chemotherapy is the use of chemotherapy prior to any other treatment such as surgery or radiation. Adjuvant chemotherapy takes place at the same time as one or multiple other therapies.) Recently, pre-clinical data evaluating the optimal timing and combination of chemotherapy and hormone blockade supports the use of simultaneous therapy.6
Numerous small phase II trials using neoadjuvant and adjuvant chemotherapy in men with high-risk PC have been performed, with encouraging results.7 A small but interesting trial, and one which makes an argument for early chemotherapy in high-risk men, was performed by Wang et al.8 They randomly assigned 96 men with high-risk PC or advanced metastatic PC to mitoxantrone plus combined hormone blockade (CHB) versus CHB alone. In the 38 patients without metastatic disease treated with mitoxantrone and CHB, the median survival was significantly better (80 months compared to 36 months for patients treated with CHB alone). In contrast, no survival advantage was seen with the combination of mitoxantrone and CHB in men with metastatic disease. Several large randomized phase III clinical trials are ongoing or are planned and should give us better answers to the question of whether adding chemotherapy to the treatment of men with high-risk PC is effective.
The second study in which men are being treated with early chemotherapy focuses on men with a rising PSA after local therapy (commonly called a “PSA relapse”), especially men with a fast PSA doubling time (< 6 months), and risk of shortened survival.9 Hussain et al studied 39 men (7 with clinical metastasis and 32 without) with a rising PSA of > 4 ng/mL after surgery or radiation, treated with docetaxel followed by CHB for 12-20 months. The most interesting finding in the study was that five of the men treated with the combination maintained a low and stable PSA at 0.1ng/mL for a median of 18.9 months after therapy. Three of these five men had soft tissue metastasis at entry but remained in a complete remission.
A third group consists of men with hormone-refractory prostate cancer (HRPC). HRPC is commonly defined as a rising PSA despite castrate (= 20 ng/dL) levels of testosterone, but no visible cancer outside the prostate, such as in the bones or lymph nodes. Men who develop HRPC have a high likelihood of developing visible metastatic disease (in approximately nine months, according to one analysis11), especially if they do not achieve a PSA nadir of less than 0.05 ng/mL anytime after the initiation of CHB.12 The argument that chemotherapy should be utilized as soon as HRPC is diagnosed is suggested by experience and proven benefits reported in other solid tumors such as breast and colorectal cancer, where adjuvant chemotherapy is considered standard.13
Combining Chemotherapy with Novel Agents in Advanced Prostate Cancer
An important consideration when deciding on treatment for metastatic HRPC is the heterogeneity of the disease. Heterogeneity in advanced PC simply means that there are several or multiple forms or clones of PC cells existing within one patient. Therefore, the combination of chemotherapy with a novel or innovative agent takes advantage of our evolving understanding of advanced PC biology.
Table 1 contains a list of novel agents being studied individually or in combination with docetaxel in advanced PC. One of the more exciting of these novel agents for advanced PC is bevacizumab (Avastin®) which has already been approved by the FDA for kidney cancer. Bevacizumab is an antivascular endothelial growth factor (VEGF) antibody, and works by inhibiting the blood supply to tumors (antiangiogensis). In a phase II study of 79 men with advanced PC, the combination of docetaxel, estramustine and bevacizumab resulted in a PSA decline in 81% of patients, a median time to disease progression of 9.7 months, and an overall median survival of 21 months.14
Another antiangiogenic agent, thalidomide, has been evaluated in phase II studies both alone and in combination with docetaxel in men with advanced PC.15 When thalidomide was combined with docetaxel, the response rates were better than with docetaxel alone, and survival was improved. Recently, the use of the triple combination of docetaxel, thalidomide and bevacizumab in advanced PC was reported.16 Early results of this phase II trial of 60 patients show PSA response rates of 86% and significant improvement in measurable disease in many of the patients.
Another novel agent, DN-101, a high dose form of calcitriol, which is a biologically active form of vitamin D, has shown encouraging results when combined with docetaxel in advanced PC. Beer et al recently reported early results from the AIPC Study of Calcitriol Enhancing Taxotere (ASCENT).17 These results suggest an improved survival advantage with the combination versus docetaxel alone; however analysis is ongoing and larger studies are planned for the future. Interestingly, the addition of DN-101 appears to protect against side effects of chemotherapy, such as a loss of energy, gastrointestinal and thromboembolic events. (A full discussion of the side effects of chemotherapy will be presented in an article in an upcoming issue of Insights.)
Radiopharmaceutical agents, namely strontium-89 and samarium-159 have been shown to relieve bone pain in men with metastatic PC.18,19 (This was described in Oliver Sartor’s article, “Newer Concepts in the Treatment of HRPC with Bone Metastases” in PCRI Insights May 2005 Vol. 8, No. 2.) It is thought that by releasing short-range radiation, these agents may kill PC cells in bone, leading to relief of pain. Data from a small phase I study combining samarium and docetaxel has shown impressive results with a decrease in PSA of > 80% in 4 of 6 patients.20 Further studies are ongoing.
With the benefit of docetaxel-based therapy in advanced PC now well established, more men are likely to be offered chemotherapy in advanced disease. The conclusion that the only benefit one can expect is 2 to 2 1/2 months increased median survival is deceptive. This small time period is a watered-down average that includes all the men who did not respond as well as men who were treated with mitoxantrone but subsequently were treated with docetaxel. Other benefits received by chemotherapy in this group of men, such as a reduction in pain and general overall improved quality of life, also need to be pointed out. In all likelihood the use of neoadjuvant or adjuvant chemotherapy in high-risk, PSA relapse and HRPC patients is going to be utilized with increased frequency. Lastly, the combination of docetaxel with novel cancer agents is a logical extension, and exciting responses are occurring that in the past would have never been thought possible.
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