SAN FRANCISCO—A new analysis of the pivotal TAX-327 trial shows that compared with mitoxantrone, treatment with docetaxel results in improved quality of life in men with advanced, hormone-refractory prostate cancer—even if they only have minimal symptoms. And a second analysis of the same data suggests that pain relief is correlated with better survival.
In his presentation of the data here at the Prostate Cancer Symposium, a meeting cosponsored by ASCO, ASTRO, the Prostate Cancer Foundation, and the Society of Urologic Oncology, Dominik R. Berthold, MD, Clinical Research Fellow at Princess Margaret Hospital in Toronto, explained, “From the TAX-327 trial, we knew that docetaxel every three weeks is superior to mitoxantrone in terms of quality-of-life improvements. What we didn't know until now is that this is true even for patients with minimal symptoms prior to chemotherapy. These are also the first data to show a link between pain relief and longer survival.”
In the main TAX-327 trial, 1,006 men with metastatic hormone-refractory prostate cancer were randomly assigned to receive 12 mg/m2 of mitoxantrone every three weeks, 75 mg/m2 of docetaxel every three weeks, or 30 mg/m2 of docetaxel weekly for five of every six weeks. Additionally, all the patients received 5 mg of prednisone twice daily.
Docetaxel proved superior to mitoxantrone for all the endpoints studied, reported researchers led by Ian F. Tannock, MD (NEJM 2004;351:1502–1512). Median survival was 18.9 months in the group given docetaxel every three weeks, 17.4 months in the group given weekly docetaxel, and 16.5 months in the mitoxantrone group.
Forty-five percent of men taking docetaxel every three weeks had a prostate-specific antigen (PSA) response, compared with 48% on weekly docetaxel and 32% on mitoxantrone.
Additionally, 35% of patients who received docetaxel every three weeks had significant reductions in pain, compared with only 22% on mitoxantrone and 31% receiving weekly docetaxel. Finally, 23% had improvements in quality of life compared with 13% on mitoxantrone and 22% on weekly docetaxel.
For both the main trial and the new analyses, a PSA response was defined as at least a 50% decrease in serum PSA level. A pain response was defined as a two-point reduction on the five-point Present Pain Intensity (PPI) score without an increase in the daily dose of analgesics, or a 50% or greater reduction in daily analgesic use without an increase in PPI score, maintained for at least three weeks.
Again in all analyses, quality of life was assessed using the 156-point Functional Assessment of Cancer Therapy-Prostate (FACT-P) scale, in which higher scores indicate better quality of life. The test consists of 22 questions that measure physical, social, emotional, and functional well-being, and 17 items that address prostate-specific concerns.
An improvement in quality of life was defined as an increase in FACT-P score of at least 16 points that was confirmed at least three weeks later.
Docetaxel Improves Quality of Life
In the first new analysis, the researchers compared quality of life and its relation to pain in 278 men who received docetaxel every three weeks, 270 men who received weekly docetaxel, and 267 who received mitoxantrone.
Most patients had impaired quality of life at baseline regardless of whether they were in pain, as reflected by a PPI score of two points or higher, Dr. Berthold reported. Quality of life, as documented by a FACT-P score of 128 points or lower, was substantially impaired in 92% of patients with pain and 75% of patients who didn't have pain.
More importantly, docetaxel was associated with a greater improvement in quality of life than mitoxantrone was, Dr. Berthold said. Nearly one fourth of patients receiving either docetaxel every three weeks or weekly docetaxel experienced an improvement in quality of life, compared with 13% on mitoxantrone group.
Findings Hold for Men with Minimal Symptoms
The finding was consistent when the researchers looked only at the men with minimal symptoms, defined as a FACT-P score of less than 128 points or a PPI score of less than two points at baseline, he reported.
Specifically, 28.4% of the 157 patients with minimal symptoms taking docetaxel every three weeks had improved quality of life, compared with 17.3% of the 156 men with minimal symptoms on weekly docetaxel and 10.2% of the 157 men with minimal symptoms on mitoxantrone.
On the flip side, a similar number of patients taking docetaxel every three weeks and mitoxantrone experienced a deterioration of quality of life, defined as a 16-point decrease from baseline in FACT-P score. Quality of life worsened in 28.4% of patients on docetaxel every three weeks and 25% of those on mitoxantrone, a nonsignificant difference.
“The bottom line,” Dr. Berthold said, “is that we should be treating patients with minimal symptoms. This is very important.”
Pain Independently Predicts Survival
In the second analysis, the researchers explored the relationship between quality of life, pain reduction, PSA levels, and survival among men in the TAX-327 trial.
“The study showed that pain was an independent predictor of survival and that patients experiencing a reduction in pain during treatment can expect to live an average of six months longer compared with patients without pain reduction,” Dr. Berthold said. “This was a very significant result.”
Overall, men whose pain improved lived a median of 18.2 months versus 12.0 months for men whose pain did not improve. Among men taking docetaxel every three weeks, the median survival time was 21.1 months for those whose pain dissipated, compared with 12.7 months for those without a pain response.
The study also showed that men who experienced a decrease in their PSA level had significant reductions in pain and improvements in quality of life.
”The study showed that pain response is correlated with PSA response, and patients experiencing a reduction in PSA can expect a pain reduction and vice versa,” Dr. Berthold reported. Specifically, 52.4% of 124 patients who experienced a reduction in pain had a PSA response, compared with 28.3% of 290 patients who did not have a reduction in pain response.
Similarly, “quality of life response is correlated with PSA response, and patients experiencing a reduction in PSA can expect a improvement of their quality of life and versa,” he said. A PSA response occurred in 56.5% of 147 patients who showed improvement in quality of life, compared with 37.5% of 557 patients without a quality-of-life response.
After adjustment for PSA and quality-of-life response, men whose pain scores fell at least two points were 53% less likely to die than those whose pain did not dissipate, he said.
Quality-of-life response, on the other hand, was not associated with increased survival rates.
Dr. Berthold noted that the docetaxel regimen was associated with a higher risk of adverse events, such as anemia, neutropenia, and fatigue, than mitoxantrone was, but said that the improvement in survival, symptoms, and quality of life would likely outweigh the risks for most patients.
Asked for his opinion of the results, Durado Brooks, MD, Director of Prostate Cancer Control at the American Cancer Society, said that the findings open up interesting questions.
“It's the chicken-and-the-egg phenomena,” he said. “Does PSA response predict less pain or does less pain predict a PSA response?”
“Additionally, it's an interesting concept that being pain-free or having minimal pain somehow prolongs survival. Do people give up if they are in too much pain or is pain somehow a biologic marker for poor survival?”
From a more practical standpoint, the analyses cement the role of docetaxel in the treatment of men with advanced prostate cancer, Dr. Berthold said.