Clinical Laboratory Strategies: March 11, 2010

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Predicting Post-Treatment Prostate Cancer Outcomes
PSA Nadir at 2-Year Landmark Proposed
By Genna Rollins

Several studies have associated post-treatment prostate-specific antigen (PSA) nadir with prostate cancer outcomes. However, most of these analyses have evaluated absolute PSA nadir, which poses statistical challenges since PSA nadir is a time-dependent variable. Now, new research described in this issue of Strategies explores the use of a PSA nadir cutpoint achieved within a specific time frame as a predictor of long-term cancer mortality after radiotherapy.

Prostate-specific antigen (PSA) levels are a key element in following prostate cancer patients after surgery and radiotherapy. When these treatments are successful, PSA levels gradually decline within months or years afterwards, albeit with fluctuations, suggesting a lower risk of distant and micrometastasis and higher survival odds. Several studies have looked at absolute PSA nadir as a predictor of outcomes, but since this parameter is a time-dependent variable, these analyses may have had statistical limitations. New research by investigators at Memorial Sloan-Kettering Cancer Center evaluated a PSA nadir ≤1.5 ng/mL at a 2-year landmark in predicting long-term prostate cancer mortality after radiotherapy (Int J Radiation Oncology Biol Phys 2009; 75:1350-56).

“We recognize that PSA values are in dynamic motion after treatment, especially after radiation as compared to surgery. PSA levels typically drop over a period of several years and gradually plateau. But there also is what we call PSA fluctuation or PSA bounce, where, after radiation, PSA levels go up and down, which obviously present a concern for the patient,” said lead author, Michael Zelefsky, MD, a radiation oncologist and chief of Memorial Sloan-Kettering’s Brachytherapy Service. “With this study, we wanted to look at a particular, early time after treatment at which point we could say the PSA should be at a certain level. If the PSA level did not nadir within that timeframe, then would it predict for a subsequent clinical outcome for the patient?”

Several studies have used absolute PSA nadir as a predictor of outcomes. However, since PSA nadir is a time-dependent variable, these studies had some statistical limitations, according to Zelefsky. “We don’t feel that the absolute PSA nadir is sufficient information. Based on statistical principles, it may be flawed to conduct studies associating PSA nadir with survival outcomes unless you have a fixed landmark time point.”

Zelefsky and his colleagues followed 844 prostate cancer patients at 3-6 month intervals for a median of 9.1 years after the patients had been treated with either three-dimensional conformal- or intensity-modulated radiotherapy. The investigators analyzed time distributions to three events, including PSA relapse, distant metastasis, and death due to prostate cancer. Variables in the analysis included patient age, tumor staging score, Gleason score, radiotherapy dose, pre-radiotherapy PSA level, and PSA nadir value. Multivariate analysis demonstrated that nadir PSA ≤1.5 ng/mL at the 2-year post-treatment landmark was an independent predictor for progression-free survival. In addition, 5 and 10-year cumulative incidences of distant metastasis were lower in patients who achieved this nadir landmark than in those with higher values at the same point in time. Cause-specific mortality rates also were lower in patients with the 2-year ≤1.5 ng/mL PSA nadir compared with those who had higher PSA nadirs at 2 years, while higher nadir PSA levels at the 2-year point remained an independent risk factor for prostate cancer-related death.

The researchers assessed numerous time points to arrive at the 2-year landmark. “Our statistician carefully analyzed and the data demonstrated which time point would be the most revealing and predictive,” noted Zelefsky. “If you take too early of a time point, then most patients haven’t dropped to their nadir levels and you wouldn’t have a valuable predictive tool. By the same token, if you waited five years, most patients would have already nadired and that time point also would not be as predictive.”

The study provides important insight into the use of PSA levels as a tool for assessing the success or failure of prostate cancer treatment, according to Eric M. Horwitz, MD, professor and Gerald E. Hanks, MD chair of radiation oncology at Fox Chase Cancer Center in Philadelphia, who was not involved in the research. “With almost 900 patients and long-term follow-up, that is what I think is so key. It makes us much more confident and comfortable in saying that this point in time means something.” However, Horwitz warned about applying these results to individual patients. “I caution both my patients and other doctors that when we look at a study like this with a landmark analysis and two-year end point, it’s for looking at populations. When you have a patient sitting right in front of you and their PSA nadir ends up being at three years, they could get upset and start worrying.”

In Zelefsky’s view, the data point to a subset of patients potentially at risk who should be followed more closely in the future. “This type of information at early time points in the post-treatment setting could be valuable in terms of optimizing our management and follow-up of treated patients,” he explained. “The kinetics of the PSA may be a kind of surrogate for us to potentially explore whether there is residual or micrometastatic disease. We’re now recognizing in the treatment of prostate cancer that earlier salvage interventions for those who have recurrent disease may benefit the patient in the long run. Letting residual disease fester for a long time after treatment may lead to a higher likelihood of subsequent distant metastasis.”

Zelefsky cautioned that more research would be needed to understand the prostate cancer pathophysiology in patients who do not achieve a PSA nadir ≤1.5 ng/mL at the 2-year mark. “Is a suboptimal nadir level a reflection of residual disease, micrometastatic disease, or a combination of both? The PSA level is not that discerning for us as to where the residual disease is. So when we have these suboptimal nadir levels at two years, we still remain unclear as to where the disease is located,” he explained.

The study also reflects the ongoing evolution in thought about the role of post-treatment PSA levels, said Horwitz. “Since PSA entered clinical practice, we’ve learned a lot and fine-tuned how we use it. Several things we looked at early-on, we’ve now come full-circle and are looking at again. This is one of those issues,” he observed. “This study confirms that PSA is a useful tool in assessing outcomes. It’s not just an esoteric biochemical measurement.”

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