CTCs AND SURVIVAL IN METASTATIC PROSTATE CANCER

February 13, 2009 — Circulating tumor cell (CTC) count is a more powerful early predictor of survival than prostate-specific antigen (PSA), according to a retrospective study of metastatic prostate cancer patients undergoing chemotherapy.

Among 164 men with progressive castration-resistant metastatic disease, changes in CTC number 4, 8, and 12 weeks after chemotherapy were "strongly associated" with mortality risk, whereas changes in PSA were "weakly or not associated," note the authors, led by Howard Scher, MD, chief of the Genitourinary Oncology Service and D. Wayne Calloway Chair in urologic oncology at Memorial Sloan–Kettering Cancer Center, in New York City.

The new study, published online February 11 in Lancet Oncology, is a reanalysis of the IMMC38 clinical trial, which showed that 5 tumor cells or more per 7.5 mL of blood at baseline and after treatment predicted a worse overall survival.

"It's a very compelling result," said Joel B. Nelson, MD, who was not involved with the trial and is professor and chair of the Department of Urology at the University of Pittsburgh School of Medicine, in Pennsylvania. "Going forward, clinical trials will have to decide whether or not they will include CTCs as a measure of disease progression," he said in an interview with Medscape Oncology.

"We desperately need more tools to measure disease progression," he added.

However, Dr. Nelson also believes that the new study is not practice-changing and that "CTC still needs to be well-established as to when and how you use it."

To date, Dr. Nelson and his colleagues at the University of Pittsburgh have not used CTC counts clinically.

"We have not been clear about how beneficial it is. This [IMMC38 trial] is the first large multicenter study in which it has been shown to be helpful," he said, stressing that other studies have been small.

CTCs "still need to be validated as a biomarker" in prostate cancer in prospective clinical trials, said Dr. Nelson.

Dr. Scher agreed. "If CTCs were a drug, they would be in phase 2 of the clinical trial process. That means CTCs have given a strong signal [as a surrogate marker of survival], but it now needs confirmation," he said in an interview with Medscape Oncology.

Nevertheless, Dr. Scher said the new study accomplished the goal of showing that CTCs are prognostic of survival.

CTC Count: Cutoff vs Continuous

The original IMMC38 analysis evaluated survival with first-line docetaxel-based chemotherapy treatment in 2 groups of patients — those above and those below a CTC cutoff point (classified as favorable or unfavorable, respectively).

The reanalysis evaluated survival based on lab values at baseline and at 4, 8, and 12 weeks, with no regard to cutoff values.

In effect, the reanalysis emphasizes the importance of using CTCs as a continuous measure for monitoring patients instead of as a cutoff point. Treatment "should be continued as long as CTC counts are stable or decreasing and there are no other signs of worsening disease," suggest the authors.

As part of the original study, PSA and CTC numbers were measured at baseline and before each chemotherapy cycle until disease progression was noted. Other clinical variables, including lactate dehydrogenase (LDH), were also measured, but only at baseline. CTC counts were done with the CellSearch and CellTracks systems (Veridex LLC).

Of the 164 patients in the study, 103 had died by the time of this survival analysis. The median follow-up for the 61 patients still living was 21.6 months.

In the new analysis, the change in CTC count relative to baseline at 4, 8, and 12 weeks after treatment was a strong indicator of the risk for death, but the association between change in PSA titer and survival was weak, note the authors. For instance, at 12 weeks, the hazard ratio (HR) was 1.49 for CTC change (P < .0001) and 1.21 for PSA change (P = .0424).

The investigators also analyzed the association between individual biomarkers at baseline and the risk for death.

Variables associated with risk for death were high LDH concentration (HR, 6.44; 95% confidence interval [CI], 4.24–9.79), high CTC count (HR, 1.58; 95% CI, 1.41–1.77), and high PSA titer (HR, 1.26; 95% CI, 1.10–1.45), low albumin (HR, 0.10; 95% CI, 0.03–0.39), and low hemoglobin (HR, 0.72; 95% CI, 0.64–0.81) at baseline.

Although a high CTC count at baseline is associated with mortality risk, Dr. Scher and his colleagues note that "low CTC counts at baseline do not ensure favorable prognosis" for individual patients. "There is a large range of survival times for patients with low counts at baseline," said Dr. Scher.

When discussing the increased risk for death associated with high LDH at baseline, Dr. Scher said that the next study of CTCs measured with the Veridex technologies will include continuous measurement of LDH. Thus, the prognostic value of CTCs will be compared with that of LDH and PSA.

Practical Advice for Clinicians About CTCs

The study authors offered clinicians some advice about using CTCs with metastatic patients undergoing chemotherapy.

"CTC counts tend to drop very fast if chemotherapy is working," said Dr. Scher.

The authors also note that, when using CTCs, the measuring of PSA titers did not provide "additional predictive power." This finding "argues against the making of treatment decisions on changes in PSA titers alone when CTC counts are being monitored."

Finally, when monitoring CTCs, think of them as providing a continuous evaluation of clinical status and not as a tool that provides a cutoff point, suggest the authors. "Cut points have been overemphasized," said Dr. Scher.

Use of discrete cutoff values in clinical practice could lead to some inappropriate decisions, they say. Cutoff values suggest that "therapy should be discontinued in the patient with a posttreatment value that remains in the unfavorable range [5 cells or more per 7.5 mL blood], independent of whether or not the value has declined from the pretreatment baseline," write the authors.

Study data were provided by the study sponsor, Immunicon Corporation, for this analysis. Funding was provided by the Prostate Cancer Foundation (Santa Monica, California). The researchers have disclosed no relevant financial relationships.

Lancet Oncol. Published online before print February 11, 2009.