ASCO commentary and update no. 2

In this commentary we will discuss four additional, significant papers presented yesterday in the major oral session on new prostate cancer studies.

Stephenson et al. (abstract no. 5007) have used data from several institutions to develop a prognostic nomogram for risk for prostate cancer specific mortality within 15 years among men who undergo radical prostatectomy for localized disease. The nomogram appears to be of very high accuracy and risk for prostate cancer-specific mortality appears to be very low for men with organ-confined disease and Gleason score < 8. In this retrospective study they were able to show that only 1/3,756 patients with a pathological stage of Gleason 6 disease died of prostate cancer after radical prostatectomy out of the 11, 521 patients treated at four academic centers between 1985 and 2005.

The problem with this study, however, is that it does not help a man to know whether to undergo surgery or not. It is valauble to be able to understand your potential survival benefit if you have surgery and if you have certain specific clinical and pathological characteristics post-surgery, but it would be so much more helpful to be able to predict these outcomes with the same level of accuracy before deciding to undergo surgery! As just one example of the problem, we know that some 25-35 percent of patients with a biopsy-based Gleason score of 7 are shown to have a higher Gleason score after surgery.

Antonarakis et al. (abstact no, 5008) presented data from the 25-year follow-up of Walsh’s series of patients at Johns’s Hopkins. They were able to identify 443 patients in this series who received a radical prostatectomy, who had biochemical recurrence, but who never received any further treatment until the onset of metastatic disease. Based on data from these patients, they were able to show the critical importance of very short (< 3 months) and very long (≥ 15 months) PSA doubling times as predictors of long-term outcome post-surgery.

Men with a post-recurrence PSA doubling time of < 3 months had a median time to metastasis of only 1-2 years and therefore very clearly need early initiation of second-line treatment. By comparison, men with a post-recurrence PSA doubling time of ≥ 15 months had a median time to metastasis of 15 years (with a range of 12 to 20 years). Many such men could clearly avoid further therapy altogether with minimal risk of metastasis and a high probability of death that was in no way related to their prostate cancer. In this study, it was the PSA doubling time that appeared to have the greatest impact on long-term survival, but Gleason score > 7 and time from surgerty to recurrence was also influential.

Lu-Yao et al. (abstract no. 5010) presented a complementary paper in which they analysed outcomes among 14,516 men > 65 years of age (identified from the Medicare SEER database) who were diagnosed and initially treated with conservative management between 1992 and 2002 — i.e., during the PSA era. Based on these data, the authors showed that 10-year prostate cancer-specific mortality among these patients, if they had highly or moderately differentiated T1 or T2 disease at the time of diagnosis, was ≤ 6 percent. Only in men with T1 or T2 disease and highly differentiated prostate cancer did the risk of prostate cancer-specific mortality rise significantly (to 42 percent in men aged 65-69 years at diagnosis and to 26 percent in men aged 70-74 years at diagnosis).

Yu-Lao and her colleagues noted that these survival data are all significantly higher than the historic data from the pre-PSA era published originally by Johansson et al. (in 1992), Chodak et al. (in 1994), by Yu-Lao et al. (in 1997), and by Albertsen et al. (most recently in 2005). To what extent these data substantiate the value of PSA screening in reduction of risk of prostate cancer-specific mortality will undoubtedly be much argued.

The final paper presented in this session was by Glode et al. (abstract no. 5009), and provided the first but only partial results of the SWOG 9921 trial, initiated some 10 years ago. This trial randomized 859 men with high risk prostate cancer, after prostatectomy, to either 2 years of complete androgen deprivation (with gosereline acetate + bicalutamide) or to 2 years of cATD combined with mitoxantrone + prednisone chemotherapy. Dr. Glode joked that the data monitoring committee for this trial had decided to allow the investigators to publish these partial data because of the increasing risk of mortality among the investiagators themeselves!

The most important data from this study to date is the extremely low mortality rate overall. Only 17 patients have died to date, and only 7 have died of prostate cancer. The 5-year estimate of bichemical recurrence-free survival among the 426 men randomized to the hormone-only arm of this trial is 92.9 percent, and the 5-year estimate of overall survival is 95.9 percent. Only the 69 patients known to have positive lymph nodes at the time of surgery and treated with hormone therapy alone had 5-year estimated biochemical recurrence-free survival and estimated overall survival of less than 90 percent (at 88.8 and 88.3 respectively).

The secondary data from this trial are the data around time to recovery of testosterone levels to the lower limit of normal (≥ 50 ntg/ml). The median time to recovery of such testosterone levels among the 397 men on whom data was available in both arms of the trial was 11.7 months. The percentages of men with recovery of this level of testosterone at 6 and at 18 months were 16 and 89 percent respectively.

These data certainly appear to suggest that 2 years of cADT is a viable form of adjuvant treatment for men at high risk post-surgery who do not have positive lymph nodes. Whether it is better than radiotherapy or radiotherapy + cADT is obvioulsy unknown, and the trial will probably need to be followed-up for another 7-10 years before we will know whether there was any additional benefit to the addition of the mitoxantrone + prednisone to cADT.

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