Metastatic prostate cancer survival has not improved over time

Maha Hussain, MD, FACP

The last 2 to 3 decades have witnessed an unprecedented change in the overall profile and management of prostate cancer. This was driven in great part by the introduction of PSA into the clinic and the investments in research that contributed to transforming the management of end-stage disease: metastatic, castration-resistant prostate cancer (mCRPC).  

Irrespective of how one views the role of PSA, there is no question that it has led to a significant stage migration, and in a disease that has no cure if it presented with metastatic disease or developed subsequent metastasis, the impact on reducing mortality is very much likely tied to treating a more favorable stage at diagnosis.

In 2004, a barrier was demolished with the demonstration that mCRPC survival can be improved leading to the FDA approval of docetaxel. The expanding list of agents capable of prolonging survival is huge progress since 2004; however, it should be noted that the collective improvement in survival with these agents is modest and mCRPC is still fatal virtually in all patients.

The observations by Wu and colleagues clearly reflect that. Therefore, it is really critical that the totality of the PSA effect is carefully evaluated by the clinical and scientific community. 

It was in the 1940s that the effect of castration was reported and gonadal suppression — or androgen deprivation (AD) — became the standard therapy for metastatic prostate cancer. However, during the past 70 years, the progress in the treatment of this disease setting has been mostly based on introduction of different modalities of delivering AD. Aside from cooperative group trials, there has been little investment in evaluating new agents targeting important biologic pathways in this disease setting in the last 20 years.

Clearly, the paradigms of drug approval is one contributing factor. The need for large trials to assess survival outcome and all that is involved in conducting such trials — in addition to the duration of follow-up needed, considering that the contemporary median survival in this disease setting is about 4 years — are other factors.

However, the recent press release by the NCI about the results of ECOG-E3805 with regard to the survival improvement with combination AD plus docetaxel clearly opens the door for advancing active agents to this disease setting, where larger survival benefits may be more possible.

Derek Raghavan, MD, PhD FACP, FRACP

This study comes from the excellent team of Ralph W. deVere White, MD, and it is very interesting indeed. Their data suggest that the hype concerning "vastly improved survival in prostate cancer" may not be accurate. That fits very much with my own view that the absolute numbers of deaths from prostate cancer in the United States each year — as listed by the American Cancer Society — have not greatly changed in several decades, and that the impact of PSA screening remains questionable in the community at large (Raghavan D. Mayo Clin Proc. 2013;88:1-3.)

However, it really isn’t quite as simple as that. The problem with high-level statistical analyses of registry data is that they lose important detail. For example, it is well known that the population in California is quite migratory, and there is a significant population of visitors from other lands who seek their medical care there and can complicate the evaluation of registry data, particularly with regard to long-term follow up and mortality/survival information. The social demography of non-visitor Californian populations is also changing, and who knows how this will impact survival and outcome data?

There is an epidemic of prostate cancer in Asians in urban societies, and the impact of this change has not yet been defined, notwithstanding the data from Wu et al that suggest that their outcomes may be better. Further, the denominator of cases has been a moving target — histological classification has changed in recent times, and the number of low-risk reservoir cases (identified by PSA) has simply swelled the bottom line in all statistical calculations.

Finally, this study covers the period from 1988-2009, and I’d just like to remind everyone that 20 years is not very long to define epidemiologic or outcome changes in a disease that is heterogeneous, with a long and variable natural history, and a rapidly changing population.

I am still reminded that there is precious little evidence to support screening in asymptomatic Caucasian men with no family history, and we really don’t know what the policy should be for blacks and men with a positive family history of prostate cancer with bad outcomes. Until there is more evidence, I encourage the latter two groups to be closely involved with their urologists.