- What’s the Biology of the disease?
Consider this, a patient can arrive at having metastatic prostate cancer through one of two paths. One is after experiencing a rising PSA after radical prostatectomy or radiation therapy and eventually developing metastases. The other is when metastases are discovered at the time of initial diagnosis, without any prior treatment for the disease. If this is recurrent disease and the patient has already had local therapy, it is possible this could be slower moving than if it is a brand-new diagnosis. You would think that this would be an easy thing to know but some methodological challenges make this a tough call.
If it is newly diagnosed, we don’t really have an idea if this is a slow-growing disease that has been in there a long time or whether it is a newly formed rapid process. We have been analyzing some data along these lines and I first published on this over ten years ago. In that paper, we found that the tumors that initially presented as metastatic disease are more likely to be of a higher Gleason grade. This suggests that when a patient presents with de novo metastatic disease the disease biology may be such that the tumor formed and spread to radiographically evident metastatic sites early. The patient with a relapse after surgery who develops radiographically evident metastases actually had non- radiographically evident metastases all along, they were just slow growing and took a while to show up on scans.
Bear this in mind when reviewing clinical trial data. The CHAARTED study, for example, included both patients with de novo metastatic disease and those who had previously undergone local therapy ( about 70% had no prior therapy, 10% radiation, 20% prostatectomy) whereas in the LATITUDE study ALL patients had de novo metastatic disease and were ineligible for the study if they had undergone prior radiation or prostatectomy. In light of the fact that the survival curves are almost identical, it may be a hint that perhaps ADT plus Abi is a bit better than ADT plus docetaxel, but we really don’t know that for sure.
But if we are really going to talk about the biology of the disease we need to determine what are the molecular differences in terms of the key drivers of aggressive prostate cancer and how common, or uncommon, they are in the recurrent vs de novo metastatic patients. What are the proportions in each with aberrations in p53, Rb, TMPRSS-Erg, BRCA2, MSH2 etc? All of these are currently being studied. So, one day we’ll know. For now, however, it may be worth gathering the data by sending biopsy material for next-generation sequencing. Gather the data.
- What can we learn from the Relatives?
The key point is to take a family history. If there is a strong history of prostate, ovarian, pancreatic or breast cancer, consider germline genetic testing and, perhaps more importantly, bring genetics counselors onto the case.
And while we’re at it, we also might want to think more deeply about the NON-cancer family history. Is cardiovascular disease a big risk? Lipids? Stroke? etc. knowing all this may be beneficial in counseling the patient about his general health while on ADT.
- What is the Extent of disease?
But the other layer of complexity that is emerging rides on the hope that we may be able to cure a small number of individuals who harbor oligometastatic disease. This new hope, which has yet to be proven, rides on the development of two new technologies – better imaging and better pinpoint radiation. The new imaging, PSMA and Axumin PET, are the results of molecular tracers that can highlight specifically where prostate cancer metastases.
The ‘new’ radiation is stereotactic body radiotherapy (SBRT), which allows more directed radiation to be delivered with the advantage of not having to create a ‘field’ and thus, it is hoped, the treatment can be focused on the metastases, and not on the normal tissues.
This is not available everywhere and, most importantly, is not a proven therapy. Those of us who design clinical trials for a living understand that to prove that radiation of oligometastatic disease would take many years and require a control arm. As a result, this may be one of those rare technologies that get adopted for use without an adequate ‘put up or shut up’ phase III trial. Since many men with oligometastatic disease will live a decade or more, designing and completing a clinical trial in this space will take upwards of 15 years. Some have been proposed, and it is being discussed, but there is nothing that I know of in the pipeline yet.
- Should the patient be treated with Abiraterone?
Abiraterone has the advantage of being orally available and having a more agreeable safety profile than its counterpart docetaxel (I use the tradename “Taxotere” below, for the purposes of acronym integrity).
When treating a patient in the hormone-sensitive metastatic setting it is reasonable to ask if the abiraterone needs to be continued indefinitely or whether the benefit is in the early phases of the treatment only. I have written about this elsewhere on UroToday.com.
Personally, I tell patients we will make these decisions on a year by year basis. If a patient is treated with ADT plus Abiraterone and, a year later, has a PSA of zero, there is a reasonable chance he will respond for the next year, and the next. It’s at this time that the potential for toxicity with hypertension and potassium abnormalities may become a worry. So, I think its reasonable to consider decreasing the dose or even stopping it altogether in the exceptional responders. If the psa blips up, we could restart. We don’t really know what to do in these circumstances. Treatment with Abiraterone as per Latitude can be a long-term process, allowing for reasonable discussion of whether docetaxel is a reasonable first choice.
- Should the patient be treated with Taxotere?
The case to give patient Taxotere is simple: Improved survival comes with only 6 doses of a generic and reasonably well tolerated therapy. After the sixth cycle, the patient can remain on ADT alone without worry of monitoring, toxicity or cost of abiraterone.
So, the pendulum may swing back for some clinicians and patients. Recognizing the short duration, long benefit and low cost of docetaxel, it may be a better choice.
- Don’t forget General Health!
I try to emphasize this fact when sitting down with a newly diagnosed patient:
If they don’t exercise, they should start.
If they already do, they should continue
Resistance work with weights is important to maintain muscle mass and stimulate metabolism
Working ‘against gravity’ is also important to maintain bone strength.
Check lipids, follow blood pressure, do a baseline bone density scan. If the patient doesn’t already have a primary care doctor, they should get one. Many patients with metastatic prostate cancer will die of other causes. The treatment for the prostate cancer may increase the risk of cardiovascular disease and thus, we must be mindful of it.
Written by: Charles J. Ryan, MD