My post to this blog that was written yesterday indicated that for certain men the early use of chemotherapy (docetaxil) could provide significant life extending benefits, especially for men with very advanced prostate cancer. For the purpose of clarification, in this case early use means in men who are still hormone responsive.
Given that chemotherapy is only approved for men who were no longer hormone responsive, or castrate resistant, this could be a game changer for the treatment of men with metastatic prostate cancer. I indicated that this could open up a whole new potential world of rescheduling treatments, new protocols as well as the possibility of combining treatments with chemotherpy.
As I think about this I come to the conclusion that besides doing good research and seeing which combinations could work to extend survival, we need to remain aware that some drugs, particularly toxic chemotherapy drugs like docetaxil should not be combined with other drugs.
This concern is driven home because there has been prior research that shows that docetaxel (Taxotere) is amplified when used with CYP17 inhibitors like ketoconazole and Zytiga.
A clinical study of docetaxel multi-dosed at 100 mg/m(2) and 200 mg ketoconazole result in a 100% increase docetaxel activity and an increased incidence of febrile neutropenia. In another study, concomitant ketoconazole increased docetaxel exposure 160% with 1,200 mg daily, 60% with 800 mg daily and approximately 30% to 50% with 600 mg daily.
A trial using weekly docetaxel and ketoconazole resulted in increased docetaxel exposure by 160% with 1,200 mg daily, 60% with 800 mg daily and approximately 30%-50% with 600 mg daily.
Docetaxil is a toxic drug, it is designed to kill cells and it does not discriminate between normal, healthy cells and cancer cells. Amplifying its effects will cause severe side effects and possible kill the individual. Granted, killing the su
Trials evaluating the early use of chemotherapy with other existing approved drugs will need to be done with very careful and specific management. This management will include reduce dosing and closely monitor subjects.
Actually, the product insert in docetaxil recommends a 50% decrease in dosing when used in combination with ketoconazole. It also recommends avoiding combinations with all CYP3A4 potent inhibitors like Zytiga.
So, as I said yesterday the use of early docetaxel opens up the potential for a new protocols for treatment of men who are still hormone responsive, however any such trials must proceed with careful thought and consideration. Amplified dosages of docetaxil will kill the cancer, but it will also kill the man. Idon’t believe that this is consistent with our overall goals.
Joel T Nowak, M.A., M.S.W.
When I was first diagnosed with metastatic prostate cancer one of the first questions that I asked my doctor was whether it made sense for me to start chemotherapy immediately. I very clearly remember him telling me that there was absolutely no evidence that starting chemotherapy at this early stage would do anything to extend my life. I went along with him, but I do admit that I was cynical.
Having now survived many years and spending these years learning about this disease I do have to admit that he was right. I have learned that what seems logical might not be actually what is real. Evidence is the best guide.
Today, it was released that hormone therapy along with docetaxel (chemotherapy) might improves overall survival in prostate cancer. Preliminary results from an NIH-supported clinical trial showed that some men with hormone-sensitive metastatic prostate cancer who received docetaxel at the start of standard hormone therapy lived longer than men who received hormone therapy alone.
The study known as E3805 was a randomized controlled clinical trial that enrolled 790 men with metastatic prostate cancer between July 2006 and November 2012. All men received initial ADT, either ADT alone or ADT with docetaxel every 3 weeks for 18 weeks.
Early results showed a significant improvement in the overall survival for men who received ADT plus docetaxel compared to ADT alone (3-year survival rates of 69.0% vs. 52.5%, respectively).
However, there is an important caveat as the majority of benefit was limited to men receiving both ADT and chemotherapy who had significant metastasis (3-year survival rates of 63.4% vs. 43.9%, respectively). As the result the investigators noted that the use of chemotherapy in combination with ADT should be limited to men with high-extent (multiple metastases) metastatic prostate cancer.
There are plans for further follow-up on patients with less extensive metastasis who participated in E3805 in order to define the effect of this treatment combination.
These results are significant as they will be practice changing. Clinicians will now have to consider giving chemotherapy much earlier in men with significant disease. Where they are going to get tripped up is in deciding if prior to administering chemotherapy with all its toxic effects should Provenge, Zytiga or Xtandi be used?
Joel T Nowak, M.A., M.S.W.
Men initially diagnosed with advanced prostate cancer often face a serious question, whether traditional primary treatments that would remove or make smaller their primary tumor (“debulking” the tumor) provide any advantage or extend their survival. Since the most commonly used method to debulk tumors is surgery or radiation the question becomes if the risks of these treatments still provide a man with a statistical advantage over skipping primary treatments.
In a paper by Culp et al. in European Urology there was some preliminary data to suggest that the debulking of the primary tumor may offer a positive long-term survival benefit in at least some men with metastatic disease at time of diagnosis.
Culp et al. used Surveillance Epidemiology and End Results (SEER) data for the period 2004 to 2010 for patients initially diagnosed with TxNxM1a–c disease (Stage IV). Culp divided the men into three study groups:
1- Men who received a radical prostatectomy with or without adjuvant external beam radiation therapy (the RP group)
2- Men who received brachytherapy with or without adjuvant external beam radiation therapy (the BT group)
3- Men who received no form of surgery or radiation therapy at all (the NSR group)
The study analyzed a large cohort of 8,185 men of who were separated into groups composed of:
1- 245 men were in the RP group.
2- 129 men were in the BT group.
3- 7,811 men were in the NSR group.
With an average (median) follow-up of 16 months they found that:
1- 3,115/8,185 patients (38.1 percent) died of prostate cancer.
2- 33/245 men (13.5 percent) were in the RP group.
3- 34/129 men (26.4 percent) were in the BT group.
4- 3,048/7,811 men (40.7 percent) were in the NSR group.
They projected that the 5-year overall survival was
1- 67.4 percent among men in the RP group
2- 52.6 percent among men in the BT group
3- 22.5 percent among men in the NSR group
The projected 5-year prostate cancer-specific survival was
4- 75.8 percent among men in the RP group
5- 61.3 percent among men in the BT group
6- 48.7 percent among men in the NSR group
Culp concluded that having primary treatment either a radical prostatectomy or having brachytherapy were both, associated with a lower risk for prostate cancer-specific mortality, or you could live longer.
Their results were similar regardless of the sub-stage of metastatic disease. They also found that the risk for prostate cancer-specific mortality among the men in the RP and the BT groups included
1- The presence of stage T4 disease
2- The presence of high-grade disease
3- A PSA level at diagnosis > 20 ng/ml
4- Age of 70 years of more
5- The presence of node-positive disease
Culp was very careful in the interpretation of the data, and so should we be, because there are a number of limitations of the data available from this analysis. For instance there is a lack of information in the SEER database about variables known to influence the survival of patients with metastatic prostate cancer (including treatment with systemic therapies).
Despite the limitations of the data we need to encourage men who have an initial diagnosis of advanced prostate cancer, especially node positive disease to have a serious conversation with their doctor about moving a head with a “primary” type of treatment, despite the fact that the disease has already left the gland.
Joel T Nowak, M.A., M.S.W.
To all of my American readers and anyone else who celebrates, I wish you a healthy and happy Thanksgiving.
To those of you who do not celebrate Thanksgiving Day, I want to point out that it can still be a time that is important for all of us. It’s always good to take time, take a deep breath and appreciate what we do have. It is always good to take stock of all the bounties that we each have no matter if we have just a few or many.
Even though we have cancer we have many gifts and blessings which we should appreciate every day. Take time to think about what you do have, not what you don’t have. Slow down, relax and appreciate what it is that you do have. Make a list of these blessings and appreciate them.
We all have barriers in our life, but we also have good, positive things in our life, always remember this fact.
I know at least one blessing we all share, one which we all should give thanks for each and every day. I am talking about the ability to wake up in the morning, wiggle our toes and think about what the new day might bring. We are all still alive and that is an excellent reason to give thanks each and every day of the year.
Personally, I want to tell each of you in this group that among the things I give thanks for is that we have found each other, we have found a way to come together and help each other fight this disease. This is just one of the many things in my life that I am thankful for having in my life.
To all of you and to your families, I wish you a very healthy Thanksgiving Day and Thanksgiving year.
Joel T Nowak, M.A., M.S.W.
Fail First Therapy or Step Therapy has been a topic I have written about in prior posts. It is my considered opinion that as it works its way into the treatment protocols for advanced prostate cancer it will have nothing but a very negative result for our health and longevity.
What is Fail First Therapy (FFT) also known as Step Therapy? FFT is a process whereby insurance companies decide to control prescribing decisions for our treatments based solely on health care cost savings, not on our doctor’s decisions and not on what might be best for us survivors. Nothing is simply black or white, there is always some grey and this is also true with FFT.
There are times that FFT makes sense; specifically I’m talking about the use of generic versus the more expensive versions of drugs. We are in an economic crisis with our exploding healthcare costs so when drugs are the same I have no issue with an insurance company insisting that the generic drug be prescribed. To take this logic even farther, I can say that in situations where there are two competing drugs both that have exactly the same modes of act an insurance company dictating which of these two drugs should be used is understandable as long as there is a dialogue between the insurance company and the prescribing doctor.
When FFT goes beyond these two conditions, the use of a generic or the use of a drug with the same mode of action, FFT has absolutely no place in our treatment protocols. Insurance companies are not licensed doctors so they have no business in dictating prescribing decisions.
Recently, some insurance companies have taken it upon themselves to institute FFT where they have a preferred drug, Zytiga with prednisone over Xtandi in the treatment of metastatic advanced prostate cancer in the post chemotherapy stage. This means that their subscribers must fail a course of Zytiga and prednisone first before Xtandi would be paid for by insurance coverage. How did they decide on a preferred drug, the answer is simple, its an economic decision. The cheaper drug is the preferred drug because it is cheaper, not be cause it has the same mode of action or is any more or less effective! There is no evidence that either of these drugs is superior or inferior.
This situation can be detrimental. Many men are unable to take prednisone that must accompany Zytiga. There are even some indications that for some men failing a regime of Zytiga can lead to poorer performance of Xtandi!
Malecare has begun to aggressively question the insurance companies that have instituted this type of policy. Commonly, when we receive a response to our protests we are told that both Zytiga and Xtandi have the same mode of action as they both are hormone therapies and so FFT is appropriate. Yes, they both are hormone therapies, but their mode of action is totally different. Zytiga blocks the production of testosterone from the testes, the adrenal glands and from the tumor itself while Xtandi blocks any testosterone that has been produced, no matter from where it is produced, from entering into the cancer cell and supporting its growth. Each of these drugs is hormone therapy, however their mode of action is totally different. These drugs are not interchangeable drugs and only our doctors have the legal right to decide which treatment would be appropriate for us and when it is appropriate.
The really good news is that I have recently learned that we have in fact made one small positive step in resolving this very significant issue for those of us with metastatic advanced prostate cancer. The insurance company, Health Partners in Minnesota has decided to lift its FFT policy in the Medicare Part D space. That means that senior patients covered by this plan will no longer need to first fail Zytiga with prednisone to be able to have insurance coverage for Xtandi when legally prescribed by their doctors in the post chemotherapy stage of treatment.
Personally, I would like to thank Health Partners for they have now taken a step to really becoming our health partner.
Joe T Nowak, M.A., M.S.W.