The long-term survival of patients with metastatic prostate cancer

In the late 1980s and early 1990s it was generally considered that men diagnosed with metastatic (but still hormone sensitive) prostate cancer had an estimated survival of 18 to 36 months from the time of diagnosis — including their time on treatment with hormonal therapy. And prior to 2003, there was no known treatment that had any meaningful effect on the survival of men who had a rising PSA after they had started on hormonal therapy.

Many specialists in the treatment of advanced prostate cancer (and at least some of their patients) are convinced that the overall survival of men with metastatic prostate cancer is much longer today than it was in the early 1990s. We have been told that the median survival of a man diagnosed with metastatic prostate cancer today may be as much as 5-6 years, but actual data to support this belief are very hard to come by.

It does need to be recognized in this discussion that most men today are not being initially diagnosed with extensive, metastatic prostate cancer that is widespread in the boney tissues. Rather, the majority of men with metastatic disease today are men who have progressed through various stages (including micrometastatic stages) until their doctor can say, “Yes, there is a clear signal of metastasis on your bone scan.” In other words, they are commonly being diagnosed with an early form of metastatic disease because we have “stage-shifted” the development of prostate cancer as a consequence of earlier diagnosis and earlier treatment.

There have now been several publications from clinical studies providing information on the survival of patients who have ceased to respond to standard, traditional forms of hormone therapy (e.g., an LHRH agonist alone, orchiectomy alone, or some forms of hormonal combination). In recent years, the earlier terms “hormone refractory prostate cancer” (HRPC) and “androgen independent prostate cancer’ (AIPC) have, in fact been replaced by the term “castration-resistant prostate cancer” (CRPC). A significant subset of these men are defined as having metastatic CRPC (mCRPC), meaning that they have evident metastasis on a bone scan or a CT scan, and that they have failed at least two forms of hormonal therapy (customarily an LHRH agonist and an antiandrogen and withdrawal of the antiandrogen).

The first drug combination to show any impact on the treatment of men with mCRPC was docetaxel + predisone. In the so-called TAX 327 study, according to long-term survival data published by Berthold et al. in 2008:

  • For men receiving docetaxel + prednisone every 3 weeks, the median survival was 19.2 months, with a range from 17.5 to 21.3 months.
  • For men receiving docetaxel + prednisone once every week, the median survival was 17.8 months, with a range from 16.2 to 19.2 months.
  • For men treated with mitoxantrone + prednisone, the median survival was 16.3 months, with a range from 14.3 to 17.3 months.

(Remember that the combination of mitoxantrone + prednisone had shown no impact on patients survival in earlier trials; its only effects were on pain and quality of life.)

In April 2009, the results of the IMPACT trial in men with minimally symptomatic mCRPC were announced. According to the product prescribing information for sipuleucel-T (Provenge):

  • For men receiving three doses of sipuleucel-T, the median survival was 25.8 months, with a range of 22.8 to 27.7 months.
  • For men receiving three doses of a placebo (a “dummy” injection), the median survival was 21.7 months, with a range of 17.7 to 23.8 months.

It is important to note that these patients had generally less advanced disease than the men in the TAX 327 trial, which is reflected in the fact that the men in the placebo arm of the IMPACT trial had a median survival 5.4 months longer than the men in the mitoxantrone + prednisone arm of the TAX 327 study. On the other hand, the patients enrolled in the IMPACT study could already have been treated with docetaxel.

At the Genitourinary Oncology meeting in San Francisco, earlier this year, data were presented showing that cabazitaxel (Jevtana) + prednisone was able to extend (by 2.4 months) the survival of men with mCRPC who had a rising PSA after treatment with docetaxel + prednisone compared to a placebo (a sugar pill) + prednisone. According to the cabazitaxel prescribing information:

  • For men receiving cabazitaxel + prednisone, the median survival was 15.1 months, with a range of 14.1 to 16.3 months.
  • For men receiving a placebo + prednisone, the median survival was 12.7 months, with a range of 11.6 to 13.7 months.

So we know that docetaxel + prednisone given every 3 weeks can extend median patient survival by 2.9 months compared to mitoxantrone + prednisone, and we know that cabazitaxel + prednisone can extend median patient survival by another 2.4 months for patients who have a rising PSA after treatment with docetaxel + prednisone, giving us a total theoretical median survival benefit of 5.3 months or a median survival of about 21.6 months after initiation of treatment with docetaxel.

Interestingly, a small (non-randomized) study just published by Shamash et al. suggests that a regimen as simple as diethylstilbestrol (DES) + dexamethasone has a significant impact on the survival of men with CRPC:

  • For men treated with DES + dexamethasone, median overall survival was 18.3 months, with a range of 15.4 to 23.3 months.

However, there are other things that we really do not know:

  • We don’t really know whether hormone therapy still provides only 3 years of survival from the time of first diagnosis of metastatic disease — because most men today start to receive hormone therapy long before there are clear signs of metastasis (and there are at least some data — e.g., the Messing et al. data from ECOG 3886 — that suggest that early use of hormonal therapy may be able to significantly extend survival).
  • We don’t really know whether the use of various types of intermittent hormonal therapy might affect overall survival in men with metastatic disease; some would certainly argue that the use of 5α-reductase inhibitors (5-ARIs) as “bridging” therapy in between sessions of standard hormone therapy impacts disease progression and potentially impacts survival — but we don’t have “proof” in the form of data from a well-conducted, randomized clinical trial.
  • We have no idea whatsoever of the potential overall survival of men with minimally symptomatic mCRPC who are treated sequentially with sipuleucel-T, then docetaxel, then cabazitaxel. Is their median overall survival > 25.8 months?
  • We don’t even know the optimal timing of chemotherapy with docetaxel + prednisone in a man with a rising PSA after treatment with sipuleucel-T. Does that have to be based on some other signal of disease progression? We do know that treatment with sipuleucel-T has no significant impact on time to disease progression (as opposed to overall survival).

And all of this comes while we are investigating the clinical effects of a host of new products (abiraterone acetate, ipilimumab, dasatinib, MDV 3100, etc.) that might get used before, after, or in conjunction with the treatments that are already available.

From the viewpoint of drug developers, the overall survival of patients with late stage prostate cancer is not of the highest priority. Their highest priorities are: (a) demonstrating that their [new] drug does something better than the current standard and (b) optimizing belief that their product(s) represent some new and better standard. The most recent example of this is seen with cabazitaxel. The primary goal of the developer was to show that cabazitaxel therapy could extend the survival of patients with mCRPC when the patients were no longer responding to docetaxel (the standard of care of first-line treatment of mCRPC) so that it became the new “standard” for the treatment of patients who ceased responding to docetaxel-based chemotherapy.

From the viewpoint of a patient, however (and we hope from the viewpoint of his doctor too), the key question is shortly going to become, “What is the sequence of treatments that will optimize the survival of a patient with a rising PSA after first- and second-line treatments and who can be assumed to have micrometastatic prostate cancer?” Such men can already live for 15+ years with their cancer, but that isn’t true for all men with micrometastatic disease. There are others who are at risk for a much earlier demise because they have especially aggressive, andogen-resistant forms of prostate cancer.

The prostate cancer community needs to come together to work out how best to answer the above question — and it isn’t going to be easily or quickly resolved.

10 Responses

  1. Today’s post is an important contribution, thanks for writing it. Not only did you provide an excellent summary of where we have gone, but you have asked some pivotal questions about our future.

    How do we sequence the treatments that we know extend life and then add in any new ones that come along is a vital issue not yet settled.

    The drug development history for AIDS is a good model for the treatment of cancer, including advanced prostate cancer. Today, by the sequencing and combining of the small steps made in drug development we have created AIDS treatment cocktails. These cocktails that have made the majority of AIDS cases into a chronic disease.

    Cancer treatments will have to follow a similar paradigm. We also need to have similar goals, making prostate cancer a chronic disease that will allow men to live long enough to die from something else.

  2. Thank you for this very helpful article. As my husband decides whether to begin his first cycle of Provenge, our minds race with all sorts of questions. We are grateful for options. With several medications to help with prostate (and other) cancers (and looming questions as to private insurance/Medicare covering), an algorithm weighing costs vs benefits to one’s life would be helpful right about now in sorting through choices specific to my husband’s needs. One simple, inexpensive and immediate thing I can do for him is — bring him a hot cup of coffee and a hug to begin this day!

    Brooks Sautner

  3. Dear Brooks:

    That cup of tea and the associated hug may have a long-term therapeutic value that far outweighs any other medication — especially with respect to quality of life!

  4. A correspondent has brought to my attention an article by Oefelein et al., originally published in 2004, that made an attempt to better define the long-term survival of men with hormone-refractory prostate cancer.

    While this article is based on a retrospective analysis of data from a relative small number of patients, the data provided do appear to confirm that the median long-term survival of men with hormone-refractory disease was of the order of 4 to 6 years from the time of onset of hormone-refractory status, even then.

  5. Is the Dr. Budwig diet compatible with hormone therapy? Will it help with survival? How much flax oil should be taken everyday? Can anything else help apart from traditional treatments, hormones and chemotherapy?

  6. Mr. Williams:

    We regret that we have no specific information related to the use of the Budwig diet in combination with hormone therapy. We suggest you join our social network, where there may be other patients who have experience of using this diet, and where people will be happy to share their experiences with you regarding the benefits of everything from diet and exercise to pomegranate juice and other supplements. A great deal of the value of such therapies appears to depend on the biology and the mindset of the individual patient.

  7. When drugs provide only 3 to 4 months of additional survival compared with a placebo, how can the cost to achieve that scant improvement be justified? Is there also a marked improvement in quality of life from taking these drugs? That certainly would make it worthwhile from the patient’s perspective. But if QoL was worse while on these drugs, why use them for a few months of additional survival?

  8. Dear Bob:

    Decisions about the “value” of an extra few months of life, and what one is prepared to do to achieve them, are extremely personal, and they depend on all sorts of different factors that have great significance for some and less significance for others.

    It is way beyond my pay grade to be able to answer the question you ask. I know that the manufacturers’ of both abiraterone acetate and enzalutamide were able to show that not only did treatment with these drugs (in chemotherapy-naive patients with CRPC) extend survival, they also extended time to the onset of bone pain, so they did indeed (one had to presume) affect quality of life as well as life itself, but in the end only a specific patient and his family can determine the potential value of those extra months of life.

  9. I had a radical prostatectomy 6 months ago and have recovered well. I had a high-risk, aggressive cancer with Gleason 4 + 5. My PSA rose to over 2 μg/L after 3 months, suggesting that this is micrometastatic disease elsewhere and that I may need to start hormone therapy when my PSA is around 10 μg/L. My PSA is at present 4.7 μg/L.

    Would starting hormone treatment earlier be of benefit with no symptoms, considering the side effects? I am 75 and in good health. Also, would there be any advantage in a bone scan before symptoms show? I look forward to your comments.

  10. Dear Bob:

    That’s really a conversation you need to have with your urologic oncologist or medical oncologist, The “best” time to initiate androgen deprivation therapy (ADT, also known as hormone therapy) is still undetermined, and the real question, an any case, is whether you would benefit from salvage radiation therapy along with a short course of ADT now or simply wait until ADT alone becomes advisable — in which case you probably don’t want to start it until you feel you need to (and no one can agrees on when that might be; some centers would tell you to wait until you started to have symptoms; others would say do it when your PSA reached 10 or 20 ng/ml).

    A bone scan isn’t going to tell you anything with a PSA of 2 ng/mk. However, you could certainly ask your doctors whether your could be referred to a nuclear medicine center that could give you an Axumin PET/CT scan. That might be able to tell you exactly where the recurrence was occurring, and that might help everyone to determine whether radiation + adjuvant ADT was worth trying.

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