Hormone therapy effective in man with PSA > 21,000, but …


An article in just published in Onkologie reports the diagnosis and (short-term) treatment of widely disseminated, metastatic prostate cancer in a 64-year-old Croatian man with a PSA of > 21,000 ng/ml.

Quite apart from the fact that this is believed to be the highest known PSA level at the time of initial diagnosis is the fact that this man was still, according to Persec et al., completely free of any symptomatic evidence of disease at the time of diagnosis: no bone pain, no problems with urination, etc.

One of the things that has been evident in the management of prostate cancer since the advent of the PSA test is the degree to which management of patients’ PSA levels has become a driving force behind discussions about patient treatment. Patients commonly express enormous concern when their PSA levels rise — even if it is from one near to undetectable level to another near to undetectable level — and physicians need to be able to offer sound guidance and make good clinical decisions  based on such information.

The patient discussed by Persec et al. was actually diagnosed with a PSA level of  21,380 ng/ml (although we do wonder about the accuracy of PSA tests in assessing such a level of prostate specific antigen). He was subsequently shown to have chronic anemia, an elevated alkaline phosphatase, a Gleason score  of 9, multiple liver metastases, and  diffuse bone metastasis. He was treated with a bilateral subcapsular orchiectomy and bicalutamide. At 3 months of follow-up, his PSA had dropped to 29 ng/ml. Based on historic evidence in the management of patients diagnosed with metastatic disease, his prognosis would be a survival time of 18-36 months. Of course what we don’t know is just how long this gentleman has been living with his disease. Is it 1 year or 25?

For many years, a small subset of clinicians has argued that treatment of patients with hormone therapy for a rising PSA is not clinically justified until there is clear evidence of metastasis or other symptomatic evidence of progression that needs to be treated. Why have they made this argument? Because the data to support early hormone therapy is associated with limited evidence of a real survival benefit, and hormone therapy very definitely is associated with a broad range of complications, including complications that can lead to patient deaths. Some patients who have been on such long-term hormone therapy have also been vociferous in making the argument that such long-term treatment may not be worth the adverse effects for men who have no clinical symptoms of metastatic disease.

The case reported here does make one wonder, yet again, when it is most appropriate to initiate hormone therapy for the majority of patients. It seems sad to us that after 60 years of using hormone therapy as the “gold standard” for the treatment of metastatic prostate cancer (because it has a very definite palliative effect on the symptoms of late-stage, metastatic disease), we are little wiser today than we were 20 or so years ago about the appropriate timing of such therapy, and the need to customize hormone therapy in ways that will optimize both the quantity and the quality of life of individual patients.

Certainly the advent of intermittent androgen ablation has  allowed many patients to limit the amount of hormonal ablation they may need once it is clear that their PSA is rising and their disease will no longer respond to localized treatments. However, we also suspect that a large number of men who are started on hormone therapy when their PSA levels are well  below 5 ng/ml may not be benefitting from such treatment. Indeed, it is arguable that early hormone therapy may actually accelerate the development of hormone-refractory disease in patients with a long PSA doubling time.

We don’t even know with certainty that early hormone therapy is benefical for men with a low PSA doubling time of 3 months or less after the failure of localized therapies. It may be time for us to go back and really see if we can do better at assessing the appropriate timing of hormone therapy in subsets of patients so as to optimize their survival and their quality of life. Managing PSA levels alone is certainly not always in the patient’s best interest.

Since the PSA test became available, the identification of patients with very high PSA levels like this patient’s at the time of diagnosis has become very rare indeed — and this is a wonderful thing. However, it is also in the best interests of the largest number of patients to know whether traditional hormonal therapies have a real clinical impact on survival — especially since very different, new therapies are likely to be available in the near future which can also be used to treat men with a rising PSA after first-line therapy, and parhaps as alternatives to traditional androgen deprivation. We are still treating far too many men with early hormone therapy with minimal evidence for its clinical benefit.

4 Responses

  1. Mike,

    I really agree with the waiting. In June 2006 my oncologist gave me the option of going on ADT or waiting until (if) I really needed it. So I got 18 months of no ADT before I did the combined ADT/Taxotere. I will always be glad I waited and had that time. I really hate being on ADT. I think it is really dangerous if the patient has any cardiac issues.

    Bill

  2. Bill,

    I, too, am waiting. My PSA is now about 16.66 and my doubling time is now in the “years” catgory. My level seems to going up about 0.12 per month. My question: what caused you to accept the ADT/Taxotere treatment? I am concerned re ADT because I also have cardiac issues.

    Bruce

  3. Bruce,

    The decision point for me was the PSA doubling time that got to be less than 3 months. At the time there had been some encouraging results from Phase II trials that the combo of ADT and Taxotere could put some patients into long-term (5+ years) of unmanaged remission. I took the shot, but for me it did not work. In fact, when I came off that treatment my PSA doubling time increased, and my actual PSA level approached the levels they were at when I was diagnosed. My cancer seems to be a low PSA producer (my terminology) and right before surgery it was only 8.67 but the cancer had fully involved my prostate and spread outside with stage T3bN1Mx.

    So I went back on ADT on January 15. We will see what happens next. I am not sure how long I will stay on it.

    On a personal level I am not convinced ADT increases survival time for people like me. I know some people swear by it but I think it comes down to the type of cancer. Some types just seem figure out a way around these treaments (more aggressive cancer) and other types are just more natually inclined to go slow and thereby “seem” to react better to treatment.

    I am certainly no expert and can’t tell you what to do. Also keep in mind ADT affects people differently. Some do not even notice it; other have side effects. Have you been to Terry Herbert’s Yananow web site? If not you should visit it. There is a lot of good information.

    If you are interested in more about my story, you can see it here.

    Good luck,

    Bill Manning

  4. Each man needs to decide when to initiate a therapy that, like most therapies, affects his QOL. That said, there is some evidence that early hormonal suppression improves survival.

    Early versus delayed hormonal suppression … the evidence for early treatment.

    Hormonal suppression has been the mainstay of treatment for advanced forms of prostate cancer. Although early clinical studies suggested that major improvements and even sporadic cure could occur, later randomized prospective investigations showed that hormonal treatments were palliative rather than curative. The real question then became one of comparing quality of life issues with survival potential in utilizing hormonal suppression as early or delayed treatment.

    1. As a result of the data generated by Veterans Administration Cooperative Urologic Research Group showing high toxicity in patients treated with estrogen therapy, delayed hormonal suppression was initially accepted as standard practice. Reanalysis of those data using cancer-specific deaths showed improved cancer-specific survival with early hormonal therapy in selected patients diagnosed with early stages of advanced disease. A large and growing body of clinical data now suggests a superior benefit to early hormonal therapy. Aside from the survival benefit, it is now well established that early hormonal treatment significantly delays the onset of disease progression, which may correlate with an improved quality of life.

    2. In a randomized study by the U.K. Medical Research Council Prostate Cancer Working Party Investigators Group, results demonstrated a 32% survival benefit with early hormonal suppression over delayed suppression, and at the same time pathological fracture, spinal cord compression, ureteric obstruction, and development of extra-skeletal metastases were twice as common in deferred patients. Improving quality of life is thus an important issue in applying hormonal suppression at an early stage of advanced disease.

    3. In another randomized clinical trial, Messing and co-workers compared immediate and delayed treatment in patients who had minimal residual disease after radical prostatectomy. After a median of 7.1 years of follow-up, 7 of 47 men who received immediate antiandrogen treatment had died, as compared with 18 of 51 men in the observation group (P = 0.02). The cause of death was prostate cancer in 3 men in the immediate-treatment group and in 16 men in the observation group (P < 0.01) and the researchers concluded that “Immediate antiandrogen therapy after radical prostatectomy and pelvic lymphadenectomy improves survival and reduces the risk of recurrence in patients with node-positive prostate cancer.”

    5. Granfors et al. reported the results of 91 patients with clinically localized prostate cancer who were treated for pelvic-confined prostate cancer. Patients had surgical lymph node staging and were then randomized to receive definitive external-beam radiotherapy or combined orchiectomy and radiotherapy. Patients who received radiation alone without hormonal treatment were treated with androgen ablation at clinical evidence of disease progression. Results were reported at a median follow-up of 9.3 years. Clinical progression was observed in 61% of patients treated with radiotherapy alone and in 31% of patients who received combined treatment (P = 0.005). Mortality rates were 61% and 38%, respectively, and cause-specific mortality rfates were 44% and 27%, respectively (P=.06), in groups 1 and 2. Differences in favor of combined treatment were mainly seen in lymph node positive tumors. Node-negative tumors showed no significant difference in survival rates. The authors concluded the progression-free, disease-specific, and overall survival rates for patients with prostate cancer and pelvic lymph node involvement are significantly better after combined androgen ablation and radiotherapy than after radiotherapy alone. These results strongly suggest that early androgen deprivation is better than deferred endocrine treatment for these patients.

    5. Bolla et al. reported results of 415 patients with locally advanced prostate cancer. Patients were randomized to receive radiation therapy alone or radiotherapy plus immediate treatment with goserelin for 3 years. The median follow-up was 45 months. Kaplan-Meier estimates of overall survival at 5 years were 79% in the combined-treatment group and 62% in the radiotherapy group (P = 0.001). The proportion of surviving patients who were free of disease at 5 years was 85% in the combined-treatment group and 48% in the radiotherapy-alone group (P < 0.001). The authors concluded that adjuvant treatment with goserelin, when started simultaneously with external-beam radiation, improved local control and survival in patients who had locally advanced prostate cancer.

    6. For many years, there has been published evidence that demonstrates that the lower the tumor burden the better the response to hormone suppression. This was clearly demonstrated by Crawford et al. in 1989. In this study, men were stratified by the degree of their cancer progression at diagnosis. The response to combined suppression was as follows:

    a. Advanced disease with major symptoms such as bone pain, weight loss, etc., responded for only 8.5 months.
    b. Advanced disease with minor symptoms, responded for 15.4 months.
    c. Advanced disease limited to lymph nodes, responded for 4 years.

    In this study, 10% of the patients in the a. category were still responding after 4 years while 35% of the patients with disease limited to lymph nodes were still responding after 10 years. This is a clear indication that hormonal response is directly proportional to the degree of disease progression at the time of diagnosis and that each patient’s disease can elicit a different response to treatment.

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