Two new terms needed in the management of advanced prostate cancer

It is rapidly becoming apparent that we are going to need two simple, new terms to be able to use in discussion of the evolution of progressive prostate cancer after “standard” forms of androgen deprivation therapy (ADT) have failed to work. So … anyone got good, scientifically sound suggestions?

In the first place, the term, “castration-resistant prostate cancer” is clearly no longer accurate (whether it was ever a good term or not). This term was coined, not so long ago, to describe men who had progressive disease after treatment with:

  • “Standard” ADT, meaning bilateral orchiectomy (surgical castration) or single-agent, continuous LHRH agonist therapy or continuous LHRH + antiandrogen therapy or almost any form of intermittent ADT and
  • Continous use of LHRH + antiandrogen therapy in any man who had stopped responding to single-agent LHRH therapy or any form of intermittent ADT and
  • Subsequent antiandrogen withdrawal

However, it is now clear that such men are not necessarily “castration resistant” (i.e., unresponsive to hormonal therapies) because many of them clearly still respond to therapy with the new hormonally active agents like abiraterone acetate and enzalutamide. We need a new term to describe this set of men (who are still naive to drugs like abiraterone acetate and enzalutamide). Other terms that have been use to describe this condition in the past (regardless of whether the patients had metastatic disease or not) include “hormone refractory prostate cancer” (HRPC) and “androgen-independent prostate cancer” (AIPC). Neither of these terms is going to be appropriate either.

The other set of patients who are going to need to be defined are those men who have progressive disease after all known forms of hormonal manipulation, including all those described above as well as men progressing after treatment with drugs like

  • Ketoconazole and itraconazole
  • Low-dose estrogens
  • Abiraterone acetate
  • Enzalutamide

It may be that we should resusciate the term “hormone refractory” to imply this set of patients, but there may be better terms. As just one example, the hormonal axis on which all hormonal therapy for prostate cancer is based is the so-called “hypothalamic–pituitary–adrenal” (HPA) axis. If a patient becomes refractory to all attempts to manipulate the functions of that axis, perhaps we should define their condition as “HPA axis therapy resistant” or “HPA axis therapy refractory” prostate cancer (HTRPC ).

Anyway … now’s your chance to get creative!

7 Responses

  1. Thanks for identifying the need and proposing the challenge!

    Regarding the first term, I wonder what can be said histologically about prostate cancer cells that now laugh at: (a) induced hypogonadism and (b) first-level AR binders? For example, do they (a) demonstrably make their own pre-androgens (e.g., using CYP17)? and (b) have demonstrably different androgen receptors?

    A histopathological description, if possible, would be best — perhaps “APM/mAR” cells (for “androgen precursor-manufacturing/mutant androgen-receptor” cells).

    But if the only sure information is the natural history, please critique the term “IHR/RAR prostate cancer”:

    (a) IHR = “IH-resistant” = resistant to induced hypogonadism (i.e., resistant to surgical castration or LHRH agonists/antagonists) and
    (b) RAR = “reactivated androgen-receptive” = characterized by ARs becoming active again despite previously effective blockage.

  2. You wanted simple:

    — Traditional Hormone Resistant (THR) and
    — Modern Hormone Resistant (MHR)

  3. Dear Paul:

    I suspect that many specialists in the biology of prostate cancer would point out that the acquisition of hypogonadism (i.e., induced hypogonadism) can occur for a variety of reasons that have nothing to do with prostate cancer at all. This would suggest that just because a man was resistant to treatment for IH did not also imply that he was resistant to treatment for ADT-refractory prostate cancer. (Just an observation.)

    With respect to your second suggestion (RAR), the cells in questions are not actually “reactivated” at all. They have never been “de-activated” to treatment with drugs like abiraterone acetate or enzalutamide, and one of the potential hopes is that enzalutamide (or a drug like enzalutamide) might, in the future, be able to be used as a first-line hormone therapy that could actually replace LHRH receptor agonists, moving these to second-line hormonal therapy.

  4. Jerry:

    These suggestions are most certainly simple. However, the scientific gurus of the prostate cancer community are probably going to want something that has a deeper scientific basis (especially since “traditional” and “modern” are a moving targets over time.

  5. Interesting.

  6. Why not make it simple by modifying the current stage designations? i.e., Define Stage IVa, for one type, IVb for another, etc. (assuming these conditions are unique to Stage IV prostate cancer; if not, do the same for Stage III.

  7. Dear Jim:

    Clinical staging has historically always been therapy-independent. In other words, it is intended to “stage” a patient at the time of diagnosis, regardless of how he (or she) subsequently gets treated. However, you make a good point … Maybe it is time to reconsider the entire staging paradigm … although that would really put a cat among the academic pigeons, since the concept would affect all cancers.

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