Should LHRH agonist be continued when the patient is hormone refractory?

From Cancer Guidelines Wiki

Should LHRH agonist be continued when the patient is hormone refractory?

An important yet unanswered question is whether a patient should continue LHRH agonist therapy once his disease has progressed while on androgen deprivation. The continued castrate state could also needlessly expose a patient to the adverse events of having lowered testosterone. In addition, a significant portion of men who have been medically castrated do not have recovery of their testosterone once the LHRH agonist is stopped, and are thus being dosed with a drug redundantly. Finally, as the cost of this class of drugs is significant, cost-effectiveness is also important. (Obviously, this question does not pertain to patients who have undergone a surgical castration).

There are no RCTs addressing this question. There are two retrospective reviews that analysed two unique datasets and assessed the outcome of patients who did and did not maintain their castrate state when treated with chemotherapy in the pre-docetaxel era. In essence, one study suggested a benefit[1] and the other did not suggest a benefit.[2] At most, we can suspect that continuing the LHRH agonist does not worsen a patient’s prognosis. If, however, a patient is having significant adverse events from maintaining a castrate state (hot flushes, depression, weight gain) it is reasonable to hold the LHRH dosing. However, it should be recognised that some patients have a rapid recurrence of their testosterone and anecdotally more rapid recurrence of their cancer and respond to re-instituting a castrate state. Moreover, it is contended that based on the molecular biology of prostate cancer, it is intuitive that avoiding physiological androgen level (ie growth factor) availability to cancer cells will possibly still retard tumour progression versus return of physiological levels of testosterone.

In accordance with the design of the trials that have led to the survival advantage for docetaxel in castrate-resistant prostate cancer[3][4] the arguments appear to favour continuation of the LHRH agonist agent. Another tenuous reason for maintaining a castrate state can be derived from the activity of second-line hormone manipulations, with the amount of benefit–if there is one–to be defined by the continuing large phase 3 trials of the newer agents such as abiraterone. Specifically, this observation details the sensitivity of some cancer cells to androgens even when growing in a castrate environment. However, it is unknown whether these newer agents require a castrate state for maximum benefit.

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Evidence summary and recommendations

Evidence-based recommendationQuestion mark transparent.png Grade
There is insufficient evidence to make a recommendation as to whether a patient should continue LHRH agonist therapy once his disease has progressed while on androgen deprivation.
D


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References

  1. Taylor CD, Elson P, Trump DL. Importance of continued testicular suppression in hormone-refractory prostate cancer. J Clin Oncol 1993 Nov;11(11):2167-72 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/8229130.
  2. Hussain M, Wolf M, Marshall E, Crawford ED, Eisenberger M. Effects of continued androgen-deprivation therapy and other prognostic factors on response and survival in phase II chemotherapy trials for hormone-refractory prostate cancer: a Southwest Oncology Group report. J Clin Oncol 1994 Sep;12(9):1868-75 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/8083710.
  3. Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004 Oct 7;351(15):1502-12 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15470213.
  4. Petrylak DP, Tangen CM, Hussain MH, Lara PN Jr, Jones JA, Taplin ME, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004 Oct 7;351(15):1513-20 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15470214.

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Appendices