The LHRH “flare” reaction: do we really know what we thought we knew?


While it has never been categorically proven that adding an oral antiandrogen like flutamide or bicalutamide (Casodex) to injections of LHRH agonists (e.g., leuprolide actetate) improves overall patient survival, there had been little doubt in people’s minds that giving an antiandrogen for a week or two before a first LHRH agonist injection prevented the problem of disease “flare” associated with this first injection of the LHRH.

However, a retrospective analysis of data collected by a highly respected research group at Harvard has called even this piece of knowledge into question.

The study reported by Oh et al. was specifically designed to investigate whether oral antiandrogen therapy before initiation of LHRH agonist therapy was associated with fewer clinical disease flares — caused by short-term increases in serum testosterone levels in response to initiation of LHRH therapy in men with metastatic prostate cancer.

Oh et al. studied data from 1,566 patients with metastatic prostate cancer who were treated with LHRH agonists in Veterans Affairs hospitals in the USA between 2001 and 2004. For all patients, the researchers looked for evidence of spinal cord compression, radiation therapy, fractures, bladder outlet obstruction, and narcotic prescriptions for pain within 30 days of starting LHRH therapy. Their analysis showed the following:

  • 1,245/1,566 patients (79.5 percent) received oral antiandrogens before initiation of LHRH agonist treatment.
  • Hispanic men, married men, and those without prior cancer were treated less often with oral antiandrogens.
  • Complication rates did not differ by receipt of oral antiandrogens.
  • Spinal cord compression and pathologic fractures were extremely rare whether antiandrogens were used or not.
  • There was no decrease in the likelihood of any of the clinical events measured associated with treatment with an antiandrogen either within ≤ 6 days or after  ≥ 7 days before LHRH agonist treatment.

The authors came to the clear conclusion that oral antiandrogen therapy given prior to initial treatment with LHRH agonists in patients with metastatic prostate cancer was not associated with any significant differences in risk for fractures, spinal cord compression, bladder outlet obstruction, or narcotic prescriptions. Rates of spinal cord compression or fracture were < 1 percent in the first 30 days after initiation of LHRH agonist therapy regardless of antiandrogen use.

So is there really no clinical significance to the “disease flare” caused by that first LHRH injection? We do — definitively — know that there is a significant rise in serum testosterone levels in patients for up to 2 weeks after they receive their first injection of an LHRH agonist. We also know that clinical flare reactions used to be “real” and were recognized in the very early clinical trials of LHRH therapy. However, we also know that in a clinical trial of the 3-month depot formulation of leuprolide acetate (carried out well into the PSA era), “No flare reactions were observed and patient assessments of bone pain and urinary symptoms were unchanged.”

In the days when LHRH agonists started to be used to treat metastatic prostate cancer — back in the mid to late 1980s — most men were being diagnosed with advanced prostate cancer and many with very clear signs of bone metastases. PSA levels in such patients (when they started to become available) were normally > 100 ng/ml at the time of diagnosis, and not uncommonly > 1,000 ng/ml. These men had really advanced disease. A sudden, short-term jump in their testosterone levels might well have led to clinical symptoms that included fractures, spinal cord compression, and bladder outlet obstruction, and the concomittant use of radiation and narcotics to treat the consequent pain.

Today — and even in the period between 2001 and 2004 when the men in this study were being treated — it would be most unusual for a patient to receive his first LHRH injection when his PSA level was that high. Indeed, relatively few men in the USA today even get diagnosed with a PSA that high. The “New” Prostate Cancer InfoLink suspects that what Oh and his colleagues have shown is another consequence of “stage shifting.” In other words, when men are diagnosed earlier, and receive their first LHRH agonist injection with a significantly lower disease burden than used to be the case, it may be the case that the short-term increase in serum testosterone level induced by the initial LHRH injection has significantly less clinical impact than used to be the case, and that pre-LHRH oral antiandrogen therapy should now be reserved primarily for those relatively few patients who are diagnosed with truly advanced prostate cancer, a PSA level of 100 ng/ml or higher, and clearly evident metastases at the time of diagnosis.

One Response

  1. Your explanation appears reasonable. Though I have been a proponent of antiandrogen prior to LHRH injection for safety’s sake, most men I have talked to who did not receive antiandrogen prior either had no side effects that they complained about or only experienced some general discomfort with the initial activity of the LHRH medication.

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