Clinical Flare: A Crisis That Can Be Avoided
Reprinted from PCRI Insights May 1999 vol. 2, no. 2

Clinical flare is a drug-induced bodily response that can cause such symptoms as bone pain, compression of a nerve root, spinal cord compression, or blockage of one or both ureters. It is often painful and always dangerous.

A true story always tells so much more than reported material abstracted from everyday life. Here are two case histories obtained by us just recently.

Patient #1 is MF, an 81-year old man who had been following a watchful waiting approach until his PSA rose to 31. He then received a 3-month Lupron® injection without any regard to possible flare and five days later he developed back pain. Radiologic studies showed hydronephrosis on the right side, and then, a cystoscopy revealed a tumor obstructing the right ureteral orifice. A right percutaneous nephrostomy had to be performed to decompress the kidney. Then, a right ureteral stent was placed requiring a 5 hour operation. The patient suffered a massive heart attack two days later. The patient had not been placed on an anti-androgen anytime during his clinical course.

Patient #2 is MB, a 44-year old man diagnosed with PC when he discovered a lump in his neck and a biopsy showed prostate cancer. His first PSA was 5,700, and a bone scan showed disease in the thoracic spine.

He was treated with simultaneous administration of Lupron® and Casodex®. There was no pretreatment with Casodex® to block the flare response that occurs with initiation of any LHRH agonist, be it Lupron® or Zoladex®. Two days after his treatment was started, MB experienced excruciating pain in his thoracic spine and had to be rushed by ambulance to the hospital.

He spent five days in the hospital and received a ten day course of radiation therapy to the thoracic spine. A MRI showed no spinal cord compression, but a nerve root was said to be compressed.

Both patients were inappropriately treated. Major precautions need to be taken if there is a significant tumor burden and a risk of clinical flare upon starting a LHRH agonist. The use of Nizoral® for 48 hours prior to starting Lupron® or Zoladex® or more prolonged use of an anti-androgen (as described in the following article) would have been the safer and more medically sound approach to take.

Prevention of Biochemical and Clinical Flare
By: Jonathan E. McDermed, PharmD & Stephen B. Strum, M.D.

What is flare?
We know that when a luteinizing-hormone releasing-hormone agonist (LHRH-A) is first started, it paradoxically causes a rise in the pituitary hormone LH. This LH rise stimulates the testicles to make more testosterone during the first 5-12 days after initiation of the LHRH-A than even the baseline testosterone. This testosterone rise will stimulate prostate cancer cell growth. This is termed “flare”.

Why is it important to prevent flare?
Flare can precipitate severe life-threatening symptoms of disease progression in patients with prostate cancer having subclinical metastatic disease in critical locations. For example, if the cancer is growing close to a nerve root, flare can result in pain in the distribution of that nerve. More importantly, if the PC is close to the spinal cord, flare can result in spinal cord compression and paralysis. If the prostate cancer involves lymph nodes near the ureters (tubes carrying urine from the kidneys to the bladder), flare can increase the size of nodes and cause compression of one or both ureters. If ureteral compression involves both sides, it leads to kidney failure or uremia. This is manifested by elevations in the BUN and serum creatinine laboratory tests. Flare increasing disease in bone can lead to severe bone pain (Patient #2).

What is clinical flare versus biochemical flare?
When tumor flare causes clinical symptoms such as bone pain, compression of a nerve root, spinal cord compression, or blockage of one or both ureters, we use the term clinical flare. If the PSA rises as a result of initiating an LHRH agonist (Lupron® or Zoladex®), but there is no clinical evidence of disease progression, we call this biochemical flare. Even so, we prefer to avoid an increase in PSA and the potential for PC growth regardless of the presence or absence of clinical symptoms.

Figure 1 The Mechanism of Flare

What is the mechanism of flare?
The hypothalamus releases the hormone LHRH which circulates to the pituitary via the hypothalamic-pituitary portal blood system, as shown in Figure 1. The interaction of this natural LHRH with the LHRH receptor in the anterior pituitary leads to the production of LH and FSH. This process occurs in the following manner. LHRH binds to the LHRH receptors in the pituitary to form a complex. This complex in turn is broken down by a peptidase-enzyme, releasing LH and at the same time freeing the receptor for more LHRH. This occurs naturally as a result of pulses of LHRH produced by the hypothalamus. This is the process believed to occur with natural LHRH.

One hypothesis as to the mechanism of flare production is that synthetic long-acting LHRH agonists (LHRH-A) such as Lupron® or Zoladex® bind to the LHRH receptor with a high affinity that is relatively resistant to the action of peptidase. This binding process results in the release of LH from the receptor leading to biochemical or clinical findings of flare.

Can we prevent flare?
The administration of an antiandrogen such as flutamide (Eulexin®), bicalutamide (Casodex®), or nilutamide (Nilandron®) prior to beginning LHRH-A treatment (e.g., Lupron® or Zoladex®) will diminish PSA flare and may prevent clinical symptoms. How do we think this occurs? The anti-androgen sits in the androgen receptor and prevents the interaction of testosterone (T) and dihydrotestosterone (DHT) with the androgen receptor. This is shown in Figure 2, from Labrie et al.1

Figure 2

Therefore, Eulexin®, Casodex® or Nilandron® can be used to occupy the androgen receptor in an attempt to block T or DHT from occupying the receptor and initiating DNA synthesis and cell division. The issue is how best to do this. Eulexin® has a half-life of less than 8 hours whereas Casodex® has a half-life of 6 days. With Eulexin®, a steady state or equilibrium is reached in 32 hours (four half-lives) as contrasted to Casodex® with which equilibrium is reached in 6 half-lives or 37 days. When these drugs are stopped, it also takes this time to eliminate the respective drug. These considerations must be taken into account in an attempt to prevent flare upon starting the anti-androgen as well as in evaluating the patient for an anti-androgen withdrawal response (AAWR) upon stopping the anti-androgen. In other words, upon stopping Eulexin® to observe for an AAWR, it is appropriate to check the PSA 3-7 days later. For Casodex®, with its long elimination period, checking would require 6 weeks. No one has studied these agents to see how and when they work to prevent flare. Moreover, little consideration has been given to Proscar® to block DHT (which is 4-5 times more potent than T) to further decrease the occurrence of flare.

Other agents can be used successfully to prevent LHRH-A induced flare. These include ketoconazole (Nizoral®), or DES. Both agents have multiple modes of action. In regard to blocking flare, Nizoral® blocks T production whereas DES blocks LH production. There are no modern studies that have reviewed these agents and their effects on PSA production insofar as the prevention of flare.

Can we better understand the flare mechanism?
We propose a study of Eulexin® or Casodex® in combination with Proscar® (finasteride) to understand how best to eliminate biochemical flare. If we eliminate biochemical flare, we eliminate clinical flare. This is our study outline.

Days Before LHRH-A	Blood Levels Obtained	Intervention
Day -7 to -1	baseline PSA, LH, T and daily PSA, LH, T	Give antiandrogen + Proscar®
Day 0 (zero)	LH, T, PSA	Add LHRH agonist
Day +1 to day +14	every 2 days or until PSA, T, LH are stable LH, testosterone and PSA	Continue antiandrogen + Proscar®
Day +28	Testosterone & PSA levels	Repeat LHRH-A dose

In consenting patients, androgen deprivation therapy will consist of either Eulexin® or Casodex® plus Proscar® starting one week before the first dose of Lupron® or Zoladex®. Blood levels of LH, testosterone, and PSA will be measured at baseline, on a daily basis prior to LHRH-A, and over the next 14 days following LHRH-A administration. Effective prevention of biochemical flare will be evident if there is no rise in serum PSA. If this study completely prevents biochemical flare, the next logical step would be to determine if this results in a therapeutic advantage for the patient with prostate cancer.

Alternatively, the use of Nizoral® to reduce testosterone levels during the first 14 days of ADT could be employed to counteract the increased LH levels normally seen upon initiating an LHRH agonist. Since Nizoral® works effectively to reduce T within 48 hours, pretreatment with Nizoral®, antiandrogen, and Proscar®, commencing two days before starting an LHRH agonist, would be reasonable to study as well. In this setting, Nizoral® would be continued for two weeks and then discontinued.

In this study we would obtain baseline T, LH and PSA two days before starting the LHRH agonist, commence Nizoral®, Proscar®, and either Eulexin® or Casodex® while measuring LH, T and PSA every day. On Day 2, the LHRH agonist is given while continuing to measure LH, T and PSA over the next 14 days or until the PSA and T are consistently falling.

Nizoral for Clinical Flare & its Value in Oncologic Emergencies
In a study by Trachtenberg et al2, 13 patients with prostate cancer who initiated high-dose Nizoral® treatment had serum hormone levels drawn before and after starting Nizoral®. Hormone levels obtained included LH, testosterone, dehydroepiandrosterone (DHEA), androstenedione and progesterone. The results of this study showed that DHEA and androstenedione levels decreased while those of progesterone and LH increased by four weeks. No patient sustained an increase in serum testosterone levels.

However, a recent abstract by Wasil et al3 contradicted these observations. In this trial, mild testosterone surges of 11.5% and 17.7% above baseline were noted in 50% (2/4) of Nizoral®-treated patients. The brief rise in testosterone in this small series of patients does not deter us from recommending Nizoral® to prevent clinical flare or to acutely lower testosterone levels in an oncologic emergency. Most of such cases were treated by orchiectomy in the past. This achieves castrate levels of testosterone within 3-12 hours (mean 8.6). Nizoral® requires 48 hours to reach near castrate levels. [Figure 3, after the work of Trachtenberg et al4.]

Summary
The consequences of biochemical flare are unknown, but we cannot imagine that biochemical flare can be good for the patient with PC. Clinical flare can lead to medical emergencies ranging from increased bone pain to ureteral compression and uremia to cord compression and paralysis. The potential to develop any of these problems should be anticipated in men with locally advanced or metastatic bone disease. Measures to prevent biochemical and clinical flare, as outlined above, are mandatory in the proper management of men with PC.

The problems of clinical and biochemical flare are seriously neglected by the majority of physicians initiating treatment with LHRH agonist therapy in the world today. This must be corrected. We urge any patient who has experienced this type of problem to contact the PCRI. We will alert the FDA and request a WARNING label on all LHRH agonists. Alternatively, the use of the new LHRH antagonists such as Abarelix®5,6,7 from Praecis pharmaceuticals may ultimately become the preferred choice of therapy. These agents lower testosterone within 48 hours and reduce testosterone to castrate levels by one week in 76% of patients compared to 0% of patients receiving conventional LHRH agonist therapy.8 Unlike LHRH agonists, they do not stimulate LH release with the subsequent increase in testosterone. In the next issue of Insights, we will discuss the LHRH antagonists.

References:
1. Labrie, F, Belanger A, Dupont A, et al: Science behind total androgen blockade: from gene to combination therapy. Clin Invest Med 16:475-492,1993.
2. Trachtenberg J: Ketoconazole therapy in advanced prostatic cancer. J Urol 132:61-4, 1984.
3. Wasil T, Kreis W, Budman D et al: Rapid fall in serum testosterone levels with oral ketoconazole. Proc Am Soc Clin Oncol 16:347a, 1997.
4. Trachtenberg J, Halpern N, Pont A: Ketoconazole: a novel and rapid treatment for advanced prostate cancer. J. Urol 130:152-153, 1983.
5. Menon M, Glode LM, Martin K, et al: Abarelix (PP1-149), a novel and potent GnRH antagonist, induces a rapid and profound reduction in testosterone and PSA in advanced prostate cancer patients. J Urol 159:334A, 1998.
6. Garnick MB, Gittelman M, Steidel C, et al: Abarelix (PPI-149), a novel and potent GnRH antagonist, induces a rapid and profound reduction in prostate gland volume (pgv) and androgen levels before brachytherapy (BT) or radiation therapy (XRT). J Urol 159:220A, 1998.
7. Garnick MB, Campin M, Kuca B, Tomera K: PSA kinetics: rates of decline are significantly more rapid following therapy with the GnRH antagonist Abarelix-Depot (A-D), compared to superagonists Lupron® (L) and Zoladex® (Z) in prostate cancer (PrCa) patients (pts). J Urol 161:98, 1999.
8. Garnick MB, Tomera K, Campion M, Kuca B: Abarelix-Depot (A-D), a sustained-release (SR) formulation of a potent GnRH pure antagonist in patients (pts) with prostate cancer (PrCA): phase II clinical results and endocrine comparison with superagonists Lupron® (L) and Zoladex® (Z). J Urol 161:340, 1999.

Prostate Cancer Research Institute (PCRI)

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