**5. Discussion**

Should biopsy specimens be tested for PIBF to see if a given patient should be treated with mifepristone?

We do not think it would be unreasonable to see if a given specimen produces PIBF, but can we be sure that the tests are sensitive enough to deprive a patient the potential great benefit of treatment with mifepristone?

Can measurement of serum PIBF be helpful in determining if the cancer is responding to mifepristone or if mifepristone therapy is no longer working?

There have been developed more sensitive and specific serum PIBF assays [2]. However, based on measurement of serum PIBF in patients with gynecologic cancers or breast cancers that are P receptor positive, or even associated with breast cancer antigen 1 or 2, the serum level of PIBF may not be helpful for these purposes [54, 55]. It is the PIBF in the tumor microenvironment that seems to be most important, and this, of course, would be difficult to measure.

The 200 mg daily dosage of mifepristone does not appear high enough to block the glucocorticoid receptor. So, another important question, is if it is the action of mifepristone on blocking the P receptor that leads to its efficacy in treating cancer why does it seem to work in cancers that are not associated with the classic nuclear P receptor?

The evidence supports the fact that it acts on membrane P receptors. Activation of the nuclear P receptor initiates transcription, which is a slower process, whereas rapid activation of the membrane P receptor is a more rapid signaling action [46].

Do cancers need to secrete P to activate the membrane P receptor?

It is possible that at a certain stage cancer cells can make P or a P-like substance sufficient to interact with membrane P receptors. There is evidence that a large variety of cancer cells express the human chorionic gonadotropin (hCG)-beta subunit gene [56]. Activation of the hCG beta subunit gene to produce hCG could lead to local P production by the cancer cells. Alternatively, there may be some other mechanism to activate the membrane P receptor to make PIBF. Even with this scenario, mifepristone could still block the effect of this theoretical non-P membrane P receptor agonist.

Does mifepristone only works when the cancer is at the stage of rapid metastasis?

It is possible that all cancers have mRNA to produce PIBF, but only at a certain level, that is, perhaps stem cell level is the membrane progesterone receptor is activated and PIBF is manufactured. Thus, it is possible that activation of tumor secretion of PIBF only occurs at the stage when it is ready to rapidly metastasize. About 20% of meningiomas are associated with the classic nuclear P receptor. However, a large study comparing mifepristone vs. placebo for unresectable tumors did not find any therapeutic benefit for mifepristone vs. placebo [57]. This could be because meningiomas are slow growing tumors and the PIBF mechanism is only seen with rapidly growing tumors. However, it is also possible that some meningiomas are considered benign. Thus, maybe it is the ability to make PIBF that is one factor allowing the tumor to follow a benign vs. malignant course. One benefit of this large study was to demonstrate a very good safely profile for mifepristone with few side effects [57].

Since a compassionate use IND is required by the FDA, that organization is reluctant to grant an off-label use unless all "standard" treatments have been exhausted. Thus, most of the study subjects in our center have been patients with very advanced cancers where there are few, if any, reasonable treatment options.

One exception is a man, who at the age of 58 was found to have bilateral renal cell carcinoma with metastases to local lymph nodes [42]. Renal cell carcinoma can be multifocal, and even when several lesions are present, the tumor is generally not extremely aggressive. Today the recommendation is renal sparing surgery and to remove the tumors every time one reaches a certain critical size [58–60]. But 16 years ago, the recommendation was bilateral nephrectomy.

Since there were no chemotherapy or immunotherapy agents16 years ago for renal cell carcinoma, and the patient did not want to become a dialysis cripple, the FDA approved a compassionate use IND for oral mifepristone following a laparoscopic hemi-nephrectomy with retention of a kidney with three lesions left untreated.

After 10 years of single agent treatment, there were no new tumors. The three lesions previously noted on the left kidney remained stable [42]. After 10 years his diabetes caused kidney failure and the start of dialysis. Thus, he had the 1½ kidneys removed. After 2 years of hemo-dialysis, he was approved for a kidney transplant. He is still doing well 16 years from initial diagnosis [42].

This case showed that mifepristone can also work to inhibit tumor growth even when not at the rapidly growing cell stage. Whether this is specific only for renal cell carcinoma, or applies to other malignancies, needs to be determined. Thus, perhaps one should consider using mifepristone in earlier stage metastatic cancers following tumor remission following treatment with chemotherapy or immunotherapy to possibly inhibit recurrence or negate the need to treat with another chemotherapy or immunotherapy regimen with morbid side effects.

One final thought. Frequently, once a tumor has widely metastasized chemotherapy or even immunotherapy may frequently extend life somewhat at the expense of significant side effects from treatment. Mifepristone therapy is devoid of major side effects, and thus may provide possibly a longer higher quality life than "approved therapy." The treatment of patients with cancer has provided huge profits both for the pharmaceutical companies and the treating institutions. So realistically it is unlikely that mifepristone therapy will become popular in capitalistic societies.

#### *Progesterone and Glucocorticoid Receptor Modulator Mifepristone (RU-486) as Treatment… DOI: http://dx.doi.org/10.5772/intechopen.93545*

However, in some countries needed to provide effective, yet inexpensive treatment, one could consider offering patients oral government provided mifepristone rather than expensive chemo or immunotherapy agents. The cost of a mifepristone pill in China is 50 cents. In fact, since growth of tumors is still consistent with a prolonged good quality life, one could save money on expensive diagnostic tests to monitor progression. Possibly mifepristone could be considered first line therapy for metastatic disease with consideration of other therapeutic modalities only if health deteriorates despite mifepristone therapy.

Since the drug is available as a generic already, it is unlikely any pharmaceutical company will invest in larger studies to prove its efficacy. Hopefully, the published anecdotal cases, and the easing of the requirements for compassionate use, will encourage other clinicians treating patients with advanced cancer to try the drug and publish their findings. If enough treating physicians request compassionate use IND for mifepristone use, perhaps the FDA will eventually drop the requirement of compassionate use IND, facilitating the use for treating physicians around the world. Many countries, similar to the United States, at this time also restrict the use of mifepristone solely for the purpose of therapeutic abortions, and in some countries, it is completely illegal, at least at the relatively inexpensive price for the 200 mg dosage to use this drug. The use of the 300 mg dosage that does not require a compassionate use IND is cost prohibitive. Possibly the manufactures may one day reduce the price considerably or it will be manufactured by a generic company at a much lower price when the patent expires. Perhaps at a lower cost, insurance companies will be happy to pay for off-label use of mifepristone realizing how much cheaper it is for cancer therapy than conventional chemo or immunotherapy regimens.

As previously mentioned, clinical trials with mifepristone for cancers associated with the classic nuclear P receptor were "disappointing" and thus clinical trails were not pursued. When these studies were initiated 20–30 years ago, the hope was that metastatic cancer can be "cured." It is now realized that the best hope for advanced cancer is a truce with extension of a better quality of life. Also, at that time the goal of therapy was to induce a tumor response as evidenced by complete or partial tumor regression. We think if they had used the endpoints of quality and length of life, they would have had the satisfaction of treatment as we have had in these anecdotal cases. The majority of cases do not show tumor regression but stable disease and improved quality and length of life.

As far as side effects, the drug has been well tolerated. In higher dosages mifepristone can, by blocking the glucocorticoid receptor, lead to higher serum cortisol levels which acts on the mineralocorticoid receptor leading to hypokalemia. One has to be careful when using other drugs that can interfere with the metabolism of mifepristone leading to hypokalemia. We had one unreported case of a woman adding mifepristone to her ongoing treatment with alpelisib, which in itself can cause hypokalemia. Whereas the combination led to hypokalemia, neither drug by itself caused it. She was taking just the 200 mg dosage of mifepristone.

Similarly, case number 9, who was taking the 300 mg dosage, did develop hypokalemia when she was switched to another bronchodilator for her COPD, but reverted back to normal when it was stopped. She was taking the 300 mg dosage of mifepristone [45].

One man with stage IV non-small cell lung cancer became more somnolent when adding mifepristone to his fentanyl that he was using for pain. Though we advised him to reduce the dosage of fentanyl, he chose to just stop the mifepristone and died 2 weeks later. He had only taken the mifepristone for 2 days.
