Efficacy of the Progesterone Receptor Antagonist Mifepristone for Palliative Therapy of Patients with a Variety of Advanced Cancer Types

Discussion

Although clinical experience is limited, to date, all patients with a variety of very extensive cancer types have demonstrated some type of improvement in clinical symptoms or slowing of the progression of disease following treatment with mifepristone. There were few, if any, side-effects of the medication (reduced price courtesy of Danko pharmaceutical). Because it is an off-label use third party payers do not reimburse for the mifepristone therapy. It costs about $450 per month.

Mifepristone is a synthetic 19-norsteroid that has a high affinity for both progesterone and glucocorticoid receptors resulting in a competitive inhibition of both types of hormones (13, 14). At a certain dosage symptoms of adrenal insufficiency, e.g. weakness occurs. The decision to use the dosage of 200 mg/day was based on the demonstration of some response as far as shrinkage of some tumors known to be progesterone receptor positive, but without significant side-effects (15-19).

In the murine studies we conducted in mice with tumors that were not likely to be positive for progesterone receptors, the improvement was not in the disappearance of tumors but in increased longevity and much improved body conditioning scores (8-11). Similar observations were noted in two patients with extensively metastatic colon cancer, i.e. improved longevity, improved quality of life, a halt to the rapid progression but no disappearance of metastatic lesions (12). It is interesting that in a phase II trial of mifepristone for untreated metastatic breast cancer known to be positive for progesterone receptor, the conclusion was that mifepristone had only minimal activity (19). The parameters evaluated were complete regression of metastatic lesions (no patients), partial response, i.e. some disappearance or shrinkage of tumors (3 women), stable disease in 11 and progressive disease in 14 (19). Thus compared to other agents, these responses were disappointing in this supposedly ideal group (19).

However, based on our observations, we believe that the response to progesterone receptor antagonists should not be judged on tumor regression, but on an improvement in quality of life, length of life and disease stabilization rather than remission. Thus, it may serve more in a palliative than a curative role, at least as a single agent.

Interestingly, using the same dosage of 200 mg/day, the breast cancer study found lethargy and nausea in 68%, anorexia in 29%, vomiting in 29%, hot flashes in 50%, and skin rash in 32% (19). None of the patients in the present study had these complaints. However, they were not given quality of life questionnaires with these specific complaints. They were merely asked questions concerning their energy, pain and whether there were any significant side-effects. All patients had some improvement in the first two categories and no one complained of side-effects. We were concerned that 400 mg/day may induce significant glucocorticoid deficiency side-effects and could lead to symptoms of adrenal insufficiency, e.g. nausea, anorexia, weakness, confusion and abdominal pain. Since the main objective was palliation, we elected not to try this higher dosage.

Our studies of human leukemia cell lines showing mRNA for PIBF in all cell lines tested leads us to suspect that the palliative effect of mifepristone was acting on the progesterone receptor and not on the glucocorticoid receptor (7). However, the nature of this study does not allow us to draw any conclusions as to the mechanism of action of mifepristone in these cases. To best distinguish whether the palliative effect is related to progesterone receptor antagonism vs. glucocorticoid receptor antagonism, one might try treating with a more pure progesterone antagonist, e.g. onapristone (20). Onapristone has induced tumor responses in primary breast cancer positive for progesterone receptors (20). Our preference would have been to use onapristone rather than mifepristone. However, only mifepristone was commercially available. Higher dosages may be possible if one develops the proper pure progesterone antagonist.

The possibility exists that mifepristone blocks the receptor for cortisol, but not for some of the synthetic glucocorticoids, e.g. prednisone or methyl-prednisone. If this is found to be true, one could consider higher dosages of mifepristone with the addition of synthetic glucocorticoids and possibly synthetic mineralocorticoids.

In the United States mifepristone is a restricted drug. It can only be used by licensed abortionists. One needs special permission from the Food and Drug Administration to use it off-label. Approval can only be obtained for cases where no known approved therapy exists or the patient has proven resistant at this time to standard therapy. It is hoped that this study could stimulate interest in trying mifepristone for various cancers in other countries than the United States where the anti-abortion politics are not so strong that it is very difficult to freely prescribe this drug even if the end-point is termination of cancer and not pregnancy.

The case of thymic epithelial cell cancer had come for her annual gynecologic examination and mentioned that she was diagnosed with this very rare cancer for which there appears to be no adequate chemotherapy. Unfortunately radiation therapy had failed to halt progression. She was advised of our theory that some types of cancer may ‘borrow’ a mechanism from normal pregnancy that is used to escape natural killer cell surveillance. She was also advised of our preliminary positive data showing that a treatment with mifepristone seemed to prolong length and quality of life in the mice with various cancers that were treated.

We said we could apply to the FDA for permission to use this drug. We chose 200 mg per day because this dosage had been safely used in other conditions, e.g. Cushing's syndrome and meningiomas without causing adrenal insufficiency unlike 400 mg/day. The FDA approved her use of the drug not because she was end-stage, but because there was no other chemotherapy known to halt the tumor (she failed to respond to the experimental use of octreotide).

Since she was under the continued observation of her oncologists and had CT scans at two month intervals in her case we had the opportunity to observe her progress for two years. The lesions did not grow or increase in number, whereas they had been growing and increasing in number for six months prior to therapy. She had prior symptoms of mildly diminished energy, which she reported improved for the two years she was on the mifepristone and she maintained normal activities.

She was the first human case that we treated. She was still nervous that the mifepristone though halting tumor progression, did not induce a remission. A consultation with a different radiation therapist led to the attempt to ‘eradicate’ the cancer with a second course of radiation therapy which ultimately led to complications and her death. Besides the halt in tumor progression, the fact that she lived longer than almost all other cases with this cancer suggests that the mifepristone did have some palliative benefit.

The man with the extremely aggressive transitional cell cancer of the renal pelvis quality of life had deteriorated so much that he was in hospice. We certainly could not ask the patient to fill out a standard quality of life form. Sometimes predictions of imminent death are not accurate and a patient who lives two months instead of one week could happen by chance alone. However, the fact that for the first time metastatic lesions decreased in size or disappeared and he showed significant improvement in energy makes us believe he was benefited by the mifepristone therapy.

The leiomyosarcoma was the only cancer that showed almost complete remission with mifepristone therapy. The previous failure to respond to other chemotherapy and anti-estrogen treatment leaves little questions that this tumor responded to the progesterone receptor antagonist. The end-point used for this patient was observation of disease progression by CT scans.

The end-point of assessment in the case of colon cancer was the demonstration of failure of any growth of metastatic lesions or appearance of any new ones by CT scan whereas the disease had progressed with prior chemotherapy. Though she was not administered a formal quality of life questionnaire, our phone interview (she lived in a different state and we did not make her physically come to our office but allowed her to be monitored by her local oncologist) concluded that she had a marked improvement in energy and pain similar to the findings of the aforementioned cases of colon cancer similarly treated (12).

The 58-year-old woman with pancreatic cancer was under hospice care. Questions regarding her pain and energy were answered by her husband, who was a physician. He was amazed with the quick improvement in pain and energy once treatment started. Since we advised him that based on animal and human experience we think this medication only has palliative benefit, he opted to try a new chemotherapy regimen intending cure, which unfortunately produced complications that led to her death.

The 23-year-old male with metastatic malignant fibrous histiocytoma was told he had terminal disease. We were all extremely happy when he showed a dramatic improvement in his symptoms, especially pain and energy, with therapy. We were disappointed, however, that his life was not extended past four months. He had been told that he would probably die within one month.

When we applied for funding for larger formal human studies we were refused, with the suggestion to resubmit after obtaining some preliminary human data. Based on these anecdotal experiences, we have been finally able to obtain a grant to study the effects of mifepristone on stage 4 non-small cell lung cancer, which has failed two different standard chemotherapy regimens. This will be a phase 2 salvage study. The primary end-point will be progression free survival. The efficacy/safety endpoints will be response rate, overall survival (the expected survival is 2 ½ months for this group) toxicity assessment and quality of life as assessed by lung cancer symptom scale (LCSS).

The FDA would not allow the evaluation of a group with less severe disease. Lung cancer was chosen because the oncologists at our institution have an interest in studying this group. We have no anecdotal experience with humans with lung cancer, but mice with spontaneous lung cancer responded very well to this therapy.

There probably are some countries where the political issues of using an ‘abortion’ drug may not be as much of an impediment for using mifepristone in treating cancer. It is hoped that the sharing of our anecdotal experiences, suggesting a significant palliative effect of this type of therapy, may generate interest in larger studies of end-stage patients with other cancers or the use of this drug, or other progesterone receptor antagonists for less advanced cancers. Perhaps this treatment when administered at earlier disease stages could show an even greater ameliorative effect, either alone or in combination with other therapies. Hopefully, this study will stimulate other cancer centers to design controlled studies for a variety of cancer types.