Abstract
Background/Aim: It has been hypothesized that many, or even most cancers, utilize a unique immunomodulatory protein, called the progesterone induced blocking factor (PIBF) to allow spread of the cancer. Support for this concept has been provided by cancer cell line studies showing that PIBF is produced by these cancer cells and mifepristone suppresses this protein and inhibits proliferation of these cells. Furthermore, controlled murine studies with several spontaneous different types of cancer showed a clear beneficial effect of mifepristone over placebo control. Finally, there have been a variety of anecdotal reports showing efficacy of mifepristone in providing increased length and quality of life in patients with different types of advanced cancers. Case Report: Single agent mifepristone was found to provide significant palliative benefit for a 51-year-old male whose metastatic advanced fibroblastic osteosarcoma progressed despite surgery, radiotherapy, multiagent chemotherapy, and targeted therapy. Conclusion: Thus, osteosarcoma can be added to the list of cancers, not necessarily associated with the classic nuclear progesterone receptor, that seem to respond to progesterone receptor antagonist therapy.
- Osteosarcoma
- progesterone receptor antagonists
- progesterone induced blocking factor
- mifepristone
- metastases
Osteosarcoma is a less common cancer accounting for less than 1% of all cancers (1). It is most common in early puberty, or patients aged 50-70 (2). Though it is most commonly found in long bones, including the femur, tibia, and humerus, it can also be found in the pelvis (3).
Unfortunately, once the osteosarcoma has been diagnosed, it is likely that it has already metastasized, especially to the lungs, which leads to a median time of progression of 10 months when radiographic evidence of lung lesions appears (4, 5). Thus, the modern concept of treatment for osteosarcoma, except possibly low-grade lesions, includes neoadjuvant therapy with doxorubicin, cisplatin, and high dose methotrexate, followed by surgical resection of the osteosarcoma. Subsequent to surgical resection, adjuvant chemotherapy is recommended.
Wide surgical resection, or limb amputation, are the types of surgical techniques performed. There are various factors that help the surgical oncologist determine which type of procedure to perform (6, 7). It seems that the majority of surgeons at present perform the technique of wide excision, with limb sparing surgery, as opposed to amputation (7).
Regarding adjuvant chemotherapy, there have been several clinical trials evaluating the efficacy of tyrosine kinase inhibitors, which are considered as multi-target drugs. Both oral multi kinase inhibiting drugs, regorafenib and pazopanib, are being used in clinical trials for osteosarcoma (8-10). Regorafenib targets angiogenic factors (VEGFR1-3, TIE2) and oncogenic kinases (KIT, RET, RAF). Pazopanib inhibits VEGFR, PDGFR, and cKIT.
One of the major developments in the treatment of a variety of cancers is immunotherapy, where antibodies are developed against key factors needed for tumor progression, and especially against factors that allow the cancer to evade immune surveillance. One of these immune targets is the programmed cell death ligand 1 (PDL-1), which is a cell surface protein that inhibits CD8+ T-cell mediated immune response. Antibodies directed against PDL-1 and PD-1 are known as check-point inhibitors and have been found quite useful in prolonging life and improving quality of life in patients with a variety of cancers (11). Two of the well-known check-point inhibitors are nivolumab and pembrolizumab.
PDL-1 has been reported to be expressed in some sarcomas, including osteosarcomas (12-14). Indeed, one trial evaluated single agent nivolumab and found a clinical benefit, i.e., a partial response, or stable decrease, was found in 50% of the treated cases (15).
There is evidence, that the progesterone induced blocking factor (PIBF) is another immunomodulatory protein that can help both the fetal placental unit and a variety of cancers to evade immune surveillance by natural killer (NK) cells in the respective microenvironment (and probably also macrophages and T-cells) (16-20). Furthermore, therapies utilizing antibodies against PIBF have not been developed for treating cancer similar to antibodies against PDL-1 and PD-1. PIBF seems to require stimulation of a membrane P receptor for its production. Progesterone receptor modulators have shown, in anecdotal reports, significant palliative benefits for very advanced cancers where no other treatment option was available (21-26). Though this type of therapy would be considered hormonal therapy, rather than immunotherapy, the end effect is intended to be similar to immunotherapy with check-point inhibitors, i.e., to remove a block allowing immune cells to attack cancer cells.
Since there had been one anecdotal case report of a significant palliative benefit in a patient with a malignant fibrous histiocytoma, a decision was made to treat a 57-year-old man with advanced fibroblastic metastatic osteosarcoma with mifepristone, who was progressing despite chemotherapy (22).
Case Report
The patient was diagnosed at the age of 46 with a fibroblastic intermediate grade osteosarcoma of the right tibia. He received neoadjuvant radiation therapy followed by resection of the right proximal tibia, removing a 6 cm tumor. Following surgery, he was given a chemotherapy cocktail of doxorubicin, cisplatin, and high-dose methotrexate for 9 months. He suffered from multiple side effects during this treatment. The tumor recurred in the same area as the previous resection. At this time, a 1.6×1.3 cm upper lung nodule and a 1.2×0.9×0.78 cm right lower lung nodule, were also seen.
Subsequent to the second tibial surgery, he was treated with ifosamide and etoposide for 5 months. This treatment produced the typical side effects seen with this therapy. This treatment continued for another 6 months, but now alternating with high dose methotrexate. However, the chemotherapy was stopped, because it did not seem to stop disease progression (the two lung lesions continued to grow, and new right tibial lesions were seen). At this time, he was advised that there were no other treatment options. Subsequently, Foundation 1 testing revealed targeted mutations in CD104, FGRI, and KRAS. He was subsequently treated, based on this testing, with the targeted drug regorafenib. CT scans 8 months later showed continued disease progression. He now had four left lower lung lesions, and the upper right lung lesion grew in size. He also demonstrated a metastatic lesion to the ischiorectal fossa, one in the right lower leg and one in the right pelvis (sizes 5.1 cm, 4.1 cm, and 6.5 cm, respectively).
The regorafenib was better tolerated than previous chemotherapies, but he was suffering from significant pain in his hands and feet. He also complained of somnolence. Though the disease progressed, his oncologist explained that there were no more treatment options. The oncologist suggested that the patient continue with regorafenib because possibly the cancer would progress even more aggressively if he stopped the drug.
The patient heard that the oral progesterone receptor, mifepristone, had been used for various advanced cancers, and some have seemed to respond to this therapy as manifested by improved quality and length of life. The patient was explained that mifepristone had never been used for the treatment of osteosarcoma. Nevertheless, the patient wanted to give this therapy a try. A compassionate use investigational new drug (IND) application was requested to the USA Food and Drug Administration, and permission to use mifepristone off-label was granted, based on anecdotal experience when used for a variety of other cancers.
His oncologist suggested that the mifepristone be used in conjunction with the regorafenib. Five months on combined therapy, for the first time, there was no disease progression noted after radiologic evaluation. There were no additional side effects with the addition of mifepristone.
The patient decided that since while taking single agent regorafenib, his cancer progressed, and it was stable once mifepristone was added, and since he was still suffering from pain in his hands and feet, he decided to stop the regorafenib and continue single agent mifepristone. The pain in hands and feet abated after three weeks.
For five more months, positron emission tomography scan assessment showed stable disease. The patient was able to participate in activities that he enjoyed the most, i.e., national and international travel. Though without suffering any side-effects, despite some pain from his metastatic lesion to his ischiorectal fossa, he elected after consultation with his oncology team to have a radical resection of the mass in the ischiorectal fossa, his right pelvis lesion, and right leg osteosarcoma.
The biopsied specimen showed minimal treatment affects in the malignant lesions in the ischiorectal fossa. However, the right lower leg and the right pelvis mass lesion showed subtotal necrosis consistent with treatment effect. The surgery resulted in relief of his pain. His energy remained good and was still ambulatory and able to continue his passion of travelling while continuing single agent oral mifepristone 200 mg daily (the same dosage that was originally given).
Five months later, the four lesions that had remained stable in his right lower lung, seemed to have coalesced and now appeared as one larger lesion. He had no respiratory symptoms. A conference amongst his oncology team occurred. The purpose was to decide if he should be treated with palliative radiation to the lower right lung lesion. The lesion in the right upper lung remained stable in size. The patient consented to have five days of palliative radiotherapy to the right lower lung lesion. One month following radiotherapy he is still feeling “pretty good”, continuing physical therapy following his surgery with no respiratory symptoms. In fact, the patient stated that because he had significant side effects from every chemotherapy regimen, but no side effects from mifepristone, and because the surgery six months ago had markedly relieved his pelvic pain, he actually feels significantly better now, seven years from his first surgical treatment. The patient has now been treated for 1 ½ years with mifepristone and the last year only with single agent mifepristone, 200 mg orally per day.
Discussion
As mentioned, there is evidence that mifepristone suppresses the PIBF protein, and that this is the hypothesized mechanism of the significant palliative benefits seen for advanced cancers treated with antiprogesterones (19). Mifepristone has been shown to suppress the PIBF protein in culture (27). PIBF has been found to be expressed in many cancers (28-30). However, PIBF is not included in Foundation-1 testing.
Nevertheless, with the likelihood that this man’s tumor utilized PIBF to avoid immune surveillance, and with no other treatment options available, the patient decided to try the extremely well tolerated anti-progesterone mifepristone. There is clear evidence that this drug slowed cancer progression in this patient. Because of the significant side effects that he expressed with the multiagent regimen containing doxorubicin, cisplatin, and high dose methotrexate and regorafenib, he has had the most palliative benefits from mifepristone, despite starting this drug at the time of his most advanced cancer progression. The patient stated that he feels better now in the last 10 months of exclusive single agent mifepristone therapy than any time in the 7 years since his cancer was first diagnosed. In this man’s case, the use of tyrosine kinase inhibitor, regorafenib, did not seem to stop progression. The efficacy of mifepristone has been demonstrated in non-small cell lung cancer positive for the EGFR mutation that progressed despite treatment with the third-generation tyrosine kinase inhibitor, osimertinib (31).
Foundation 1 testing did not demonstrate any mutations in the PDL-1 or PD-1 markers, therefore, a check-point inhibitor was not an option. However, it should be noted that the treatment with mifepristone has shown increased longevity and improved quality of life in a case of non-small cell lung cancer positive for the PDL-1 marker, who progressed despite treatment with nivolumab (32).
Palliative surgery, and/or radiotherapy, was performed in this osteosarcoma patient, while taking mifepristone to slow disease progression. This apparently had been similarly suggested for multifocal renal cell carcinoma (33). This was the first time when the effect of mifepristone on tumors that have not regressed but remained stable was seen histologically. One of the excised lesions showed minimal drug effect and the other two showed significant drug effect.
Conclusion
The fact that treatment with a progesterone receptor antagonist has shown in some advanced cancer cases important palliative benefits, supports, but does not prove, the hypothesis that cancers, similar to the fetal placental unit, utilize a unique immunomodulatory protein (PIBF) to escape immune surveillance, and that therapy aimed to suppress this protein can restore innate immune suppression of cancer growth and metastases (19). The anecdotal report supports the concept that membrane P receptors are responsible for PIBF production and are the target of anti-progesterone therapy (18).
Demonstration of efficacy of mifepristone in one case does not necessarily equate with a high likelihood of helping the majority of patients with this given osteosarcoma. Thus, a larger study evaluating mifepristone for advanced osteosarcoma that has progressed despite standard therapy is needed.
Hopefully, this case, added to the other case reports demonstrating obvious clinical palliative benefit for many cancer types, should encourage the addition of PIBF to Foundation 1 testing. The much less expensive dosage of mifepristone (200 mg), that is approved as an abortifacient, can be obtained by a compassionate use investigational new drug (IND) approval by the Food and Drug Administration (as was obtained for this case of osteosarcoma). This lower dose was used for the majority of the published anecdotes. This dose does not have significant anti-glucocorticoid effects, thus supporting the hypothesized mechanism that its benefit is related to suppressing the progesterone receptor and not the glucocorticoid receptor (17, 18).
The 300 mg dosage, approved for its anti-glucocorticoid effect for the treatment of hyperglycemia associated with Cushing’s syndrome, is far more expensive ($500 per pill vs. $15 per pill), but can be prescribed without an IND. If substantiated by other groups in larger studies, progesterone receptor antagonist may prove to be the best drug on the market for treating advanced cancers, considering its efficacy in multiple cancers, its oral administration (and), the lack of significant late complications, and the lack of immediate side effects (34). Mifepristone and other progesterone receptor modulators have the potential to be used in the majority of the world’s population with cancer, and could, from an economic standpoint, save a great amount of money spent for healthcare, related to cancer treatment (34).
Footnotes
Authors’ Contributions
The majority of the manuscript was written by the lead Author. Modifications in the manuscript were made by the other Authors. Diane Check runs the clinical cancer studies. Dr. Trina Poretta also served as the oncology consultant during the patient’s treatment. Carrie Wilson was in charge of obtaining the compassionate use IND.
Conflicts of Interest
The Authors have no conflicts of interest to declare regarding this study.
- Received February 13, 2021.
- Revision received February 28, 2021.
- Accepted March 1, 2021.
- Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
References
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