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Ocular Melanoma Metastatic to the Liver
This account describes one patient's experience with Tetrathiomolybdate (TM), a copper-chelator and angiogenesis inhibitor.
Please note that Sam's mother has esophageal cancer, not ocular melanoma. Esophageal cancer is very different from ocular melanoma, but Tetrathiomolybdate's inhibition of the formation of blood vessels may have application for tumors of any type. (Used with permission.)
From: "Samuel Conner"
Date: Sat, 05 Jan 2002 19:11:26 -0500
My mother (age 65) was diagnosed with Stage IV esophageal cancer in the Summer of 2001. We sought prompt medical treatment and were offered a standard first-line treatment at a well-known nearby oncology hospital. The treatment was initially effective, but it was too toxic for Mom, the regimen could not be consistently implemented because of the toxicity, and it began to appear that her liver metastasis was becoming resistant to the therapy.
As it became evident that things were not going well, my siblings and I began searching print publications and the web for information which might lead us to a low-toxicity, broadly applicable investigational therapy which could be implemented quickly. We were looking for investigational therapies because it appeared that the well-established conventional therapies were not working well for Mom. We were looking for low-toxicity therapies because Mom was much weakened by the progress of her disease and by the current therapy itself. We wanted a therapy which had evidence of broad applicability to a range of tumor types because we expected that we only had one chance to save Mom, and we wanted to be reasonably confident that the therapy would work (and, further, there was some uncertainty in the diagnosis of Mom's disease). We were hoping to find something which could be implemented under the supervision of a local oncologist, without the necessity of travel either to a distant oncology clinic or to the distant site of a clinical trial in order to avoid the hardships which such travel would impose on Mom in her weakened condition.
We were ultimately successful in finding a readily implementable experimental modality of seemingly broad applicability, and Mom is now receiving this regimen in addition to a 2nd line conventional chemotherapy agent.
PLEASE NOTE THAT THIS STORY IS NOT OFFERED AS, NOR INTENDED TO BE, NOR TO BE CONSTRUED BY THE READER AS, MEDICAL ADVICE. THE READER MUST SEEK QUALIFIED MEDICAL ADVICE FROM APPROPRIATELY TRAINED MEDICAL PROFESSIONALS TO DETERMINE WHETHER THE INFORMATION DESCRIBED AND REFERENCED BELOW MAY BE APPROPRIATE FOR USE IN TREATING CANCER IN ANY PARTICULAR CASE OF THE DISEASE. THE INVESTIGATIONAL MODALITY DISCUSSED BELOW REQUIRES THE SUPERVISION OF APPROPRIATELY TRAINED MEDICAL PROFESSIONALS. THIS MODALITY HAS NOT BEEN APPROVED BY THE FDA FOR USE IN THE TREATMENT OF CANCER. NO DECISION TO PURSUE SUCH TREATMENT CAN BE MADE WITHOUT THE GUIDANCE OF APPROPRIATELY TRAINED MEDICAL PROFESSIONALS. THE IMPLEMENTATION OF ANY SUCH DECISION MUST BE UNDER THE SUPERVISION OF APPROPRIATELY TRAINED MEDICAL PROFESSIONALS. THE WRITER MAKES NO WARRANTEES OR REPRESENTATIONS AS TO THE ACCURACY, COMPLETENESS, OR FITNESS FOR ANY PURPOSE OF ANY OF THE INFORMATION IN THIS LETTER. THE READER IS OBLIGATED TO VERIFY ALL INFORMATION CONTAINED HEREIN.
We did a hasty "paper" search through several years of back issues of the journal "Science", which yielded tantalizing news pieces on investigational therapies like "Boron Neutron Capture Therapy" (BNCT), which loads tumor cells with an isotope of Boron which fissions under neutron bombardment, and then bombards the tumor with a neutron source, producing a high radiation dose localized to the tumor cells --- very, very clever. Another hopeful-sounding therapy was "metronomic chemotherapy", which uses standard chemo agents in low doses with no rest periods to attack tumor blood vessels rather than the tumor cells. Followup on these leads revealed that these therapies were not good candidates for Mom. BNCT is in experimental use in humans for certain rare, aggressive and untreatable brain tumors, but it is not known whether the Boron medicine will successfully absorb into tumor cells of other types. Too risky and no-one would agree to try it. The "metronomic chemotherapy" has had no human testing at all, only lab animals, so while it looked like a hopeful, broadly applicable approach, it would be very hard to find a physician to supervise it.
Our internet search led to sites such as Jane Brockman's "Ocular Melanoma" page, which was very helpful in pointing the way to further options, such as experimental antiangiogenic therapies. Once again, however, none of these looked to us to be sufficiently likely to work, of sufficiently low toxicity, and sufficiently easy to implement.
To our great relief, we ultimately did find an investigational modality which fulfilled our criteria of low toxicity, evidence of effectiveness against a range of tumor types and local implementability. Our internet search terminated at a very helpful website called www.cancerprotocol.com, which describes in greater detail the low-dose chemotherapy regimen we had seen in the "Science" news piece. It also describes a regimen we had never before encountered, tetrathiomolybdate.
Tetrathiomolybdate (TM) is a copper-chelator. It was developed by Dr. George Brewer of the University of Michigan as a treatment for a disorder called "Wilson's disease," a condition in which copper accumulates in the body to toxic levels. Some years ago the drug was granted a sort of limited and tentative FDA approval called "orphan drug status", which permits (in the case of TM) limited use of the agent for treatment of Wilson's disease. As evidence emerged that copper might play a role in angiogenesis, Brewer tried using this treatment on cancer patients, with some success. It appears that TM is able to interfere with the formation of new blood vessels, which in turn interferes with the growth of tumors. The completed Phase I trial of this agent was published in January 2000 in Clinical Cancer Research, volume 6, number 1, pages 1-10. The trial results are very encouraging.
Here is a link to the PubMed abstract of that article, and a link to a full-text version of the article at www.CancerProtocol.com.
I have had trouble linking to this page in tests of this message. If you cannot reach it with this link, go to www.cancerprotocol.com, click on "The Role of Copper" and scroll to the bottom of that page. The article is linked there.
In August 2000, a freelance writer named Cori Vanchieri published a news piece in the Journal of the National Cancer Institute which mentions followup work with higher doses of TM. These are reported to produce therapeutic copper reduction quicker than the dose levels tested in the original Phase I trial. This gave us great hope because we were not sure that Mom would live long enough to benefit from the dose levels tested in the Phase I trial.
Here is a link to the PubMed citation of that news piece (no text, unfortunately).
Here is another link, the PubMed abstract of an article reporting more recent research on this agent using mice with human cancer cells transplanted to them.
and finally, a link to the PubMed abstract of a very recent (July 2001) review article by George Brewer on tetrathiomolybdate as an anticancer treatment. (A review article is a survey of published literature.)
This appears to my untrained eyes to be an exciting and promising approach to long-term management of tumors. It is not always possible to cure cancer, and in cases where a cure cannot be effected, it would be very desirable to have treatments which could at least stop further progression of the disease. It appears that TM may be such a modality. It is still an investigational therapy, however. The Phase I trial and prior clinical experience in the use of this agent to treat Wilson's disease have shown that it is not highly toxic, though it can depress bone marrow. The agent is orally administered, and it is sufficiently cheap (about $15/day for the drug itself) that most people can afford it (not being an FDA-approved drug for cancer treatment, it may not be covered by HMO or health insurance plans). According to the August 2000 news piece, Phase II trials in a variety of tumor types were about to begin at that time.
After reading the www.cancerprotocol.com pages, I rushed to a nearby university medical school library and made photocopies of the original Brewer et al. article and everything else I could find which appeared to be related. The next day happened to be our visit with the oncologist who was supervising Mom's treatment. We were to discuss the results of the most recent round of diagnostic imaging and the course of Mom's treatment.
I prepared a respectful cover letter inviting the oncologist to review the attached journal articles about investigational treatments and enclosed that letter with a file of the articles I had copied. As we expected, the oncologist recommended discontinuing the current therapy, as it was ineffective. To our dismay, he recommended not attempting further curative treatment. When I tried to raise the possibility of one of the investigational treatments we had learned about, the oncologist basically brushed the question aside. He did accept the articles.
We had expected a disappointing meeting and had made arrangements to see another oncologist at another hospital the next week, just in case. Months earlier, when we were beginning to be unhappy with the first oncologist, we had met with this other oncologist to discuss a broader range of treatment options. After we stumbled onto the TM therapy, we contacted him by phone to inquire about whether he might be open to experimental therapies. He expressed a willingness to consider such therapies, provided that there was persuasive scientific evidence of their potential benefit, and we immediately made an appointment to see him again. The same day as our disappointing meeting with the first oncologist, I delivered a second set of the same articles to the second oncologist's office, again with a respectful cover letter. I later made a second delivery with some further articles I had found.
Over the course of the week prior to this crucial meeting with the second oncologist, we tried to learn more about this experimental treatment, in particular how to go about obtaining the agent. The hope was that, if the new oncologist did agree to try this experimental treatment, we would be ready to move quickly with it. We did not expect him to be familiar with the treatment or how to go about obtaining it, so we tried to get everything sorted out ahead of time. A web search on the name of the agent and the name of the principal researcher, George Brewer, led to pages at the University of Michigan, and to a toll-free number for the U. Mich. cancer information line, 1-800-865-1125. The people at the information center offered very helpful guidance about how to attempt to implement this modality, in particular information about a pharmacy which would provide this agent on prescription and advice about how to do preliminary "legwork" to make it easier for the oncologist to adopt the therapy. Also, the operator of the www.cancerprotocol.com site furnished us with the telephone number of a physician who is already using both TM and metronomic low-dose chemotherapy in cancer patients, and we attempted to explore that route as well. We hoped that this other physician might be willing to consult to our oncologist as he supervised this unfamiliar treatment regimen.
Something which caught our attention was that neither oncologist was familiar with the research we presented to them. The first one had noticed the Brewer et al. article when it appeared but apparently had not read it closely enough to become excited about it. The second oncologist had never heard of this experimental treatment at all. The information provided by the people at the U. Mich. cancer information service was crucial to quickly implementing this therapy for my mother.
At our meeting with the second oncologist the next week, the doctor concurred that the first line therapy had failed and recommended that we try a second line therapy. He had read the articles I had sent him and agreed to try the tetrathiomolybdate regimen. What seems to have persuaded him was 1) the fact that the agent was already in limited use in humans for Wilson's disease and was known to not be highly toxic and 2) the encouraging results of the phase I trial reported in the Brewer et al Clinical Cancer Research article. He wrote us a prescription right then and there and ordered the necessary preliminary blood tests. That afternoon I called the pharmacy, FAXed the prescription, and ordered the drug. Mom's first 2nd-line chemo infusion was two days later, and by the end of the day after that, the meds had arrived by overnight mail and we started my Mom on the copper-lowering regimen.
Earlier in the Summer, there had been an agonizing several week delay between the first radiological evidence of cancer and the initiation of Mom's first-line chemotherapy treatment. This time around, we were very focussed and energetic and were able to get an experimental regimen prescribed within 9 days and started within 12 days of learning of its existence. This shows how important our preliminary "leg-work" was.
That was three weeks ago at this writing. Weekly blood tests indicate that Mom's copper levels are indeed falling. It looks like she will be at the desired level within about a month. Mercifully, Mom is responding well to the second line chemotherapy treatment, which gives us hope that she will live long enough for the TM treatment to reach the target copper levels and (we hope) stop further tumor growth. It is our hope that this will give us a long-term management strategy for Mom's disease.
If this modality proves to be widely effective against a variety of tumor types (the preliminary research suggests that it may be), it may be that in the future cancer will be a disease which is treated in the same way as heart disease, diabetes, emphysema, and other chronic life-threatening conditions: it will not be permanently curable in all or even most cases, but will be manageable over the long term in many or most cases.
I hope that this note is encouraging and helpful.
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Ocular Melanoma Metastatic to the Liver
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