May 15, 1997

Speakers from all over the world came to the University of Pennsylvania campus to share research and ideas on how to fight back against a common enemy: malignant mesothelioma (MM). Topics included biology, genetics, immunology, carcinogenesis, epidemiology, pathology, gene therapy, clinical studies and treatment options. I will post the relevant abstracts from the three day conference below.

My main focus was on the treatment options. I came to learn. I was impressed with the enthusiasm shown by several speakers, most notably Dr. Harvey Pass, Dr. Lary Robinson, Dr. Jack Ruckdeschel, Dr. Daniel Sterman, Dr. Larry Kaiser, Dr. Stan Mikulski and Dr. Sam Hammar. I thought there was a real spirit of cooperation, despite the language barriers, among all the doctors and researchers. I was also impressed that our friends from Japan, France, Finland, and Italy were able to speak English so well. Because of the large number of speakers, and the small amount of time allotted to them, the question and comment period that followed was often cut off, although this was usually the most interesting segment. I enjoyed the give and take and felt privileged to witness a "revolution in the making."

Here are my notes on the treatment options.

Dr. Larry Robinson (who has operated on two of my clients) gave an excellent speech about his experiences at H. Lee Moffit Cancer Center in Tampa Bay with the Extra-Pleural Pneumonectomy (EPP). He said at the outset that there is no standard treatment or magic bullet cure for mesotheliotics, and acknowledged the importance of a positive mind set by the patient in overcoming the tumor. He also stressed that the best hope that a mesothelioma patient had to prolong his life was the EPP, citing to the work of David Sugarbaker and Valeri Rusch.

Dr. Robinson's paper focused on the downsides of administering chemotherapy (adriamycin and cisplatin) prior to surgery. He and Dr. Jack Ruckdeschel, his colleague at H. Lee Moffit gave chemotherapy to three patients. The good news was that the chemotherapy cocktail reduced the size of the tumors. The bad news was that when it came time to debulk the tumor, they found that the chemo had obliterated the "extrapleural plane along the endothoracic fascia," which prevented a safe EPP. Fortunately, the three patients have shown better than expected survival with the chemotherapy alone. Because of these findings, Dr. Robinson does not administer chemotherapy prior to the EPP. He favors performing the surgery first and then following up with appropriate post surgical treatments.

Dr. Ruckdeschel raised several points throughout the conference that indicated to me that he was trying to wake people up to some common falsehoods that are casually thrown about when talking about correlating survival with various treatment options. If I understood him correctly, we should stop talking about median survival and talk about one year survival as a benchmark. The goal, he said, is to eradicate the tumor. The only plausible cure must involve the EPP procedure. Without it, the chances for survival are remote. Dr. Ruckdeschel asked rhetorically what's the point of advising a patient about median survival statistics when they want a cure. They could die on the operating table, but they could also live a long life if all goes well.

Both Dr. Ruckdeschel and Dr. Robinson were realistic about surgery's limitations. The best surgeon will not be able to scrape out or remove all traces of microscopic mesothelioma tumor. But a surgeon with a trained eye knows where to look and what to look for. Why perform a pleurectomy only, he asked, if this will only leave resectable tumor behind in a patient with a good performance status? The point: get as much of the tumor out as you reasonably can (from the lung, the linings, the diaphragm and the heart sack), and then attack with chemo and, if useful, radiation. Before the Conference a client of mine gave a glowing report about Dr. Ruckdeschel -- "we just love him." Now I know why. He is tough, gentle, smart, and an advocate.

Several doctors also raised an interesting point about pre-surgery prognostic factors. Most doctors agreed that the three keys to a successful surgery are: (1) being able to identify the size of the tumor, which is sometimes very difficult with a CT scan, (2) being able to determine whether there is lymph node involvement, also difficult to measure, and (3) being able to determine whether the tumor has penetrated the diaphragm or metastasized. In other words, there is not yet any universally accepted way to precisely and economically identify and measure the staging of a MM tumor. A doctor from Finland spoke of the MRI as a much better diagnostic tool than the CT scan (and of course the standard chest x-ray). But MRI's don't reliably tell us whether the lymph nodes are involved. The best way to determine lymph node involvement is through exploratory surgery.

Several doctors stated that many of the conclusions about whether a particular treatment modality has a favorable response percentage are skewed, they argued, because of "selection bias." That is, many patients with advanced mesothelioma that is unresectable will not be included in certain studies. So we may see a high survival ratio for a particular treatment, but it can also be said that the patient may have survived nearly the same amount of time with no treatment if nature was allowed to run its course (because of the youth and vigor of the patient, the small size and isolated location of the tumor, lymph node involvement, etc). Many of these comments were made in the context of discussions about Dr. Sugarbaker's and Dr. Rusch's published articles.

By the way, doctors from Europe universally lauded Drs. Sugarbaker and Rusch as the pioneers in developing viable surgical treatment options. Unfortunately, the doctors in Europe, Australia and Japan have not had the same success with the tri-modal therapy on their patients.

All of which raises a good point that was made by Dr. Stan Mikulski, the director of the Onconase Phase II study. Onconase has been administered since 1992 on 63 patients through 1996 (they have added another 37 this year alone, whose results were not included in the analysis presented). Dr. Mikulski pointed out that his population consisted mainly of patients who had exhausted most of their options and were found to be unresectable. To compare apples with apples, the only way to measure the efficacy of Onconase is to compare it to the population of mesotheliotics who were found to be unresectable and left untreated. Dr. Valeri Rusch reported that out of 170 or so MM patients, she did not perform the EPP on 30 because of advanced tumor. The median survival for these unlucky patients was 5.5 to 6 months. The median survival time from date of treatment for the 63 patients included in the Onconase study was 10.1 months, which is twice the untreated median survival ratio [24.7 months mean from date of diagnosis].

Dr. Mikulski has not yet published the results of the Onconase protocol. His interim conclusions are summarized as follows: (1) Onconase has demonstrated single agent activity against unresectable MM in patients who have failed previous systemic therapies; (2) the estimated overall median survival time observed for the 63 patients was 10.1 months from time of treatment; (3) of the 26 patients who have been enrolled for at least one year prior to the analysis, 42% survive today; and (4) the agent is very well tolerated (especially as compared to standard chemo agents), with only 8% of the subjects dropping out because of adverse reactions.

Dr. Mikulski, who is very personable and candid, advised me that he will be talking to oncologists on the West Coast to expand the number of clinics and hospitals that are administering Onconase. He is now spearheading a Phase III trial that will compare Onconase vs. Doxorubicin as a single agent approach. Enlisted in the Phase III trial are clinics in Detroit, Chicago, Pennsylvania, New York, Austin, Texas, among others (nothing so far on the West Coast).

Geography, in my mind, is another important prognostic factor. In general, patients treated on the East Coast of the U.S. tend to live the longest compared to mesotheliotics diagnosed and treated anywhere in the world. I think a patient's survival can be linked to (1) the expertise of their pulmonary doctor and/or oncologist, (2) where they were diagnosed geographically, and (3) the will of the patient to educate himself and his medical team, and pursue options, which may involve travel.

Currently, the only surgeons with experience in the EPP that I know about are in Florida (Dr. Robinson), Detroit (Dr. Pass), New York (Dr. Valeri Rusch), Philadelphia (Dr. Larry Kaiser), and Boston (Dr. David Sugarbaker). As a side note, I have two clients in Los Angeles who recently advised me that they have been referred to a Dr. Robert McKenna at Cedars Sinai in Los Angeles, who has advised that he has performed numerous EPPs on mesotheliotics. The point is this: in major metropolitan areas where there is a hotbed of mesothelioma diagnoses, such as Seattle, San Diego, San Francisco/Oakland, Seattle, Beaumont, Houston, etc, to my knowledge (please prove me wrong!) there are no surgical oncologists who assert themselves as experts with this tumor. In Houston, doctors at MD Anderson, a teaching hospital with a phalanx of smart surgeons, have refused to operate on any mesotheliotic, regardless of staging. This raises ethical issues, in my mind.

A corollary to the prognostic factors above is whether the patient is on the internet. Many of the doctors thanked me for referring patients to them. Other doctors also were amazed at how quickly the word gets out about cutting edge treatment options. The availability of patients who eagerly want to pursue options should help the medical community organize clinical trials.

Doctors from France, Japan and Italy presented the results of phase II clinical studies using combined chemotherapy agents. In France, a mix of Cisplatin, Fluorouracil, Mitomycin and Etopside were used in four cycles on 50 patients with unresectable MM. The response rate (meaning the rate of patients who showed at least 50% shrinkage in the tumor) was 34% with a mean response duration of 11.7 months. The overall median survival time was 16 months. The French doctor indicated that he was pleased with these figures, and said they were not too different from the median survival times for patients with lung cancer. He said they might start using interferon and interleukin 2 along with the standard combination. [Dr. Ruckdeschel, who has a very quick mind and has no patience for nonsense, pointed out that the survival rates between lung cancer and mesothelioma patients are not as close as the French doctor suggested].

Another French Phase II study used Taxol (Paclitaxel) and Cisplatin (CDDP) in 17 advanced unresectable pleural MM patients. They concluded that this combination was not effective (median survival was 18 months from diagnosis). They are now pursuing a phase II trial using chemotherapy and immunotherapy (interferon and IL-2).

Several doctors, Dr. Harvey Pass and Dr. Ruckdeschel among them, compared the progress in treating mesothelioma with the giant strides made in treating Non Small Cell Cancer (NSCC). Twenty years ago the medical community pronounced the NSCC patient dead on arrival. Now, it is one of the cancer cell types that is the most amenable to treatment. They noted that there is a move away from pessimism in the medical community, but we all know it is a very slow move (see notes about MD Anderson terminating the EPP and the lack of good surgeons on the West Coast and in the Midwest). More trials are needed. Articles are published frequently, but the question is whether the doctors in small rural towns or in big city hospitals are taking the news seriously. With the onset of the internet and its gateway to timely medical information, and the increasing incidence of mesothelioma diagnoses in the U.S., there should be no shortage of patients to fill the protocols. We need more and better trained doctors.

In Italy, a clinical trial using intrapleural and systemic recombinant interleukin-2 (rIL-2) on 31 pleural MM patients showed a response rate on the tumor mass of 22.5%. The response rate on pleural effusions was 90%. Side effects were moderate. Given the existence of side effects, several doctors questioned whether this was worthwhile since pleural effusions can be treated surgically fairly easily and painlessly.

Dr. Ruckdeschel also raised the point that taxotera (a chemo agent manufactured in France) has been shown to target the pleura and is highly toxic to malignant mesothelioma cells in vitro. Several doctors responded that they would like to see a phase II trial using taxotera as a single agent approach to MM. In addition to Taxotera, other chemo agents with promise included Hyaluronanidase. According to Dr. Pass, although this agent has not been thorougly tested in a trial, studies indicated a 50% response rate. Dr. Pass was "intrigued" with the possibility that Hyaluronanidase might help facilitate the invasion of the tumor by cisplatin, since mesothelioma tumors secrete agents that stimulate the production of hyaluronan.

Photodynamic Therapy. A doctor from Amsterdam, Holland spoke about the use of Photodynamic Therapy (PDT) during surgery on nine (9) MM patients as a promising addition to the anti-meso arsenal. The speaker noted that Dr. Pass was the pioneer in this approach. Dr. Pass, who is an excellent speaker with a refreshing ability to cut through the jargon, commented that we are climbing the learning curve with the help of new technologies, such as upgraded diode lasers, sensitizers and light delivery systems.

By the way, Dr. Pass is a very warm human being with an endearing "bedside manner." Among all the speakers, he seemed to know the most about more subjects. A modern Mesothelioma Renaissance Man! In a non-threatening manner, he made intelligent criticisms of other speakers' work and offered helpful insights about his own experiences as a surgeon and researcher. He seemed at home on virtually any topic ranging from immunology, genetics, chemotherapy, clinical trials, and politics. Like Dr. Kaiser, Dr. Robinson, Dr. Sterman, and Dr. Ruckdeschel, Dr. Pass has a genuine enthusiasm about beating back mesothelioma.

Gene Therapy: The Best is Yet to Come. Gene Therapy aims to boost the body's immune response to foreign invaders like mesothelioma tumor cells. [Link to the PRIMER on the webpage] To put the state of the art for gene therapy in historical perspective, a speaker compared where we are now to where aviation was at Kitty Hawk when Orville and Wilbur Wright soared a few hundred feet some two feet off the ground. Baby steps. The UPENN gene therapy team in all was very conscientious and realistic. When patients call in, they understand the conflict: patients want to be cured. But UPENN cannot offer a cure at this time. First, UPENN must tackle fundamental problems, such as figuring out how to transfer the altered gene to all of the mesothelial cells (which can be diffusely distributed). Also, it's difficult to engineer a cancer eating virus or antibody when we don't know at the genetic level how mesothelial cells turn malignant.

Dr. Sterman seems to know as much as anyone in the world about the gene therapy approach to MM. He spoke of the Phase I clinical trial, which involved 15 patients who have been followed from November 1995 to January 1997. The study was allowed to proceed because they had obtained some interesting responses with mice. In mice, the gene therapy actually shrunk full blown pleural mesothelioma tumors down to a microscopic level. However, even with the tumor regression, the mice still died. The 15 human subjects ranged from age 37 to 74 and the mean age is 65. The most important finding from the study from the scientific viewpoint is that they did find evidence that the gene actually transferred to some of the mesothelioma tumor cells. Unfortunately, the genes would not transfer beyond 3 or 4 tumor cell layers, which is not good because mesothelioma tumor clusters can be several centimeters thick.

Of the 15 patients, 7 died after treatments. The median survival after treatment was 23 weeks. They found no evidence of tumor regression. Toxic side effects were minimal and one of the patients is still living 17 months after the treatment.

Which raises the question, why would anyone want to participate in the UPENN study? UPENN has strict criteria for eligibility: no prior chemo, no pleurodesis, no resection, good performance status, etc. If a person has a stage I tumor that might be resectable, why would he opt for something experimental at best? I asked Dr. Sterman about this ethical quandary. His answer was clear and thoughtful. He personally screens all the applicants, and there have been hundreds. If the applicant's status indicates that he/she may have a more reasonable hope for a longer survival using surgery, chemo and/or radiation, Dr. Sterman will advise them to seek help from specialists, the names of whom he will glady give the patient.

UPENN has several trials on going. It appears that the US and Australia are the leading countries in the race to find a gene therapy treatment for mesothelioma. Dr. Sterman hopes that they can develop a gene therapy that can be administered during a surgical debulking operation. Also, it is very expensive to manage, staff and equip a qualified team of gene therapy researchers. It sounded like we were very lucky that the University of Pennsylvania and a few other organizations were underwriting the research.

An interesting side note: an australian geneticist spoke more optimistically about the use of gene therapy in humans. He said their goal is to help the body do what it in extremely rare circumstances is able to do on its own--that is, a "spontanous regression." The body can attack and kill the invading cells in particular organs. Why can't the white blood cells and macrophages then spontaneously attack and kill cancer cells? A question easier asked than answered. The doctor showed us the magical case of a woman in Austrilia with a large pleural mesothelioma tumor. She did not have any treatment but a few months later he took a CT scan and it was clear that the tumor had radically regressed! How? They took a biopsy and examined the tumor tissue and found a swarm of macrophages and lymphocytes that her body spontaneously generated to fight off the tumor. Incredible. As usual, Nature sets the best model. [If we could find away to clone her white blood cells!] The Australian doctor felt strongly that the prospects were good for finding a gene therapy partial solution to the mesothelioma problem.

But here's a question. Many of the researchers indicated that the incidence of disease was stabilizing in their countries. Only the industrialized countries sent representatives (nobody from Africa, Latin America or South America attended). On a curve, it is forseeable, especially in "enlightened societies" who have banned the commercial and industrial use of asbestos fibers, that after a sufficient latency period you would not expect to see any substantial number of mesothelioma cases. In the U.S. for example, where there are very few background exposure hotspots (e.g., Libby, Montana, Globe, Arizona, Coalinga, California), if you assume that all friable asbestos has been abated and no more fresh asbestos products are being used, it would seem logical that one day we will be seeing markedly fewer cases. The question is: by the time we find a "cure", what will be the size of the MM population? In the U.S., the number of new cases will be peaking in 2010 or so. I wonder sometimes whether our government takes the nihilistic view that the costs of trying to find a cure for mesothelioma are outweighed by the benefits because eventually we will be seeing fewer cases and the epidemic will fade away quietly.

Which brings up the AIDS model. The US Government has financed basic and clinical research on finding a cure for AIDS. Why? I think it has to do with the political savvy of the AIDS patients and their advocates. They have been very strident about getting their message out and demanding government subsidies and assistance. Asbestos victims have a few advocacy groups, and this is not meant to rebuke the work that they have done, but certainly our "crusade" has not had the same political impact. One of the doctors at the conference privately suggested to me that we form a foundation to help fund basic research by independent thinking medical and scientific experts who will pursue the lure of a cure with the same zeal that swept Watson and Crick to discover the DNA double helix. This is a good idea.

It is difficult to distill three days and over 50 speeches into a catchy theme. But the take home message seemed to be: we have come far, but we have a long way to go. They seemed to appreciate that their task was not academic. They realized that the stakes are high, that thousands of people worldwide are afflicted with this terrible disease. I detected an esprit de corps among these medical pioneers, a passion, if you will, to search out and destroy malignant mesothelioma and prevent it from ever rearing its ugly head again. Unfortunately, there was very little mention of issues like prevention, responsibility, and quality of life.

Also in the audience were several friends of asbestos. I noted a representative from the National Insulation Manufacturers Association and several doctors who have happily testified for the asbestos comapnies: Dr. Bernard Gee (a likeable English fellow), Dr. E.A. Gaensler, and Edward Ilgern, an industrial hygienist who consults for the W.R. Grace Co. It's sad that instead of devoting their talents and intelligence to finding a cure or helping to reduce the risks still faced by millions, these medical mercenaries have joined up with the dark side to help the asbestos industry cover up or sugarcoat their nasty record of death and disease.

Which raises two problems I had with the conference: one, the totally unproven and unsupportable suggestion that mesothelioma may be caused by a contaminated poliovaccine (SV40), and, two, a haphazard and ill-placed speech by Edward Ilgern, a consultant to the W.R. Grace Company, who rushed through a speech that, in my mind, sought to downplay the existence of tremolite related death and disease in Libby, Montana. He also tried to argue the tired argument that chrysotile does not result in serious death because we have not seen a rash of mesotheliomas around Coalinga, California. I looked it up on the map and it appears to be a tiny little town in central California about 7 miles West of Interstate 5 and about 40 miles SW of Fresno as the crow flies. I wonder how many people have lived there for more than 20-25 years who might have been exposed to what I'm told is a chrysotile mountain.

First, the poliovaccine whitewash. From 1953 to 1963, the poliovaccine used in the U.S. was (I'm told) contaminated with SV40, a virus. Researchers in Italy (also funded at the University of Chicago) suggested that the SV40 was capable of infecting the mesothelial cells. The researchers suggested that the SV40 may act in combination with asbestos fibers in inducing cancer. However, there is no research that studies the incidence of mesothelioma among non- asbestos exposed persons who received the SV40 poliovaccine compared to asbestos exposed persons who did not receive the vaccine. The "hypothesis" was hotly debated. In the crowd were several long time friends of the asbestos industry who no doubt were already contriving ways to incorporate this flimsy argument into their next court room testimonial in an effort to muddy the waters for the jury.

It would not surprise me if the Asbestos Industry Trade Associations has begun to recruit researchers who will give credence to the poliovaccine virus causes mesothelioma argument. If the SV40 virus truly were a mesothelioma co-factor, in view of the fact that millions of Americans were vaccinated against polio from 1953 to 1963, it would seem logical that we would be seeing a substantially higher number of mesothelotics without any exposure to asbestos.

The Libby whitewash. Ed Ilgren, a W.R. Grace consultant, spoke about the incidence of disease in Libby, Montana, home of the W.R. Grace/Zonolite Co. Vermiculite processing mine and mills. He suggested that 50% of the reported mesotheliomas in 1982 among Libbyites could not be linked to asbestos exposure. He said that the diagnoses lacked confidence because an autopsy was not performed. He also said one could not safely point to tremolite asbestos as a co-factor because there were other sources of asbestos exposure in and around Libby. He noted that the town's drinking water was contaminated with creosote, implying that other carcinogens were responsible for the high incidence of cancer in Libby. He did not mention the fact that for years W.R Grace dumped hundreds of tons of tremolite contaminated mill tailings into the river upstream from the town's water supply intake pipes. Nor did he talk about the incidence of asbestos related diseases among actual employees with more than ten years of exposure or their relatives. Nor did he even attempt to make the issue relevant by bringing up-to-date the number of reported mesothelioma, lung cancer and asbestosis cases that have been diagnosed since 1982 ( a very large number). It left me puzzled and dissatisfied.

I could tell that he had a bias so I approached him after his presentation. I asked him about the data he relied on and where he got it (he thanked several corporations before his speech for their assistance, including Grace, Manville, Union Carbide and others). He asked who I was. I told him I was a lawyer. He asked if I represented plaintiffs. I said yes. He then said that he would not speak to me, that it would be "a conflict of interest." I reminded him that I was simply asking him what data he was relying on and, moreover, the facts I was relying on where verified under oath from Grace employees (like Earl Lovick). Imagine it. He can get up before a hall filled with scientists, doctors, researchers, industry apologists and government officials and downplay the carcinogenesis of tremolite and chrysotile asbestos, but he won't talk to a lawyer who was asking simple questions about what data he was relying on to reach his sweeping conclusions.

He later admitted that the Grace mining and milling plants were "shitholes". He also kept wanting to draw a distinction between the nasty plant conditions before Grace purchased the plant and the scrubbed version after Grace bought it. He kept repeating the year 1976. I reminded him that W.R. Grace bought out the Zonolite Company in 1963. The "shithole" to which he was referring was in fact owned and operated by the same company who pays him to testify that tremolite is benign and that the plant was clean -- W.R. Grace.

A few more parting shots: three days of speeches from the world's best and brightest did not yield any discussion on possible treatments for peritoneal mesothelioma. They seem to be forgotten.

Also, it's cliche, but it bears repeating: an ounce of prevention is worth a pound of cure. There was no mention that Mesothelioma is preventable if we eliminate asbestos exposures. There was a speaker from Russia who spoke about the carcinogenesis of asbestos in rats -- hardly a fresh topic! Meanwhile, in Abest, Russia, they continue to mine and manufacture millions of tons of raw asbestos. There were speakers from Canada, which continues to be the world's leading exporter of chrysotile asbestos. I understand many asbestos products are still being used in France, and I'm sure this is the case in most of Asia and Japan, as well as South Africa.

Finally, a bit of history.

An epidemiologist from Canada spoke about the high levels of asbestos in the air in the towns of Asbestos, Thetford Mines andBlack Lake, all located in Quebec. These open pit asbestos mines were open for business in 1880. He wanted to assess the risk faced by women in these mining towns for getting mesothelioma. Tremolite asbestos was a significant source of the airborne fiber. Dr. Camus talked about his research methods to determine what the levels of exposure were for housewives in these towns back in the 1930s, 1940's, 1950's and so on. One source was the women themselves. He asked them about the levels of dust in the town. They reminesced about how on windy days the entire town was covered in a fog. They spoke of a fine film of asbestos dust on the city sidewalks each morning. They joked that on Sunday Morning the town busybodies could tell who was going to Church and who wasn't by the size of the footprints on the sidewalk! He showed us pictures from the 1950s showing that the mill tailings piles were taller than the top of the church steeple in the town. We also saw photographs of the asbestos contaminated piles that backed up against the homes and yards of the townspeople.

The epidemiologist talked about the mesothelioma risks that bystanders (women who did not work in the mines or mills) in Asbestos and Thetford Mines faced relative to the general population elsewhere. He said that a threshold level above which a person will likely contract asbestosis is "25 Fiber Years." To put that number in context, he estimated that the inhabitants of Thetford Mines had cumulative exposures of 122 Fiber Years! Dwellers of Quebec had the equivalent of 74 Fiber Years. He noted that there were a higher incidence of mesothelioma cases in Thetford Mines, which was a richer source of tremolite than the town of Asbestos.