Does Early Stage Diagnosis of Malignant Mesothelioma Improve Prognosis?

For many years now I have been hearing asbestos company lawyers argue "that there is no medical benefit to the early detection of malignant mesothelioma." Below is an excerpt from a speech recently given by a prominent asbestos company defense lawyer at an asbestos lawyers conference in Boston. To quote:

"No studies have been done which establish any benefit to finding pleural or peritoneal mesotheliomas at an early stage. The 'evidence' is largely anecdotal and varies widely from one individual to another. Because the tumors are typically found only after they have spread, and are incurable even if they are discovered while the patient is symptom-free, early detection has virtually no medical benefit."

The statement is disturbing for a number of reasons.

First, there is something ghoulish about a lawyer for a company that has poisoned people advocating that there is no need to monitor the health effects caused by their poison. The attitude seems to be: yes, we made a poison that invaded the lungs of many innocent people, but there's no proven way to combat or prevent the bomb from exploding, so let it be and let us alone. Doctors have a duty to "do no harm." I wish lawyers were guided by the same credo.

Second, the statement is debatable at best and misleading at worst (see below). There may not be any definitive studies out there which establish a clear benefit, but there are plenty of studies which affirm that early detection is vital because it allows the patient to choose from more treatment options. At the "individual" level, what is more important to the patient than having the power to select from multiple choices? Drs. Sugarbaker, Pass, Rusch et al have published articles which support the thesis that certain MM patients have a better prognosis when diagnosed early and treated by multi-modal therapy -- and few doctors will recommend extrapleural pneumonectomy or pleurectomy / decortication if the tumor has trespassed the visceral pleura into the mediastinum, diaphragm, and/or lymph nodes.

Third, the "incurability" argument is tainted by conflict of interest. The asbestos companies have shelled out millions of dollars to disprove that asbestos causes cancer, but they have not spent a dime to find a cure. In this world, you have to give action to get action. A wrongdoer has a duty to mitigate the damage he inflicts. Instead of paying high priced lawyers to excuse their misconduct, they ought to be funding research on finding tumor markers, vaccines, immunotoxins and other therapies. AIDS was also considered "incurable" ten years ago. Now, after millions have been spent to find a cure, AIDS patients have a real chance at survival. Same for breast cancer.

Fourth, the "incurability" argument hinders the ability of patients to obtain aggressive and innovative therapy. Insurance carriers these days are exceedingly reluctant to cover any medical procedure that is considered "experimental." There are a handful of surgical oncologists in this country who are truly dedicated to helping mesothelioma patients survive and find a cure. I have had clients who arranged to meet with these experts, but at the last moment their insurance carrier denied coverage and ordered them to see a non-expert who offered only palliative care or no care at all. The HMOs are still entrenched in the "death management" mind set for mesotheliotics. This is a vicious circle -- there won't be a cure if we don't fund the research and without the research the insurance industry will continue to refuse to cover innovative therapies. It's also a tragedy.

Fifth, the consensus among the doctors I correspond with is that if there are "no studies," it is because nobody has every tried to create an early detection program, fund it, implement it, and publish the results. Most mesothelioma patients are NOT detected in the early stages -- sometimes because general doctors fail to read the signs. Moreover, it's not clear exactly what "early stage" means, as even at Stage I a patient with a 1 cm tumor can have 500 million tumor cells active and growing. Most mesotheliomas -- approximately 80% -- can be detected from CT scans and chest films, along with a clinical picture (weight loss, shortness of breath, pain in shoulder, pleural effusion, asbestos exposure history). Multi-modal extrapleural pneumonectomies are certainly expensive in dollar terms. The goal should be to a find a cookbook variety screening test that would obviate the need for "radical" approaches.

The key is to give people in high risk populations (e.g., shipyard, steel mill, paper mill, petrochemical plant workers, insulators) a choice. For example, Dr. Robert Cameron has discussed the possibility of a "prophylactic ablation" for high risk patients. The idea is that mesothelioma can only arise in malignant mesothelioma cells. What if we removed or destroyed all the healthy mesothelial cells? A technique could be developed to use photodynamic therapy to kill the mesothelial cells in the pleural space, or perhaps inject an anti-tumor drug that would accomplish the same objective. This would remove the soil so to speak for a possible tumor to grow. The pleural linings would bond together and the impairment if any would be minimal.

Sixth, if we do nothing, we learn nothing. If we don't invest the research dollars now and develop a wider range of treatment plans down the road, we will never have a chance to find a cure. I think history has taught us that with enough money, we can put a man on the moon. It takes will and it takes money. The best and brightest are humming with great ideas for gene therapy, immunotherapies, tumor-killing viruses, vaccines, "angiostatins and endostatins" (which purportedly kill tumors by starving their blood supply), interferon and PDT. In talking with doctors like Dr. Cameron and Dr. Jablons, there is a real excitement over the possibility that good therapies can be developed. But without a serious financial commitment at the basic science level, doom and gloom will be a self-fulfilling prophecy.

We cannot rely on private enterprise to get it done. The drug companies are driven by profits. They are not willing to invest the millions of dollars it takes to develop and test a new drug when "only 4,000" Americans die each year from mesothelioma. They look at the statistics. The conventional thought is that in 30 to 50 years the incidence of disease in America will be negligible (what about the rest of world where asbestos is still being mined, milled and used?). They are not willing "to fire up the vats" without better prospects of an upside. This is not a money-making proposition. It's about doing the right thing. That's why we should first look to the companies who are responsible for the disease -- the asbestos companies -- and secondly to the US Government, who allowed the companies to peddle their poison for far too long before issuing its ban in the 1970s.

Since the tortfeasors have refused to voluntarily clean up their mess, the solution is legislation. Congress ought to force the asbestos companies to pay a surplus of every settlement or jury verdict dollar to a research foundation. The government should match each dollar. The money can be managed by a blue chip team of the best mesothelioma doctors, doctors like Dr. Pass, Dr. Cameron, Dr. Sterman, Dr. Jablons, Dr. Taub, Dr. Ruckdeschel, Dr. Sugarbaker, Dr. Rusch, Dr. Robinson and Dr. Hammar.

Towards this end, my firm by the year 2000 hopes to establish a Mesothelioma Research Foundation. The goal of the Foundation will be to fund basic science and clinical research in order to help expand the treatment options available to mesothelioma patients. My first step will be to ask the asbestos companies to come forward and pay their share. Next, I will ask our political leaders to fashion a legislative solution. Along the way, I will ask the plaintiff's bar for contributions.

The money is available. It's a question of will. The tobacco companies just "invested" $40 million in television commercials to combat proposed state and federal legislation that would have hindered their ability to sell more cigarettes. We need to get started. We have known -- including the US Government -- that asbestos causes lung cancer since the 1940's. Here we are, almost 60 years later, and still the medical community has largely a fatalistic attitude about mesothelioma.

We need to get started! It generally takes about 15 years to bring an experimental drug out of the laboratory and into human patients. Only one in 1,000 compounds tested makes it into clinical safety trials in humans, and only one in 20 of these are eventually approved by the FDA.

What's out there now? There is a phase III protocol using Onconase, but I have not read anything truly uplifting (I wish I was wrong). I have heard about a drug made by Bayer that is being tested with other chemotherapy agents in Rochester, MN and San Antonio, Texas. The drug is called BAY 12-9566. The drug apparently had a favorable response in a mesothelioma patient in a phase I study for a wide range of cancer patients (it is not confirmed that the subject actually had mesothelioma). Bayer is considering the idea of developing a "compassionate use program" for mesothelioma patients. The drug will be tested in phase I trials for pancreatic and small cell lung cancers in 1999. We encourage Bayer to open up the studies to mesothelioma patients and hope that they will publish the results of their phase I trials soon.

I sent the quote from the asbestos company lawyer to several doctors who diagnose and treat mesothelioma patients.

Dr. Samuel Hammar,
Pathologist
Diagnostic Specialties Laboratory, Inc. Bremerton, Washington

Dear Mr. Worthington:

I am responding to your letter concerning "No Medical Benefit to Early Detection of Mesothelioma." In general, I do not agree with that statement but would state that it is difficult to detect mesotheliomas at an early stage of the disease at the present time. If one could devise a test in which you could identify mesotheliomas when the tumors were in stage 1 or less in the anatomic staging scheme, I think that would potentially result in more therapeutic options for patients with mesothelioma. I am convinced that there are a group of patients with stage 1 mesotheliomas, especially epithelial mesotheliomas, that significantly benefit from extrapleural pneumonectomy or from radical parietal pleurectomy and visceral pleural decortication.

I am also of the opinion that as time goes on the biology of mesothelial cells will become better understood which could lead to a test in which mesotheliomas could be detected at a very early stage, specifically, a stage before they became clinically detectable. What I have often wondered about in mesotheliomas is whether a platelet-derived growth factor, a factor produced in 1/4 - 1/3 of patients with epithelial mesothelioma could be used as a way of early detection. It is not clear to me at what point in time this growth factor appears, but if it could be detected at a point where the tumor was not grossly visible or a point where the tumor was just beginning, maybe it could be used as a marker of when a patient should be given some type of therapy which might include chemotherapy, radiation therapy or photo-ablative therapy.

The problem, as I see it, is that at the present time relatively few cases of mesothelioma are detected at an early stage. This is probably due to the fact that it take a significant amount of tumor to produce clinical symptoms and because mesothelioma is not like a lung cancer that produces a nodular mass and is therefore difficult to detect in standard radiographs or CT scans. I am one who thinks that once a mesothelioma progresses past anatomic stage 1 there are no treatment modalities that can halt the growth of that tumor. When this occurs it is my opinion that more effort should be spent in trying to keep the patient pain free than trying to cure him.

I would like to see more studies done at trying to detect tumor markers of mesothelioma (perhaps serum markers) in people who were exposed to asbestos that would result in the tumors being detected at a stage before they were clinically apparent. If that was done, maybe those patients could be treated in a way that resulted in a significant survival rate.

There are antibodies that are now being developed against certain cancers, specifically lymphomas that seem to be able to cure the diseases in a very short period of time with only minimal side effects. If a tumor marker for a mesothelioma was found that was highly specific, I could envision the same type of therapy working in mesotheliomas, specifically an antibody tagged to radioactive iodine that would search out the mesothelial cancer cells, attach to them and then kill them. As in lymphoma, you would have to have something absolutely specific for cancerous mesothelial cells that would do minimal harm to the normal mesothelium and to the body in general.

Sincerely,
Samuel P. Hammar, M.D.
November 2, 1998

Dr. John C. Ruckdeschel
H. Lee Moffit Cancer Center, Tampa, Florida

Dear Mr. Worthington:

The statement that there was no benefit to early detection is technically accurate, however, it is misleading. Very few centers treat mesothelioma and there is very little existing literature codifying the long-term survival of patients with surgically treated disease. All of us who are active in treatment of the disease know that if it is found in a resectable state, that a portion of those patients will be cured by an extrapleural pneumonectomy. However, there have been no studies to date testing any technique for this. I know that many of the former patients are under regular study, but have nor seen any of the follow-up data on this serial analysis. As you are painfully aware, these patients are mostly diagnosed late.

Consequently, I don't think there is any strong evidence to refute the concept other than the common sense fact that the only curable patients are those that we do find early. Best wishes.

Sincerely,
John C. Ruckdeschel, M.D.
Professor of Medicine and Center Director
November 9, 1998

Dr. Robert Cameron
UCLA Medical School, Los Angeles, California

Dear Roger:

The absolute statement about no benefit to early detection is technicallly true. No one has ever shown any benefit to early detection (of course no one has ever really tried and mesothelioma once present is almost always diffuse and for the most part currently rarely curable.).

However, a recent patient brings up an interesting sideline to this. If patients are known to have high asbestos exposure, i.e., worked for Johns Manville for 20 years, etc. does prophylactic removal of the pleura PREVENT mesothelioma? This also has not been answered but makes sense in patients who are at particularly high risk as "an ounce of prevention is worth thousands of pounds of treatment."

Therefore in screening patients, perhaps high risk individuals should undergo prophylactic pleurectomy to prevent the need for treatment of an normally incurable disease. If we can develop new treatments (by the way, Bayer has a new drug which looks promising although it has been used in only one patient so far and we are looking into doing more with it) then screening may become more important. Sorry I cannot refute the other lawyers statement any better but unfortunately, we have not done a good job at scientifically proving him wrong!!

Robert Cameron
November 18, 1998

Note: Dr. Cameron and his team of doctors/scientists at UCLA are working on an experimental IL-4 toxin, as well as new angiogenesis inhibitors, which UCLA hopes to put into clinical trials in the next year or so. They are also hoping to obtain the Bayer anti-enzyme. Dr. Cameron performs the pleurectomy / decortication procedure. His strategy is to preserve a healthy lung because of the probability of recurrence in the other pleural cavity. He compares the EPP to a radical mastectomy, which is no longer in favor.

Dr. Robert Taub
Columbia Medical School, New York City

The statement needs to be analyzed. It seems to refer to the inadequacy of current methods of screening of high-risk populations for early detection of mesothelioma; parallel arguments exist for lung cancer. It may also be referring to the observation that surgery alone has not made a statistical impact on the overall survival of mesothelioma patients.

This, however, is to be clearly distinguished from what happens in individual cases who are diagnosed with tumor that is confined to a small, operable area. Mesothelioma, bad as it is, is not synonymous with a death sentence because not everybody with the disease dies from it; we need to focus upon those who don't. Now that operative mortality is down to 6% or less, we should not dismiss the intuitive likelihood that selected patients who are both asymptomatic and operable and that have their tumor extirpated have a better chance of living than if their tumor is not removed.

Also, the reports of long term survivors after multimodality (surgery, chemo, radiation) treatment is encouraging. Thus, for individual patients right now, we need to find our how best to identify those patients who have the best chance of falling on the "tail" end of the survival curve.

Dr. Robert Taub
November 1, 1998

Dr. David Jablons
UCSF/Mt. Zion, San Francisco, California

Roger:

We need to have a grass roots movement and like all things we need to get some grant money to fuel the science to find a cure or at least better therapies, early detection, etc.

It can and will be done. Let's make this happen! There is plenty of money in these settlements and in the industry or through legislation such that a small percentage (which would represent a major increase over current funding) could be directed into research.

Best,
David Jablons
November 1, 1998

Abstract provided by Dr. Lary Robinson:
Eur Respir J 1998 Oct; 12(4):972-81
Malignant pleural mesothelioma.
Boutin C, Schlesser M, Frenay C, Astoul P

Dept of Pulmonary Diseases, Hospital de La Conception, Marseille, France.

The incidence of malignant pleural mesothelioma (MPM) has risen for some decades and is expected to peak between 2010 and 2020. Up to now, no single treatment has been proven to be effective and death usually occurs within about 12-17 months after diagnosis. Perhaps because of this poor prognosis, early screening has incited little interest. However, certain forms may have a better prognosis when diagnosed early and treated by multimodal therapy or intrapleural immunotherapy. Diagnosis depends foremost on histological analysis of samples obtained by thoracoscopy. This procedure allows the best staging to the pleural cavity with an attempt to detect visceral pleural involvement, which is one of the most important prognostic factors. Although radiotherapy seems necessary and is efficient in preventing the malignant seeding after diagnostic procedures in patients, there had been no randomized phase III study showing the superiority of any treatment compared with another. However, for the early-stage disease (stage I) a logical therapeutic approach seems to be neoadjuvant intrapleural treatment using cytokines. For more advanced disease (stages II and III) resectability should be discussed with the thoracic surgeons and a multimodal treatment combining surgery, radiotherapy and chemotherapy should be proposed for a randomized controlled study. Palliative treatment is indicated for stage IV. In any case, each patient should be enrolled in a clinical trial.

Dr. Harvey Pass
Karmanos Cancer Institute and Wayne State University, Detroit, Michigan

Dear Roger,

I agree with the message that you are trying to convey on the net regarding the earlier detection of mesothelioma. In order to accomplish this, however, there will need to be a collaborative effort uniting bench work and clinical efforts between institutions which have (1) an interest in the disease (2) ongoing expertise, not only clinically but at the bench and (3) insight.

For this disease, one needs a consortium of centers which will develop a multitude of Phase I-III trials, establish a tissue bank, and meet on a regular basis. Serum, lymphocytes, tissue all need to be banked with the patients permission prospectively. Its a huge effort and logistical challenge.

It is encouraging that this issue has stirred so many hearts.

HP
December 1, 1998

*** POSTED NOVEMBER 30, 1998 ***

Defense Lawyer's "No Benefit" Theory Promotes Doom and Despair, Dr. Corey Langer, 12/23/98

I recently received your letter dated 10/30/8 regarding the potential benefit of early detection of mesothelioma. My reply follows:

To date, no randomized studies adequately address this issue. The ideal trail would randomize early stage mesothelioma patients to best supportive care of palliative unimodal therapy vs combined modality surgery and chemotherapy with or without radiation. However, the absence of trials proving benefit does not constitute proof of the converse: that early detection and diagnosis yields no benefit. Sugarbaker and colleagues reviewed results of multimodal treatment in 94 consecutive patients (PROC ASCO, Volume 14, March 1995, A-1083), and reported their findings at the American Study of Clinical Oncology Meeting in 1995. Treatment consisted of extra-pleural pneumonectomy, postoperative chemotherapy (CAP regimen) for at least two courses and XRT (45 Gy). Mean age was 54. Patients had either stage I or II disease (JCO 11: 1172-1178, 1993). Median survival was 21 months, and overall survival at two years 48%, considerably better than instonic controls. In addition, the five year survival rate exceeded 20%. This sort of approach obviously needs to be compared to either surgery alone or chemotherapy alone, but such an effort would require international cooperation.

While early pleural mesothelioma can potentially be detected early, peritoneal mesothelioma generally defies early detection. Such patients usually present with abdominal distention +/- ascites. Even here, aggressive surgical debulking followed by interpertioneal therapy may lead to long term survival benefit (CJ Langer, J of Surg Oncol., 60:100-105, 1995).

The contention that earlier detection yields absolutely "no medical benefit" is misguided and potentially harmful. It cultivates and spreads the prevailing ethos of therapeutic nihilism that unfortunately imbues both the medical and legal communities.

I hope my answers prove helpful.

Yours truly,

Corey J. Langer, M.D.
Attending Physician
Medical Oncology