Prognosis of Mesothelioma
Mesothelioma is a cancer of the mesothelial linings of the lungs (pleura), heart (pericardium) and abdomen (peritoneum) caused by exposure to asbestos, though this fact was not recognized until 1960, when J. C. Wagner and colleagues – investigating mesothelioma’s occurrence among workers in Cape Province, South Africa – discovered that 32 of the 33 subjects had been exposed to naturally occurring asbestos as a result of diamond mining.
The prognosis for mesothelioma is generally poor, with most oncologists giving patients about one year, though seldom more than 18 months, to live. This is supported by studies showing survival rates in 41 patients at about 21 months, with the majority showing distant recurrences of the tumor cells, with or without local recurrence, even after surgical and multi-modality treatment (i.e., surgery and dual chemotherapy).
Another study of 183 patients treated via surgery (parietal pleurectomy), showed survival rates of about 17 months, with 3.8 percent succumbing to the surgery itself. The most favorable responses were among those who had no mediastinal nodal involvement (of lymph nodes) and no epithelial history; that is, no cancerous cells outside the original tumor location.
Prognosis in mesothelioma is also limited by mesothelial tumor’s resistance to many chemotherapeutic drugs, or agents. This may be due to an overabundance of a protein called MRP (multi-drug resistance-associated protein) implicated in drug resistance, as well as expanded gamma-glutamylcysteine synthesis.
Single-agent chemotherapy regimens rarely produce positive response rates in excess of 20 percent, and the agents used - doxorubicin, epirubicin, cisplatinum and carboplatin – produce even poorer results in mouse studies, where response rates did not exceed 15 percent.
Dual chemotherapies offer more hope. Though overall response rates remain below 30 percent, with no proof that new doxorubicin formulations are better than the original, or that combinations of doxorubicin are better than a single regimen, some combinations
(doxorubicin and dacarbazine; or doxorubicin with cyclophosphamide) have proven even more disappointing than anticipated.
However, one Phase II clinical trial used a combination of mitomycin and cisplatin and showed response rates of 26 percent, which is better than doxorubicin/cisplatin (at 14 percent), though there was no reported survival advantage in terms of overall prognosis.
Addition of a third chemotherapy agent (doxorubicin, vinblastine or interferon-alpha) also showed no distinct benefit, though a recent clinical trial in France – using four chemotherapy agents (cisplatin, mitomycin, 5-fluorouracil, or 5-FU, and etoposide, or VP16) – did result in a 38-percent improvement among 45 patients, providing a median survival rate of 16 months.
Combination chemotherapy clinical trials in Australia did not improve prognoses beyond one year in 41 percent of patients, however, and the tradeoffs – between the number of patients who respond better to dual chemotherapy regimens, and the number who survive – seem to have an upper limit.
Multi-modality therapies (surgery and chemotherapy, for example, or surgery and radiation, particularly intensity-modulated radiotherapy) deliver even more promising results. At the Memorial Sloan-Kettering Cancer Center, where parietal pleurectomy combined with (intrapleural or external) radiation therapy delivered via implantation (of iodine or iridium) is the gold standard, survival rates have improved dramatically, at least in terms of historical expectations.
The Dana Farber Cancer Institute uses extrapleural pneumonectomy, or EPP surgery (debulking with intracavitary treatment) in combination with two cycles of paclitaxel and carboplatin with concurrent doses of radiation to also deliver improved survival rates, providing the hope of future prognoses in which mesothelioma patients survive for up to two years.
The best weapons in the medical community’s arsenal for delivering an accurate prognosis rely on evaluating tumor histology and pathologic stage, as well as the patient’s gender, asbestos exposure (severity and duration), smoking, level of symptoms, lateral progression of the cancer, and clinical staging.
The prognosis for mesothelioma is so poor largely because mesothelioma is a rare enough cancer that doctors either don’t recognize it or diagnose it correctly. This leads to skewed mortality statistics and serious underreporting of the incidence of the disease, and thus fewer research dollars devoted to curing it.
Epidemiological surveys worldwide reveal patients were exposed to asbestos in about 70 to 80 percent of all cases where mesothelioma is diagnosed, and where histories were carefully detailed, so the link between asbestos and mesothelioma is no longer in doubt.
The disease manifests slowly, with about six percent of those affected over the age of 35 dying within 15 years of the first exposure. The upper limit for this manifestation seems to be 40 years, but patients exposed half a century earlier, or more, have been shown to have mesotheliomas as well. Among those 40 years old or younger, half had been exposed to asbestos in childhood.
From 1940 through 1979, estimates target the number of workers exposed to asbestos in the United States as 27.5 million, with an average annual death rate (in the late 1990s) of 3,000.
The mortality rate for mesothelioma is further skewed by the fact that asbestosis (a respiratory disease) and fibrosis are often absent, rarely severe, and show up only about 40 percent of former patients undergoing autopsy. And one study argues against the favored theory, that smoking is a factor in malignant mesothelioma, by showing that cigarette smoke is a synergistic component (with asbestos) in bronchial carcinomas.
The estimated total legacy of asbestos exposure, in economic terms, is estimated at about $200 billion in the U.S. over the next 40 years, and at least $80 billion in the European Union – a total likely to go higher as countries like Russia, India and China (which do not prohibit asbestos use in manufacturing) begin to pay the legacy costs of asbestos among aging workforce populations.
In fact, the incidence of mesotheliomas in the U.S. may have already reached its peak, but the same can’t be said for the European Union or Australia, where peaks are not expected for another 10 to 15 years. In non-Western nations (including Japan), peaks may be delayed for two decades or more.
While the prognosis for mesothelioma has not improved appreciably over the last 5 to ten years, interest by the medical community has, which may lead to better diagnostic procedures (most notably serum markers), better treatments (via novel immune and gene therapies), and, ultimately, longer lifetimes.
As some researchers and public health advocates note, the rising rates of mesothelioma worldwide should be a call to arms for immediate and highly focused research, with the enormous medical and social costs of the disease another powerful economic incentive to discover effective treatments.
This will occur only when science and the general public can move beyond the generally pessimistic prognoses provided by a medical community tied to the past, and into a more hopeful (and cooperative) framework provided by the mesothelioma research network.
For an explanation on some statistical terms used in medical studies, click here.
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