Sunday, May 19, 2013

Antiangiogenic Agent Thalidomide No Good in Mesothelioma

Malignant pleural or peritoneal mesothelioma is invariably fatal cancer with options that are largely supportive in nature. The current first-line chemotherapy regimens including pemetrexed with or without cisplatin or carboplatin do not provide long-term survival. This cancer is highly angiogenic and thus preclinical and early data supported the use of anti-angiogenic agent thalidomide.

However, a recent clinical trial published in this month's issue of the journal Lancet Oncology shows that thalidomide when added to chemotherapy does not provide any additional benefit.  

The cancer in patients receiving thalidomide 200 mg per day for up to 1 year with supportive chemotherapy or those receiving chemotherapy only progressed in three and half months. By 33 months, 92 of 104 thalidomide treated patients and 93 of 107 patients in the control group had died. Wieneke A Buikhuisen and colleagues write in the Lancet Oncology, "Different treatment strategies are needed to improve outcomes in patients with malignant mesothelioma."
"Between May 11, 2004, and Dec 23, 2009, we randomly assigned 222 patients, 111 in each group (one patient on active supportive care later withdrew consent and was excluded from analyses). At the time of this final analysis, median follow-up was 33·1 months (IQR 22·3—66·8), and physician-reported disease progression had occurred in 104 patients in the thalidomide group and 107 in the active supportive care group; 92 patients in the thalidomide group and 93 in the active supportive care group had died. Median time to progression in the thalidomide group was 3·6 months (95% CI 3·2—4·1) compared with 3·5 months (2·3—4·8) in the active supportive care group (hazard ratio 0·95, 95% CI 0·73—1·20, p=0·72). 43 (39%) grade 3 or 4 adverse events were reported in the thalidomide group and 31 (28%) in the active supportive care group; neurosensory events were reported by two (2%) patients on thalidomide and none on active supportive care, cardiac events by two (2%) patients on thalidomide and three (3%) on active supportive care, and thromboembolic events by three (3%) patients on thalidomide and none on active supportive care." -- Lancet Oncology, May 2013.
Mesothelioma basics and incidence

Mesothelioma is tumor of lining of the lung (pleura) or lining of the abdomen (peritoneum). Exposure to mineral fibers, such as, asbestos and erionite is the major cause of mesothelioma. 

Asbestos mining and use was high in the mid-20th century, but has been phased out over the last 50 years. However, it takes 25-70 years for mesothelioma to appear. Such a long latency period is the reason we see significant incidence and roughly 2500-3000 deaths per year in the US and 5000 in Europe. Mesothelioma was very rare before 1950s.

In the United States, the incidence of malignant mesothelioma is 1-2 per million in States with minimal exposure and 10-15 per million in States with high exposure to asbestos. Other parts of the world, eg old mining towns in Northern Australia face similar incidences. And, then there are countries like India who haven't yet phased out asbestos and will be staring at this public health problem for years to come.

True incidence is much higher

Before 1999, there was no clinical classification code for mesothelioma. Therefore, physicians often misreported this cancer as malignant neoplasm of pleura, or malignant tumor of trachea, bronchus, lung. It is estimated that as much as 35% of malignant mesothelioma may have been misreported.

In 1999, with the publication of ICD-10, malignant mesothelioma got its own code (C45). In spite of this, the misreporting continues in the death certificates to the tune of 25%.

Asbestos and erionite

Asbestos is a broad term for a family of silicate minerals. There are two major groups: serpentine form of asbestos (eg, chrysotile) and amphibole form of asbestos which includes crocidolite, anthophyllite, actinolite, amosite and tremolite. Asbestos can cause asbestosis, pleural fibrosis, lung and laryngeal cancer and malignant mesothelioma.

Erionite is also a type of mineral fiber. It is more potent carcinogen than asbestos and specifically causes malignant mesothelioma.

There is no linear dose-response relationship. Some individuals are more sensitive than others (ie, genetics play a role) and there are other co-factors including SV40 viral infection. The latency also depends on the type of mineral fiber inhaled.

But, there is a "threshold" effect. Once a certain level of asbestos or related fiber has been inhaled, the person is primed to develop mesothelioma. However, the latency of 2 to 7 decades means that the cancer strikes when the person thinks that the risk is behind him. It's not like smoking where quitting helps decrease risk of lung cancer.

Public health problem that is not on the radar

Since the year 2000, almost 2500-3000 people have died every year in the US from malignant mesothelioma and 100,000 people are expected to die from this cancer over the next 40 years. 

In spite of such grim numbers, just 2-3 million of our research dollars (by NIH) are spend on this cancer, and pharma has not considered developing drugs for mesothelioma as a high value option. The irony is not lost here that asbestos companies have paid out billions to settle lawsuits but have not helped towards developing therapeutic options.

Then there are "respected experts" who have written articles arguing that mesothelioma is a fading health problem -- the asbestos use is down, therefore, mesothelioma should also slowly go away (Price and Wane, 2009; Tan et al, 2010). This is not true and their assumptions are flawed:

Not all malignant mesothelioma is caused by asbestos. Erionite is another threat. Asbestos is still present in our buildings, contaminated sites, public places, etc. As these structures are remodeled or land gets disturbed, asbestos dust gets into the air as an invisible threat. Unlike Europe, we the US have not banned all types of asbestos products. Then there are other sources of mineral fibers, like talc and vermiculite, whose risk is not well studied. 

There are geographical regions in the world that pose the greatest challenge.
(Erionite deposits in Western United States. )

People living near certain natural deposits face the unlucky choice of death or permanently abandoning their homelands. Certain villages in Turkey are cursed with mesothelioma because they used erionite-rich (unbeknownest to them) hillside stones as building material. There are natural erionite deposits in North Dakota and other parts of the US, New Caledonia sits on geological asbestos deposits, Wittenoom town in Australia is cursed by a crocidolite mine, and Casale Monferrato town in Italy is next to an asbestos factory.

In the context of off-the-radar public health problem and the cruel fact that 100% of those who get this cancer today die from it, the failed trial of thalidomide is a great disappointment. At the same time, it is a step forward because we know what not to waste time on when the patient has so little time to fight this cancer.

A patient and a survivor's story

Sources and References

Buikhuisen WA, Burgers JA, Vincent AD, Korse CM, van Klaveren RJ, Schramel FM, Pavlakis N, Nowak AK, Custers FLj, Schouwink JH, Gans SJ, Groen HJ, Strankinga WF, & Baas P (2013). Thalidomide versus active supportive care for maintenance in patients with malignant mesothelioma after first-line chemotherapy (NVALT 5): an open-label, multicentre, randomised phase 3 study. The Lancet Oncology, 14 (6), 543-51 PMID: 23583604

Carbone M, Baris YI, Bertino P, Brass B, Comertpay S, Dogan AU, Gaudino G, Jube S, Kanodia S, Partridge CR, Pass HI, Rivera ZS, Steele I, Tuncer M, Way S, Yang H, & Miller A (2011). Erionite exposure in North Dakota and Turkish villages with mesothelioma. Proceedings of the National Academy of Sciences of the United States of America, 108 (33), 13618-23 PMID: 21788493

Carbone M, Ly BH, Dodson RF, Pagano I, Morris PT, Dogan UA, Gazdar AF, Pass HI, & Yang H (2012). Malignant mesothelioma: facts, myths, and hypotheses. Journal of Cellular Physiology, 227 (1), 44-58 PMID: 21412769

Clare Wilson (2013). Inside the villages of the damned New Scientist, 218 (2912), 34-37 : doi: 10.1016/S0262-4079(13)60951-3

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