Even as improvements in the therapies available for mesothelioma patients have been made in recent years, the disease remains without cure. Most patients are ineligible for curative surgeries, so investigations into improving the efficacy of chemotherapy are among the most common research programs in contemporary mesothelioma treatment studies. Combination chemotherapy using pemetrexed and cisplatin (Alimta therapy) is considered first-line chemotherapy because it has demonstrated the most effective improvement in median time of survival when compared to every other chemotherapy regimen that has been tried. However, at some point during treatment, the disease always takes the upper hand and the chemo’s attempt to control the mesothelioma becomes more and more ineffective, until the drugs are no longer able to restrict the disease at all. When this happens in other cancers, one of the standard responses is for an oncologist to attempt another course of chemotherapy using different agents. This type of treatment regimen is known as second-line chemotherapy. Unfortunately, research has not yet identified an effective second-line chemotherapy regimen for pleural mesothelioma. Even as research into it continues, most results have been disappointing.

A group of renowned mesothelioma specialists has recently released the results of a study they conducted in hopes of identifying an effective second-line chemotherapy for pleural mesothelioma. Their study investigated the use of erlotinib plus bevacizumab for this purpose and their results have recently appeared in the journal Cancer.

This article is a summary of their findings.

Overview of the Study

A number of different agents and treatment regimens have been studied for the second-line use of chemotherapy in pleural mesothelioma patients. No standard has been identified though, so research into this question continues in hospitals around the world. Much of this research is being conducted based on our growing understanding of the biological foundations of the disease.

Some studies have demonstrated that vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) are important co-factors in the growth and spread of mesothelioma, so the authors of the present study investigated whether agents that inhibit these growth factors would be effective for treatment of the disease. Erlotinib is an inhibitor of EGFR, while bevacizumab inhibits VEGF. Combination therapy using these agents has been shown to have clinical efficacy as second-line treatment for non-small cell lung cancer and the physicians were hopeful that it would demonstrate similar efficacy for pleural mesothelioma.

The treatment plan under study called for the daily administration of 150 mg of erlotinib and for the administration of 15 mg/kg of bevacizumab on Day 1 of a 21-day cycle. Patients would be assessed for individual reactions to the treatment at each administration, while tumor assessment would be conducted through CT every two cycles.

Results

A total of 24 patients were included in the final study. As in most mesothelioma-related studies, the majority of those studied were older Caucasian men. There were 15 men and 9 women, with an average age of 62.5 years. 23 of the patients were white and one was Hispanic. 8 of the patients began the study with a performance status of 0 and 16 began it with PS of 1. The authors report on a number of other breakdowns and classifications as well.

The overall results of the treatment were disappointing. This chemotherapy regimen was not nearly nearly as effective for mesothelioma patients as it was for patients with non-small cell lung cancer. There were no complete or partial responses, but temporary stable disease was achieved in 12 patients. The other 12 patients had had progressive disease throughout the study. Of the 12 patients who demonstrated stable disease, 7 (of 8) were from the group with the best performance status (0) and 10 (of 16) presented with epithelial mesothelioma, the form of the disease with the best prognosis.

The patient cohort demonstrated a median time-to-progression of 2.2. months and a median survival time of 5.8 months. When studied at 6- month and 12- month intervals, the time-to-progression percentages were 29% and 6%, respectively, and the survival rate percentages were 46% and 24%, respectively.

Conclusion

Because of mesothelioma’s unique behavior pattern, chemotherapy remains the most commonly deployed treatment modality and this situation is unlikely to change in the near future. Advancements in the available therapies have already led to increased survival time, but more research is needed before medicine truly turns the corner on its ability to effectively treatment pleural mesothelioma. Even though this study did not demonstrate any clinical efficacy, other studies have identified alternative agents as possible treatment candidates and results from those investigations are eagerly awaited by doctors and patients alike.

Researchers have identified a number of factors in a patient’s presentation with mesothelioma that serve as important indicators of the disease’s treatability and overall prognosis. Two of the most significant indicators are the gender of the patient and the histological subtype of the disease. In terms of gender, studies have shown time and time again that men are more likely to be given a limited prognosis than are women. Regarding histology, other studies have shown that patients who are diagnosed with epitheloid mesothelioma have a better prognosis—in some cases, a much better prognosis—than do patients who are diagnosed with either biphasic mesothelioma or sarcomatoid mesothelioma, which are the other subtypes of the disease. This information is important to mesothelioma physicians as they develop individualized treatment plans because the particular forms these indicators take will dictate one particular therapy over another.

Even as researchers have confirmed the importance of these factors in numerous trials, they have also investigated if other presentational features can function in a similar manner. A feature of particular interest to physicians involves the relationship—if any—between overall asbestos burden and treatment outcomes. Researchers have known for almost one hundred years that asbestos is the only cause of mesothelioma and that longer exposures to its dust and particulate matter, especially in occupational settings, often correlate with a greater likelihood of developing the disease, but few quantitative studies have been completed that specifically addressed the relationship between asbestos burden and treatment outcome.

In response to this, a group of researchers from some of the finest hospitals and mesothelioma research programs in the United States conducted a study that addressed this question and have recently published their findings in the journal Environmental Health Perspectives.

This article is a summary of their findings.

Overview of the Study

To address the question of the relationship between asbestos burden and mesothelioma prognosis, the study looked at a population of 128 pleural mesothelioma patients that were treated in the International Mesothelioma Program at Brigham and Women’s hospital in Boston, MA. To analyze asbestos burden, the researchers used two sets of data: self-reported data from individual patients, or data given during interviews with a trained industrial hygienist, on their occupational histories and known asbestos exposures, as well as an analysis of actual lung and tumor tissue that was removed from the patients during surgery. Reported data was available for all 128 patients, while the tissue samples were available for 83 patients.

The researchers looked at a number of factors in relation to this data, including overall asbestos exposures, actual body burden of asbestos fibers, tumor characteristics and patient demographics. Each piece of information was analyzed singularly and in combination with the other factors.

Results

In the cohort of 128 patients, there were 98 males and 38 females, with a mean age of 62 years. There were 91 cases of epitheloid mesothelioma, 33 cases of biphasic mesothelioma and 4 sarcomatoid cases. When the researchers compared the relationships between histology and gender with survival time, they again confirmed the efficacy of these two factors as important indicators of survivability: epitheloid types were associated with significantly better survival times than the other histological types, and longer survival times were demonstrated, on average, by more women than men.

To compare asbestos burden levels between individuals, the researchers used the patient’s reported data as well as data from an analysis of actual tissues (when such tissues were available). They analyzed multiple samples from resected lung tissues to determine the number of asbestos bodies per gram of tissue (ABs/g lung). The median level for the entire cohort was 158 ABs/g lung. Three individuals demonstrated a radically higher ABs/g lung figure than all other patients, so their information was not included in any of the reported statistics. The researchers also created a three-tiered structure that identified different levels of exposure and categorized those levels using the following: low burden (0-99 ABs/g lung), moderate burden (100-1099 ABs/g lung) and high burden (> 1099 ABs/g lung).

The researchers did not find an overall relationship between self-reported asbestos exposures and survival times, but they did find a relationship between older age at diagnosis of mesothelioma and self-reported exposures. An analysis of asbestos body burden levels between genders showed that men had significantly-higher median fiber levels than did women (219 vs 20 ABs/g lung), which is not surprising given the greater number of men who worked in occupations with products containing asbestos.

When the researchers compared actual tissue burden levels to survival times, they were quite surprised to learn that burden level and survivability did not progress in a linear fashion. Instead, they found that those with moderate levels of exposure survived longer, on average, than those with low or high burdens. The researchers were not able to determine the reason why the low burden group demonstrated a greater risk of shorter survival than did the moderate burden group, but they suggest that if certain individuals have a natural susceptibility to the disease then they may be susceptible to a more aggressive form of it as well.

The researchers did find, however, a significant correlation between the high asbestos burden category and shorter survival times compared to the other two levels.

Conclusion

The researchers conclude that asbestos burden could be an important factor in mesothelioma prognosis, but they state that more research studies involving larger sample populations are necessary before a final determination can be established. Mesothelioma, especially its most common form of pleural mesothelioma,is a difficult disease to manage effectively and still remains an enigma in many ways. It is through the innovative research of dedicated physicians and scientists that we’ve learned all that we currently know about this terrible disease and it is through the continual renewal of this research that we’ll learn even more.

Some of the most important work in contemporary mesothelioma research involves the attempt to create targeted therapeutic agents which work directly on the cellular aberrations that are ultimately responsible for the development of pleural mesothelioma and peritoneal mesothelioma. The great hope these therapies inspire is based on the idea that if medicine can develop agents that block the specific biophysical processes which lead to tumor growth, then physicians will be able to deploy mesothelioma treatments that are much more effective than the current treatment modalities that are being used to treat the disease. Traditional cancer treatments such as surgery and chemotherapy have seen improvements in their overall efficacy, but they are still not considered curative approaches to the disease because they are only able to extend patient life—they are not able to truly save it from mesothelioma. Not only would these targeted therapies be more effective, but researchers hope they would also be more tolerable and exhibit less serious side effects than surgery or chemotherapy do.

Researchers from Italy have recently published an article that describes some of the targets of these new therapies, as well as some of the therapies themselves. The remainder of this article will be a brief overview of the targets the researchers enumerated in their article and will include some discussion of the proposed therapies as well.

Inhibition of Growth Factor Receptor Signaling

The authors note that a number of studies have shown that mesothelioma development is definitively linked with malfunctions in growth factor signaling pathways. They note that the “aberrant activation” of the receptors for the following growth factors have all been implicated in some way in the genesis of the disease: epidermal growth factor (EGF), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), hepatocyte growth factor/scatter factor (HGF/SF), transforming growth factor-beta (TGFB) and insulin-like growth factor (IGF). All of these growth factors are decidedly important for the proper function of the body, but they have also been shown to be essential in tumor genesis for a multitude of cancers.

Treatments for these aberrant activations are based on inhibiting the signaling pathways by deploying antibodies that block either the ability of a growth factor’s ligand to bind with its receptor or the ability of a receptor to receive a ligand. The authors note that research has shown that many of these agents are more effective when deployed during chemotherapy than if they are used as a single-agent therapy. They also note that agents specific to each of the individual growth factors are involved in clinical trials for mesothleioma treatment, as well as treatments for other cancers as well.

Inhibition of Intracellular Signaling Effectors: Targeting the AKT and Mammalian Target of Rapamycin Pathway

The PI3K/AKT pathway is another signaling pathway that has been implicated in mesothelioma tumorgenicity, as well as in the genesis of other cancers as well. The authors noted that “PI3K and AKT are frequently hyperactivated in cancer cells” and that this can lead to “increased tumor growth, metastatic efficiency, resistance to anticancer therapies and angiogenesis.” They also state that AKT plays a specific role in asbestos-induced disease and some previous studies have shown its inhibition can “induce growth arrest and apoptosis…” and can “sensitize MM [malignant mesothelioma] cells to different anticancer agents.”

Another class of therapeutic targets that research has identified are “downstream effectors” of the PI3K/AKT pathway, which simply means that scientists are looking for ways to not only block the signaling structures inherent in the PI3K/AKT pathway, but are looking to inhibit the activity of agents that start the signal cascade that can lead to PI3K/AKT activation. One such target that the authors describe is the mammalian target of rapamycin (mTor), whose inhibition by rapamycin has been shown to have anti-proliferative effects on cell growth.

Even as most of the therapies that have been developed to target AKT have not been fully studied on mesothelioma patients, the authors feel that the PI3K/AKT/mTor pathway is a very promising target for future mesothelioma treatments.

Inhibition of the Ubiquitin-Proteasome Degradation Pathway

Research has identified the ubiquitin-proteasome degradation pathway as another possible target for future mesothelioma treatments. The authors note that a number of preclinical studies have shown that the ubiquitin-proteasome pathway may be activated in mesothelioma genesis, as there is evidence to suggest that agents which target this pathway are cytotoxic to mesothelioma cells. There are at least two Phase II trials underway that are investigating the use of bortezomib, a compound in this class that has previously been approved for relapsed multiple myeloma, for the treatment of mesothelioma.

Inhibition of Histone Deacetylases

Agents that inhibit histone deacetylases (HDACs) are another area of contemporary mesothelioma treatment research. The authors note that these agents have been shown to “induce differentiation, growth arrest and/or apoptosis…” in research trials. Their use for the treatment of mesothelioma is being explored in multiple clinical human trials, due to the early successes these agents showed in the in vitro treatment of mesothelioma cells.

The authors note that one agent in particular—SAHA—has generated much excitement in pre-clinical studies. SAHA has already been approved for the use of T-cell lymphoma and its clinical trial for mesothelioma treatment is being watched with great interest.

Conclusion

As traditional mesothelioma treatments have not been effective for the long-term management of the disease, the creation of more effective therapeutic modalities is among the most important questions in the contemporary research of pleural mesothelioma and peritoneal mesothelioma. It will be a number of years before doctors and patients are able to look at the data from the treatments under current investigation to determine if they are truly more successful for the treatment of mesothelioma than are the current treatments, but even as these trials are ongoing, the greater knowledge that science has revealed about the disease’s underlying biology has given hope to many researchers in the field.