The development of a simple and effective blood test for the diagnosis of mesothelioma is one of the primary goals of current research into the disease. If researchers could identify biological markers specific to pleural mesothelioma or peritoneal mesothelioma, doctors would likely be able to diagnose the disease in its earlier stages. As it currently stands, mesothelioma is not often diagnosed until symptoms indicative of advanced disease require a trip to one’s doctor. If physicians were able to diagnose the disease earlier, treatments would also begin much earlier, which could greatly maximize a patient’s overall prognosis. A number of studies have shown that early stage diagnosis is one of the most important factors in achieving significant survival figures after mesothelioma treatment.

A number of markers have been proposed for this purpose, but a single one has not yet emerged as standard from the wide variety of studies that are currently being conducted. The mesothelin gene family produces a number of candidate markers that are under active investigation. Researchers from Japan have recently released the results of a study they conducted which compared two of these potential markers: megakaryocyte potentiating factor (MPF) and mesothelin variants (MSLN). Their study hopes to identify which of these substances is a more effective marker for the diagnosis of mesothelioma.

Overview of the Study

MPF and MSLN are separate products from the same glycoprotein precursor, which probably explains their shared sensitivity to mesothelioma. While both have been studied in other programs, their efficacy in the diagnosis of the disease has not yet been compared. To answer this question, the authors collected serum samples from 27 patients with pleural mesothelioma, as well from patients from the following control groups:

1. 47 lung cancer patients.
2. 35 patients with other forms of cancer.
3. 9 asbestos-exposed individuals, presently asymptomatic of any asbestos-related disease.
4. 38 healthy adults without a history of asbestos exposure.

Of the 27 mesothelioma patients, 21 had properly-identified histological subtypes, while 6 were unclassified. Within the histological types identified, 13 were epitheloid mesothelioma, 3 were sarcomatous mesothelioma and five presented with biphasic mesothelioma.

MPF and MSLN concentrations were each measured by a specific sandwich ELISA developed by the authors. Levels were first compared between MPF and each group, and then MSLN and each group, and then a comparison was made regarding which of the two was the most sensitive and specific to mesothelioma.

Results

When comparing MPF levels between the mesothelioma group and the control groups, the authors found a statistically significant difference in median MPF levels between the study group and the controls, with MPF levels always higher in the mesothelioma group as compared to the controls. They also found a significant difference in higher MSLN median levels between the mesothelioma group and all of the control groups, but less so than the MPF group. When comparing between the two, 74.1% of the pleural mesothelioma group had elevated levels of MPF, while 59.3% of the MSLN group demonstrated higher levels. Even though both MPF and MSLN were possibly indicative of mesothelioma, the authors feel that MPF has a higher diagnostic sensitivity than does MSLN.

There were no differences in either MPF or MSLN levels between the mesothelioma group’s histological sub-types.

Due to their success with MPF in this study, the authors are preparing another MPF study that will examine the relationship between MPF and disease stage, prognosis and histology.

Conclusion

The development of a truly effective serum marker for mesothelioma will be an important step in our ability to treat mesothelioma patients. The ability to return a diagnosis before the onset or spread of serious symptoms will mean that patients will have a much better chance to fight the disease. While early stage diagnosis is not the only important factor in the development of a good prognosis, it is certainly a major one, so the positive results of some of the research into more effective diagnostic tools is an encouraging sign for the future of mesothelioma treatment.

Labels: mesothelioma

Although mesothelioma is a relatively rare disease in the general population, it is not uncommon in workers—or their families—from a number of different professions, such as mining, ship building and automotive break construction and repair. Every year thousands of people are diagnosed with mesothelioma and doctors and epidemiologists know that even more will be diagnosed in the years to come. Asbestos was in heavy use during much of the 20th century and the delayed response of many countries in banning, or strictly regulating, its use means that the incidence rate of the disease’s most common forms—pleural mesothelioma and peritoneal mesothelioma— is expected to keep rising during the forseeable future. Because of these difficult facts, research dedicated to improving the traditional modalities of mesothelioma treatment continues in diverse institutions from countries all over the world.

Historically, the efficacy of the most common treatments for mesothelioma have been a great disappointment to patient and doctor alike. In many studies, median survival from time of diagnosis has been less than one year. In recent years, however, we’ve seen improvements in the surgical methods that are deployed for treatment, as well the introduction of Alimta therapy in many countries, which has increased the effectiveness of chemotherapy in treating mesothelioma. Single modality therapy has not, however, shown a general effectiveness for the curative treatment of the disease, so multimodal therapies utilizing a combination of the traditional approaches were developed and now many physicians feel that these therapies should be considered the standard approach to mesothelioma treatment.

Even as doctors have decided upon multimodal therapy as the treatement standard, there is still considerable controversy regarding which combinations are the most effective for the overall treatment of the disease and many institutions are actively exploring just this question. Researchers from the Netherlands have recently released the results of a study they conducted which compared the efficacy and morbidity results of patients who underwent some form of cytoreductive surgery—either an extrapleural pneumonectomy (EPP) or a pleurectomy/decortication (PD)—with intraoperative hyperthermic intrathoracic chemotherapy (HITHOC) then followed by radiation therapy to the thoractomy scar and drainage tracks to a cohort of patients who received an EPP and then postoperative hemithoracic radiation.

Overview of the Study

The authors compared two cohorts of patients who underwent multimodal treatment for pleural mesothelioma at their institution, the Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital in Amsterdam. To be eligible for admission into either treatment cohort, patients had to meet specific admission criteria after workup, which included thoracoscopic biopsy and mediastinoscopy, as well as CT. Only patients who presented with Stage I or II disease with epitheloid or biphasic histology were allowed admission. Patients were denied these treatments if any of the following were found: “distant metastasis, mediastinal lymph node involvement and chest invasion, clinical or radiological retraction of the hemithorax, excessive weight loss... and a poor general condition.”

In the first cohort of patients, treated between January 1999 to December 2001, 20 people underwent cytoreductive surgery, HITHOC and radiation. For this cohort, 12 patients received PD and 8 received an EPP. After the actual surgery was completed, but still during the same operation, the patients received intrathoracic perfusion chemotherapy, consisting of cisplatin and adriamycin. As the final step in this process, each patient received radiotherapy with a total dose of 24 Gy to the thoractomy scar and drainage tracts.

The second cohort was treated between January 2002 and September 2005. This cohort was made up of 15 patients who were treated with EPP and then postoperative hemithoracic radiation. Unlike the Sugarbaker method, which suggests the total resection of the diaphragm and pericardium along with the affected lung and other adjacent tissues, the EPPs as performed by the authors only removed the parts of the diaphragm and pericardium where tumor was present. After the surgery was completed and the patient given ample time to heal up, external beam radiotherapy was applied to the entire hemithorax. The total dose delivered was 54 Gy, given in 1.8 Gy or 2 Gy daily fractions.

Results

The patients who received EPP with RT fared significantly better than did the patients from the other cohort. Median survival for the EPP/RT group was 29 months, while median survival for the HITHOC patients was 11 months. The EPP/RT group also scored much better on disease-free survival, with a median value of 21 months as compared to 8 months for the other group. 11 patients in the EPP/RT group experienced mesothelioma recurrence, compared to 18 in the HITHOC group. At the time of the last follow-up, 4 of the EPP/RT patients were alive. Three showed no sign of disease (23,40,54 months after surgery), while one had tumor recurrence, but was still alive 59 months after surgery. This compares to one HITHOC long-term survivor, who was still alive 65 months after surgery.

Besides the overall survival figures, recovery time and postoperative complications are another important metric of treatment utility. Here as well, the EPP/RT was better off than the HITHOC group. The EPP/RT group was a little quicker to leave ICU than was the other group, but both cohorts experienced similar days for total post-op stay. The EPP group only experienced two hospital readmissions, while seven patients from the HITHOC cohort required readmission. The EPP/RT group experienced fewer complications, 8 vs. 14, than did the HITHOC group. There were no deaths within 30 days of surgery, but two HITHOC patients died months later from complications directly linked to the surgery. 1 patient from the EPP/RT group died 6 months post-operatively, but the cause of death was never determined.

Conclusion

The authors conclude their study by summarizing a number of recent studies on the multimodal treatment of mesothelioma and they place their results within the context of those findings. The results for their EPP/RT group, where a median survival of 29 months was achieved as compared to the traditionally reported median value of 12 months, signal that this combination of therapies should be further studied. However, the same positive statement could not be made for the HITHOC cohort of patients. In fact, the authors note that the poor results returned for the HITHOC group tell them that the treatment is neither safe, nor effective and they conclude that it should be avoided in the future.

As with all research programs, further research needs to be accomplished to verify the results that were obtained in this study. However, the goal of improving upon mesothelioma treatments is slowly moving forward and doctor and patient alike can look upon the results of this study as an important step in this process.

Labels: mesothelioma

Investigations into the underlying cellular processes that lead to cancer have revealed a number of interesting findings regarding the biological conditions responsible for tumor development. Individual forms of the disease emerge from mutations and malfunctions of particular genes and the attendant changes in protein complexes and cell structures these mutations give rise to. An understanding of the myriad ways in which certain mutations can affect these agents will hopefully enable scientists to create cancer therapies that precisely target these low-level conditions. These therapies should then result in cancer treatments that are both more effective and less likely to cause serious side effects.

Research into the causes of lung cancer and other epithelial malignancies, such as mesothelioma, has shown that epidermal growth factor receptor (EGFR) is often implicated in the development of some of these cancers. EGFR is the surface receptor for a family of protein ligands known as the epidermal growth factor (EGF) family. When an EGF-member binds to EGFR, the receptor is activated and begins a cascade of downstream signaling activity important for a large number of cellular activities that are necessary for the body to function normally. However, mutations to EGFR can lead to its overexpression and/or its constant activation. When this happens, EGFR is no longer performing within the strict confines of its natural function, but is instead helping to create the conditions of tumor growth by increasing “cell proliferation, motility, and angiogenesis.” EGFR malfunction is also thought to inhibit apoptosis.

Treatments for EGFR have been developed and have shown at least some effectiveness in the treatment of lung cancer, but its effect on the development of mesothelioma, and the disease’s most common forms of pleural mesothelioma and peritoneal mesothelioma, is not really understood. Researchers are also unsure as to the effect that EGFR therapy would have on mesothelioma treatments in general. To answer this question, researchers from Japan enrolled a number of patients with pleural mesothelioma into a study that investigated the relationship between EGFR mutations and overexpression and the development of mesothelioma.

Overview of the Study

The researchers enrolled 25 patients with confirmed pleural mesothelioma into their study. There were 23 male patients and 2 females. The histological sub-types of the tissue samples were as follows: 12 epithelial mesotheliomas, 8 biphasic mesotheliomas, 4 sarcomatous mesotheliomas, and one desmoplastic mesothelioma (this is usually considered to be a sarcomatoid mesothelioma, but the researchers here treat it as a separate entity). A sample of the malignant tissue was taken from each patient and then analyzed for EGFR gene mutation or amplification and then for protein expression levels.

Results

None of the 25 tissue samples evidenced any sign of the 13 mutations of the EGFR kinase domain that have been reported as common in EGFR-implicated lung cancer incidence. Four of the samples demonstrated some form of polysomy, which is a genetic condition where cells possess extra chromosomes, while the other 21 samples demonstrated normal chromosomal structures. When the samples were analyzed for protein expression, 68% (17 of the 25) of them demonstrated some type of membrane immunoreactivity, with eight of the samples (32%) returning scores high enough to be considered positive findings for EGFR overexpression. However, protein overexpression did not correlate with overall survival in any way.

When viewed within the entire data set, none of these findings could be correlated with patient age, gender or tumor pathology. Increased survival was seen in those presenting with epithelial mesothelioma, but this is to be expected as the epithelial subtype always presents with a better prognosis than the other subtypes. Multivariate analysis did not identify any other variable as an independent prognostic factor.

Conclusion

The authors state that although their sample size was small, their results suggest that EGFR mutations only play a role in a small subset of patients with pleural mesothelioma. These findings serve as another identification of the differences between mesothelioma and lung cancer: while specific EGFR mutations have been implicated in the development of lung cancer, this rarely seems the case with mesothelioma development. In terms of gene amplification, four of the cases identified extra chromosomal pairs, indicating anti-EGFR treatment for mesothelioma will only be effective for the subset of patients who present with EGFR polysomy. The authors were unable to correlate EGFR overexpression with any survival data, whether positive or negative, noting that only epithelial mesothelioma demonstrated a survival effect within this dataset.

Labels: mesothelioma

From the earliest reports of lung disorders in asbestos workers, which date from the early 1900s, to our current time where asbestos has been conclusively shown to cause a number of terrible cancers and diseases—with the various forms of mesothelioma, such as pleural mesothelioma and peritoneal mesothelioma, probably the most feared of them—the mineral’s health effects are as terrible as they are common to those exposed to it. In light of these hazards, most industrialized nations have banned any use of the mineral, but some, such as the United States and Canada, have preferred strict regulations to an actual ban. However, even for those nations that actually have banned the use of asbestos, the extreme latency that is often associated with asbestos-related diseases means that people will continue to develop lung cancer and mesothelioma for years to come.

One of the great questions of asbestos-disease epidemiology is whether or not the underlying changes that lead to the development of these diseases can be identified earlier in an exposed person’s life, before any outward manifestations of the malignancies make themselves known. If these initial changes could be identified and subsequently tracked, then people at risk could possibly begin treatments to counteract, or at least to attempt to slow down, the progression of the biophysical changes whose endpoint is the worker’s premature death. To accomplish this, former asbestos workers would have to undergo regular screening procedures which would track the precise physiological changes being undergone, as well as quantify them to previously identified changes.

A study that completed such a process has recently been released by Austrian researchers, who analyzed many years of screening data among a cohort of former asbestos workers. Their findings definitely indicate the presence of quantifiable changes among the study’s population members.

Overview of the Study

In 1974 a number of workers from an Austrian asbestos cement factory agreed to take part in a long-term study investigating asbestos exposure. Information dating back to 1950 was captured for some of these individuals and new members were possibly added to the cohort until 1981, when the use of unprotected asbestos was banned in Austria. All these workers received regular checkups and their vital statuses were tracked as well. In 1989, additional screening procedures, including clinical examination, lung-function tests and chest x-rays, were made available to the workers. A total of 322 workers took part in these checkups and the study reports on 309 of them.

For each of the study members, a complete asbestos exposure history was available, as were the results of all checkups from 1989 to 2006. Information on each worker’s smoking history was incorporated into the overall analysis as well. The authors analyzed a number of individual factors for their effects on life expectancy and cause of death.

The workers reported on their individual work histories, including the type of work accomplished and the places in the factory in which the work took place. From this information, an analysis of the average asbestos concentrations found in the various locations was conducted and a table developed that grouped these exposures on a scale of 0 to 4, with 0 meaning very low exposure and 4 meaning very high exposure. This table was developed using an exposure scale of fibers/cm³ and was then combined with the number of time the worker spent in this location to determine a worker’s cumulative asbestos exposure, reported in “fiber years.” Chrysotile was the most common asbestos used and most workers were only ever exposed to it, although a subset of workers were exposed to amphibole asbestos fibers, of which, crocidolite was the major form.

Results

The authors report that by the end of their study in 2006, 82 of the original 309 workers had died. Of these 82, 34 died from cancer, 30 from cardiovascular diseases, 6 from respiratory diseases and 10 from other reasons not quantified. Of the 34 cancers, 6 were from lung cancer, 7 were from pleural mesothelioma, 4 were gastric cancers, 9 were digestive cancers, and there were 8 other individual cancers.

The authors found that for those who died of lung cancer, even after controlling for smoking and pure amphibole exposure, cumulative fiber years of asbestos exposure was a significant predictor of lung cancer. This was in contrast to the workers who developed mesothelioma. For this group, fiber years alone was not predictive of pleural mesothelioma onset, but amphibole exposure was highly predictive, as was long latency from first exposure to asbestos. The authors conclude, as have a number of other studies, that any exposure to amphibole asbestos is always a high risk for the future development of pleural mesothelioma.

The authors were surprised to see that higher fiber year figures were significantly predictive of stomach and some digestive track cancers. The worker’s exposures were not implicated in the development of colon or rectal cancer, but the findings linking asbestos exposure to these other cancers are some of the first to clearly show this relationship, so the authors call for more research into this question.

In terms of overall cumulative exposures, workers exposed to asbestos in excess of 70 fiber years saw their life expectancy figure decrease by 25%. Although this was smaller than smoking, it still correlated as a negative prognostic factor.

One of the most significant set of findings was the correlation between reduced lung function and a reduction in life expectancy. Any of the lung function parameters which showed a reduction in an individual worker’s lung efficiency were predictive of a reduced life expectancy. In fact, the authors state that lung function tests were much more predictive of a reduced life expectancy than were x-rays, other clinical examinations or a simple exposure history analysis. This finding should be a clear indication that measurable reduction of lung function for asbestos workers is indicative of potentially serious future medical issues.

Conclusion

The authors conclude their paper by recommending regular screening examinations of former asbestos workers. They state that their findings clearly indicate that screening exams could identify precursor stages of serious illnesses, which could allow patients to start receiving treatments before they present with full-on malignancies. They also recommend that former asbestos workers who are currently smokers immediately stop smoking, as there is an immediate benefit to one’s life expectancy when one quits smoking. All in all, this study goes a long way in showing that even as asbestos workers are prone to the development of a number of difficult malignancies, screening procedures and early treatment for them could be helpful to their future lives.

Labels: asbestos, mesothelioma

Two major procedures are used in the surgical treatment of mesothelioma: extrapleural pneumonectomy (EPP) and pleurectomy/decortication (PD). An EPP involves the complete removal of the affected lung and pleura, as well as a partial or total resection of the diaphragm and pericardium. A PD is a similar, but less radical procedure, where the lung itself is spared, but both the parietal and the visceral pleura are removed and possibly the diaphragm and pericardium. There has been considerable historical controversy surrounding the appropriate conditions for the deployment of either procedure, but recent research seems to indicate that PD is more appropriate for early-stage pleural mesothelioma, while EPP, because of the greater amount of gross tissue that is removed, is more appropriate for late stage disease and presentations with a significant local spread. EPP, however, also had a reputation for significant surgical side effects. It was often characterized by high numbers of post-surgical mortality and morbidity and while improvements in technique have certainly reduced the number and the severity of common complications, the procedure is still quite radical, so great care must be taken to ensure the best patient outcomes.

A number of studies on the outcomes of extrapleural pneumonectomy have recently been published. Researchers from the Austria are the latest to publish their findings on EPP.

Overview of the Study

The authors undertook a retrospective analysis of all patients who underwent an extrapleural pneumonectomy for pleural mesothelioma between 1994 and 2005 at the Medical University of Vienna. Of the 49 cases examined, 10 were female patients and 39 were males. 24 patients underwent a left-sided EPP, while 25 right-sided procedures were performed. Histologically, epitheloid mesothelioma was the most common subtype of the study, with 30 presentations. There were 15 cases of biphasic mesothelioma and four sarcomatoid cases. 13 patients received induction chemotherapy and 14 received adjuvant chemotherapy. All cases were examined for mortality, side effects and overall survival time.

During EPP, the entire lung, as well as the pleura, pericardium and diaphragm were resected and a mediastinal lymph node dissection was regularly performed as well. The patients were tracked post-surgery using CT scans every three to six months and underwent cytological or histological sample analysis if indicated.

Results

For all of the 49 cases, median survival was listed at 376 days. Thirty-day survival after surgery was 90%, with four patient deaths. 1-year survival was listed at 53%, 3-year survival at 27% and 5-year survival was listed at 19%. When the researches examined the numbers in terms of patient features, they found—not surprisingly—that patients with epithelial mesothelioma demonstrated significantly better survival times than did people with sarcomatoid or biphasic histologies.

The authors state that the cohort of patients who received induction chemotherapy prior to their EPP demonstrated a five-year survival figure of 52%—a very impressive figure for a disease that has generally resisted effective treatment. Patients who received adjuvant chemotherapy after surgery did not demonstrate any survival differences compared to those who underwent surgery alone. However, those patients who underwent a multimodal therapy consisting of surgery, chemotherapy and radiotherapy had the best overall survival figures. For these patients who survived five-years, 67% were free of tumor recurrence at five years. This number increased to 75% for those patients who underwent induction chemotherapy.

Conclusion

This study confirms two features of a number of previous studies:

1. Single modality therapy is not effective for the long-term survival of mesothelioma patients
2. An EPP is an effective surgical technique for the treatment of pleural mesothelioma, when performed as part of a multimodal approach using induction chemotherapy and radiotherapy.

The authors state that even though complications are common with EPP, these effects can often be planned for and controlled, so their potential occurrence should not automatically disqualify patients from receiving the surgery. As EPP techniques have improved, post-operative mortality has also been well-controlled. The procedure is still the best chance that patients with advanced disease or local spread have for achieving macroscopically complete resection–the removal of all visible malignant tissue–which is what many mesothelioma specialists feel is the end point of any surgery.

Labels: mesothelioma

The accurate evaluation of a patient’s response to cancer treatment is an important part of any therapeutic plan, but this is especially true for people being treated for malignant mesothelioma. It is an aggressive malignancy that often presents with a poor prognosis. Pleural mesothelioma, the most common form of the disease, is typically diagnosed only in its advanced stages and the median survival time for these patients is often less than one year from diagnosis. For these patients, a physician’s ability to quickly and accurately gauge an individual’s response to mesothelioma treatment could have profound implications for his or her future health.

Historically, however, this has been a difficult venture for physicians. As is often the case with this disease, mesothelioma presents unique challenges in determining treatment response. Because of its diffuse growth pattern, mesothelioma is not efficiently analyzable by World Health Organization response criteria, which focuses on tumors with bi-dimensionally measurable diameters. RECIST (response evaluation criteria in solid tumors) criteria have been semi-successfully applied in the evaluation of mesothelioma, but, again, the disease’s distinct growth pattern make site selection in the determination of a change in tumor spread a difficult endeavor, so modified RECIST criteria specific to mesothelioma was developed and is now generally in use.

CT has traditionally been the imaging technique of choice for mesothelioma diagnosis and response evaluation, although a number of studies have demonstrated that MRI provides enhanced resolution for diagnostic purposes. Many physicians feel its greater resolution could also be useful in tracking treatment response, but MRI’s use for the evaluation of response criteria has not been studied until quite recently, so there wasn’t any published data to draw a conclusion from. However, the situation has now changed: the results from the first study have now been released and they clearly show a benefit to the use of MRI.

Overview of the Study

Researchers from Germany enrolled 50 patients with proven pleural mesothelioma into their study. There were 32 males and 18 females, with a mean age of 59 years old. None of the patients received any treatment prior to the chemotherapy regimen the study employed. The plan of the study was to compare the efficacy of RECIST and modified RECIST criteria using CT and MRI in determining early patient response to treatment (chemotherapy, in this case).

After patients enrolled in the study, they underwent at least four sets of CT and MRI scans:

1. Before treatment.
2. After three cycles (out of six) of chemotherapy.
3. 4 weeks after the second scan.
4. After the six cycles were completed.

The comparison between CT and MRI using RECIST and modified RECIST took place after the 2nd set of scans were taken (three cycles into therapy).

Results

Using a volumetric analysis, i.e., change in gross tumor volume, 28 patients demonstrated a partial response to therapy, 12 demonstrated stable disease and 10 patients experienced progressive disease. MRI using the modified RECIST criteria correctly identified patient response in all cases, while the use of traditional RECIST criteria correctly identified it in only 46 cases. CT using the modified RECIST criteria correctly identified treatment response in 48 cases, but only in 44 cases when using the unmodified RECIST criteria. The authors note that CT demonstrated a tendency to underclassify therapy response.

The authors report that in dividing the patients into groups of those who responded to treatment with those who did not respond, the former group demonstrated a median survival figure of 15.1 months, while the non-responding group had a median figure of only 8.9 months. When comparing the early response evaluation scans taken after the third chemo cycle with those taken after the last cycle, they didn’t find any change between those who responded and those who did not respond. The authors speculate that early response results may then be used to infer who will respond to treatment and who will not, which should allow earlier changes and/or optimizations to treatment plans for those who are responding, as well as the avoidance of useless therapy or side effects in those who are not.

Conclusion

The authors recommend the use of MRI with modified RECIST criteria in the evaluation of early therapy response in patients with malignant mesothelioma. CT with modified RECIST may be recommended for some patients, but they state (and have shown) that MRI returns more precise results. This study, should its findings be independently confirmed, has important implications for the evaluation of patient response to therapy, as it suggests that physicians can evaluate treatment response at an earlier point than they normally do. With aggressive diseases such as pleural mesothelioma or peritoneal mesothelioma, accurate and early evaluation can help patient and physician alike make better, more informed decisions.

Labels: mesothelioma

Wired Magazine has been running a number of cancer-related articles lately and they have recently published a new one, “Top 5 Viable New Cancer Treatments,” in their blog which briefly describes a number of promising cancer treatments that are under investigation.

Wired’s Top 5 Viable New Cancer Treatments

1. Gene Knockdown

   Even though all forms of cancer exhibit their own individual growth patterns, at its most basic level cancer is defined as the uncontrolled division and replication of cells. Traditional cancer treatments, such as chemotherapy, attack cancer by attacking all rapidly dividing cells, but the problem is that the body produces many other cell types that are characterized by rapid division, and chemotherapy destroys them as well. This is the biological reason for most of side effects that are commonly associated with chemotherapy.

   Because of these side effects, new therapies are being developed that target the specific genes and proteins involved with the development of tumors. Alnylam Pharmaceuticals, a biopharm company based in Cambridge, MA, is currently developing a drug (known as ALN-VSP01) that uses siRNA to disrupt cell division and angiogenesis in tumor cells.

2. Viruses

   Because viruses are adept at infiltrating cells and propagating throughout the body they are often agents of considerable harm to humans. However, viruses are not necessarily harmful. Research into the therapeutic use of viruses for the treatment of cancer, as well as other disorders, is one of the most cutting-edge aspects of contemporary medical research. Jennerex Biotherapeutics, a company based in San Francisco, is currently engineering the vaccinia virus to specifically attack multiple types of tumor cells.

3. Small Molecules

   As we said in the “Gene Knockdown” section above, chemotherapy works by indiscriminately killing all rapidly dividing cells, both healthy and malignant. Gene therapies are only one of the ways in which medical science is looking to combat this “kitchen-sink” approach to treatment; another way is the targeting of enzymes and other small molecules involved in the biological production of tumor cells.Johnson and Johnson is investigating a drug called Tipifarnib, which targets an enzyme, farnesyl transferase, previously been implicated in the development of cancer.

4. Vaccines

   Vaccines are also being investigated as agents in the treatment of cancer. This research is proceeding along two major paths:

   1. Developing a vaccine for the actual tumor cells themselves, so the immune system learns how to fight off and remove the malignancy on its own, and
   2. The use of vaccines to prevent the contractoin of viruses than can cause the genetic damage that can lead to cancer.

   The article notes that a number of treatment candidates for the former methodology are currently in Phase III trails, while the most common example of the latter methodology is the drug Gardisil, which prevents women from contracting certain strains of the human papillomavirus, which has been proven to cause cervical cancer.

5. Epigenetic Drugs

   One of the most common findings in the molecular research regarding cancer genesis is the de-activation of what are called tumor suppressor genes (TSRs). TSRs help regulate the normally well-controlled processes of cell division and replication by stopping the growth of malignant tumors. When these genes become deactivated, one of the main bulwarks against cancer is silenced and the body becomes a greater risk for its growth. Epigenetic drugs target these inactive TSRs and attempt to turn them back on. A number of drugs are in use and others are in late development.

Conclusion

The therapies mentioned here are mostly in the experimental stages. Even though much more research will be needed before they become approved for cancer treatments, each of the therapies covered by this Wired article has shown great promise in laboratory studies. It is still too early to say what ,if any, effect these therapies will have on patients with mesothelioma or on the standard mesotheloima treatments, but one can be sure any new advance in cancer therapy is a cause of interest for patients with pleural mesothelioma or peritoneal mesothelioma.

Labels: cancer, mesothelioma

There are three distinct histological subtypes of mesothelioma: epitheloid mesothelioma, sarcomatoid mesothelioma and biphasic mesothelioma. The subtype of the disease is determined by the type of cells involved: epitheloid mesothelioma arises in epithelial cells, which line inner and outer surfaces of the body, while sarcomatoid mesothelioma arises from cells in certain connective tissues. Biphasic mesothelioma presents as a mixture of these cell types, but is categorized as its own distinct form. Determination of the histological type of the disease is an important factor in determining a patient’s prognosis. The epithelial subtype presents with the best prognosis and is the type most amenable to the available treatments for mesothelioma. Sarcomatous mesothelioma has the worst prognosis, while the biphasic form presents between these two extremes, with a prognosis dependent on the distribution of the individual cell types involved. Thus, the determination of the cell type involved is nearly as important as the diagnosis of mesothelioma itself.

Computed tomography (CT) scans are the most common imaging technique used in the diagnosis of pleural mesothelioma, itself the most common form of the disease. Although magnetic resonance imaging (MRI) and positron emission tomography (PET) offer certain benefits over traditional CT scans, as a first-line diagnostic tool, CT remains the tool-of-choice in most cases. The radiographic findings that CT returns are especially good at imaging pleural thickening and pleural effusions, which are two of the common symptoms of pleural mesothelioma. If it were possible to correlate specific CT findings with histological subtype, treatment strategies could potentially be developed earlier in the patient’s presentation, which could have major benefits for his or her prognosis.

Researchers from Canada have recently released the results of a study they conducted that looked at just this question.

Overview of the Study

The researchers conducted a retrospective analysis of 92 cases of proven pleural mesothelioma that occurred between 1997 and 2006. They gathered each of the patients’ CT scans and histology specimens and had the samples independently analyzed by lung pathologists (for the slides) and chest radiologists (for the scans).

Histologically, there were 72 cases of epitheloid mesothelioma, 15 cases of the sarcomatous subtype and 5 of the mixed form. All of the patients showed some form of pleural thickening on their scans. 87% (80 of 95) of patients presented with pleural effusions, with large effusions found in 19 (21%) of them. 42 patients demonstrated ipsilateral volume loss. A number of atypical presentations were recorded but none of these rose to the level of statistical significance. As regards tumor staging, the majority of the patients presented at stage 3 (50%) or stage 4 (35%).

During analysis, the researchers determined that two correlations achieved statistical significance: large pleural effusions were seen only in epithelial mesothelioma, while ipsilateral volume loss was highly correlated with sarcomatous or mixed mesothelioma. No other correlations were found significant.

Conclusion

The determination of the actual histological subtype of the disease is an important step in any diagnostic process, but there may be times when biopsy isn’t possible or the results returned were not conclusive or were contaminated. In these cases, CT correlations may be the best method to begin moving forward. If so, CT findings of ipsilateral volume may suggest a sarcomatous subtype of the disease, while the presence of a large pleural effusion may indicate a case of epithelial pleural mesothelioma. Study after study has shown that earlier diagnosis and subsequent treatment is one of the most important factors for patients with mesothelioma, so the confirmation of the findings as presented in this study could have a real benefit to newly-diagnosed patients everywhere.

Labels: mesothelioma

Kanzius RF therapy, an experimental cancer treatment currently under investigation by researchers at the MD Anderson Cancer Center in Houston, TX, is getting closer to human trials. The therapy works by attaching nanoparticles to tumor cells and then broadcasting radio frequency (RF) waves at the body which heat up the particles, effectively “cooking” the tumor cells and killing them in the process. What makes this therapy so promising is that the laboratory studies completed thus far have shown it is 100% effective at killing cancer cells without causing any side effects at all.

The therapy was invented by inventor and retired radio and TV engineer John Kanzius, who was diagnosed with leukemia and then underwent chemotherapy in 2003 and 2004. Mr. Kanzius and his RF therapy were recently featured on the television news magazine 60 Minutes.

Nanoparticles are microscopic particles whose length is measured in nanometers, a unit of length equivalent to one billionth of a meter. Due to their tiny size, nanoparticles are among the most active areas in all of contemporary science and medical research. For the Kanzius therapy under discussion there, gold is usually used as the binding nanoparticle because it is FDA-approved for use in humans and is generally well-tolerated by the body. The gold nanoparticles are coated with cancer-seeking molecules and then injected into the patient, where they can freely move through the patient’s system until they bind with the cancer cells they are targeting. The major difficulty with the therapy has been the development of cancer-specific targeting molecules. The researchers at MD Anderson have targeted a molecule known as C225 as the focus of the binding agent. While it is present in many cancer cells, it is also found in some normal cells, so care is needed in the application of the therapy.

Even still, the therapy is moving closer to human trials. Mr. Kanzius is working on a new form of his RF generator machine. This new version will be the size of a CT-scanner and will allow testing of larger subjects—such a design will facilitate the beginning of human trials. While questions regarding the treatment’s efficacy and safety will not be answered for a few more years, many of the researchers who are aware of the project are looking to the beginnings of human trials with great anticipation. A truly effective cancer therapy without significant side effects would be a true revolution in medicine.

Labels: cancer

While the elderly make up the largest age-related percentage of people that are diagnosed with cancer, there is an overall paucity of information that compares the effectiveness and tolerability of standard cancer treatments between elderly patients and younger ones. Many people assume that due to their greater age the elderly cannot tolerate the same treatment levels as can younger patients, but there simply isn’t enough statistical information to definitively draw conclusions either way. A few small studies have been done up to now, but the results returned have been generally contradictory, with some showing no difference and others showing the elderly with a worse overall prognosis. In many cases though, the study designs have presented limitations regarding the applicability of the conclusions that can be drawn. And yet, this is a very important question. Toxicity concerns for elderly patients have led some patients to receive an arbitrarily-reduced dosage of a standard therapy, a decision resulting in poorer outcomes for patients who were potentially curable.

In light of these facts, a study was undertaken to examine the overall efficacy and safety of pemetrexed in elderly patients. The researchers conducted a retrospective analysis of the results of three separate Phase III studies involving pemetrexed. Each of the studies had similar treatment plans and dosage requirements, which enabled the aggregation of data that this study relied on. As the majority of people who are diagnosed with mesothelioma are older and may be candidates for Alimta therapy, this present study reveals especially important information for elderly people with pleural mesothelioma or peritoneal mesothelioma.

Overview of the Study

The study aggregated the results of three previous studies involving a randomized use of pemetrexed. The first study was a multicenter, randomized Phase III study involving 456 patients with histologically proven pleural mesothelioma. The sample was randomized so some of the patients received single-agent therapy using cisplatin alone, while the rest received cisplatin + pemetrexed. In the second study, 571 patients with non-small cell lung cancer were randomized to receive either pemetrexed or docetaxel. The third study involved 565 patients with advanced pancreatic cancer. Their treatment plan was randomized to receive gemcitabine alone or gemcitabine + pemetrexed.

When the three studies are aggregated, a total of 764 patients received pemetrexed. Of these patients, 271 (35.4%) were 65 years old or greater and 493 (64.5%) were 64 or under. These two groups were compared in the aggregation study for differences in efficacy, toxicity, survivability and overall response rate.

Patients in the study were mainly Caucasian males, with the elderly group demonstrating an average age of 71 years old and the younger group demonstrating an average age of 55. Most patients between the two groups had Stage IV disease, so outside of their respective ages, the groups were quite similar in overall demographics.

Results

In nearly every comparison between the two groups, response results were the same. To put it a different way, there were not any statistically significant differences between the two groups. 20.9% of the entire population demonstrated some tumor response, but when the data was parsed between the two groups, there was no difference in response, nor in overall survivability between the older group and the younger group. Complete response was achieved in three patients in the elderly cohort and in five for the younger cohort. The elderly group showed a median 4.8 months to progressive disease, while the younger group showed a 4.6 month median figure—a difference, but not a significant one. Overall survival was 8.34 months for both groups. When broken down by tumor type, the authors found no difference in response rate for the mesothelioma and the pancreatic cancer groups between the two cohorts, and while the older group in the NSCLC population demonstrated a lower response rate, it was not a statistically significant rate.

In regards to overall toxicity, a higher percentage of the elderly group (26% vs. 17%) experienced a grade 4 toxicity event, i.e., a life-threatening event requiring significant medical intervention, but this was tempered by four drug-related deaths in the younger group and none in the older cohort. The older group also experienced a higher incidence of myelosupression, which is a condition in which bone marrow activity is reduced, leading to a more limited production of red blood cells, white blood cells and platelets. The most common grade 3 and 4 toxicities experienced in the elderly group included neutropenia, thrombocytopenia, anemia and febrile neutropenia.

Conclusion

The overall results of this study clearly show that the elderly cohort experienced as effective a response to the pemetrexed treatment as did the younger cohort. While they were expected to, and in fact did experience a greater number of high grade toxicity events, if these common events are planned for when treatment begins then there is no reason why the elderly group shouldn’t be given the same treatments as the younger group. There were not any significant differences in survivability, tumor response or induction death rate. For elderly patients, such as those who are most likely to develop pleural mesothelioma or peritoneal mesothelioma, these findings are an important indication that they can respond to the standard mesothelioma treatments as well as younger patients can.

Labels: mesothelioma

Researchers from the MD Anderson Cancer Center at the University of Texas at Houston recently announced the results of study they conducted that showed that damage to particular cells that line the mouth is often indicative of damage to similar cells in the lungs and is potentially predictive of the development of tobacco-induced lung cancer, as well as other forms of cancer that tobacco is involved in. The research team enrolled 125 long-time smokers in their study and they looked at two genes that have previously been implicated in the development of cancer: p16 and FHIT. Long before any cancer actually develops, the genes that cause its later emergence have already sustained significant damage to their proper function, so the development of tests that can investigate and diagnose present gene damage are potentially very helpful in monitoring overall health and determining the likelihood of cancer development in at-risk populations.

In the present study, the research team investigated the status of p16 and FHIT in both the mouth and lungs of their sample population. They found that p16 was shut down in the lungs of 23 percent of the sample and in the mouth in 19 percent. FHIT was shut down in the lungs in 17 percent of the sample and in the mouth in 15 percent. Overall, the researchers found that in 95 percent of people whose genes were affected, the genes were affected in both the mouth and the lungs.

These are important findings because the researchers hope these results will lead to the development of easier screening tests, such as a simple mouth swab, for lung cancer and other cancers, such as mesothelioma. The development of more effective screening tests could save many lives, as most cases of lung cancer or pleural mesothelioma are only diagnosed when the diseases are in their later stages and are more difficult to treat effectively.

Labels: LungCancer, mesothelioma

Summary:Clearing the Air Over Asbestos

In the article “Innate Immune Activation Through Nalp3 Inflammasome Sensing of Asbestos and Silica,” that was recently published in the journal Science, an international team of researchers identified the manner in which asbestos fibers cause scarring and damage to the lungs and to other body tissues. While the article does not specifically chart the path by which asbestos exposure leads to the development of cancers such as pleural mesothelioma, peritoneal mesothelioma or lung cancer, their findings are considered among the first to offer specific avenues in which to investigate this carcinogenic activity.

Overview of the Study

Although we’ve known for decades that asbestos causes cancer and lung damage, the precise biological processes by which the damage occurs have never been fully understood. Even as significant amounts of research were applied to the investigation of these mechanisms, the underlying biology has always remained mysterious, so the development of targeted therapeutics for those with asbestos exposure has remained merely a dream in the minds of scientists and patients. However, with the publication of this article, these researchers have provided a clear pathogenic path from asbestos exposure to lung damage and they have even proposed the use of a currently-approved drug as a means of treatment for those at risk.

The authors of the study applied their knowledge of the inflammatory activity they previously discovered was responsible for gout—an inflammation of the big toe and foot that is often quite painful—to the immune system’s response to asbestos exposure and determined that a similar complex of proteins, known as inflammasomes, was responsible for the tissue damage characteristic of exposure to asbestos fibers. When exposed to asbestos, the immune system stimulates the inflammasome Nalp3 to release interleukin-1b(IL-1B), a chemical responsible for inflammation. Because asbestos fibers do not easily break down, the researchers speculate that when the fibers become lodged in one’s system, they trigger the regular activation of Nalp3 and IL-1B, which leads to chronic inflammation and its attendant scarring and tissue damage. The researchers compared IL-1B levels and lung inflammation between normal mice exposed to asbestos and asbestos-exposed mice bred specifically to lack the Nalp3 inflammasome and they discovered the Nalp3-less mice demonstrated lower levels of IL-1B and less inflammation than did the normal mice, clearly showing a relationship between Nalp3, IL-1B and lung inflammation.

Along with these findings, they propose that Anakinra, a drug that blocks IL-1B expression and has already been approved for rheumatoid arthritis, could be given to those with known asbestos exposure. If their model is correct, then Anakinra should prevent tissue damage to those already suffering or at risk for developing asbestos-related disease. For the same reasons, Anakinra is already being investigated for a treatment of gout.

Conclusion

As is the case with every scientific study, further research needs to be completed to confirm the conclusions of the article. Assuming, however, that this confirmation does take place, these findings represent a very important step in our understanding of the biological mechanisms involved with asbestos disease. By identifying the immune system’s response to asbestos exposure, the researchers have discovered the starting point of the pathogenic process that often leads to the development of mesothelioma and lung cancer. An elaboration of these findings, then, will hopefully lead to a greater understanding of the underlying mechanisms of asbestos-related cancer genesis, as well as to the development of treatments that target these particular biological functions.

Labels: asbestos, mesothelioma

An extrapleural pneumonectomy (EPP) is one of the major surgical options available for patients with mesothelioma. It is a radical surgery and is characterized by the complete resection of the affected lung and pleura, as well the removal of parts of the diaphragm and pericardium. Due to the extent of the surgery involved, it has long been associated with high mortality and high morbidity figures, but modern techniques have greatly reduced the incidences of these complications, especially the mortality figures. An EPP is often the only way of achieving what many mesothelioma doctors feel is the most important endpoint of surgery: macroscopically complete resection (MCR)–where all signs of visible tumor tissue have been removed from the patient. For people who are diagnosed in the mid-to-late stages of pleural mesothelioma—which is the majority of presentations—an EPP is generally their best option to prolong life.

However, even as the procedure has become more efficient and less prone to complications, there are still a number of people who will experience serious side effects from it. Because of this, an active community of mesothelioma researchers are trying to identify the clinical conditions that are most likely to have a role in the development of complications. A team of researchers from Ontario, Canada have recently added to this literature on risk factors with an analysis of their experience performing extrapleural pneumonectomies for patients with malignant pleural mesothelioma.

Overview of the Study

The authors undertook a retrospective analysis of the surgical results of all 62 patients with mesothelioma who underwent an EPP at the Toronto General Hospital between 1993 and 2007. The average age of the patient was 58 years-old, with more men than women represented in the sample population. The majority of patients presented with left-side malignancy and epithelial subtype, respectively, and the most common disease stage at time of procedure was Stage III.

In their analysis of the risk factors involved with the procedure, the authors grouped individual complications into thematic composites and focused their analysis around the following questions: induction chemotherapy-yes or no, greater or less than 60 years of age, male vs. female, early stage vs. late stage, side of surgery and greater or less than 4 units of red blood cell (RBC) transfusions during surgery. They also looked at the overall incidences of complications vs. those who did not suffer any complications at all.

Results

Of the 62 patients enrolled, 22 (35%) suffered a major complication and 4(6.5%) died postoperatively (defined within the study as death within 30 days of surgery or during the same hospital stay). Each of the four patients who died presented with a right-side malignancy, so the adjusted mortality factor was 14% for right-side presentation (4 of 28) and 0% for left-side presentation. In fact, with 54% of the patients experiencing some form of major complication, surgery for a right-side malignancy was statistically much more likely to have a post-operative complication than was surgery for a left-side malignancy, where only 21% of patients experienced serious side effects. Another statistically significant factor in the development of complications was advanced age, with patients older than 60 more likely to suffer a major side effect than were those younger 56.

One of the major questions the authors were interested in answering was what—if any—factor induction chemotherapy had on one’s risk for developing complications. Previous studies had suggested such a link, but had not definitively answered the question either way. Of the 62 patients who were studied in this cohort, 44 underwent induction chemotherapy with cisplatin before EPP. Pemetrexed or vinorelbine were the other main agents administered, although a few patients instead received gemcitabine or adriamycin. The authors found that these patients were much more likely to have lower hemoglobin levels than were patients who didn’t undergo chemotherapy, and, therefore, were more likely to require more RBC transfusions during surgery. For all patients, the median units of RBC transfusion were 4, while the median units for induction chemotherapy patients were 5.8. The authors concluded that induction chemotherapy itself was not a risk factor for complication, but requiring greater than 4 units of RBC was a major factor.

In terms of overall survival, the patient cohort demonstrated a three-year figure of 27% and a five-year figure of 23%. There was not a statistically significant difference in these survival figures between right and left EPP at 23% and 30% (even if the right EPP was more likely to lead to a postoperative complication), although there was significant difference between patients who received more than four blood transfusions and those who did not, with the former group having a three-year figure of 14% and the latter 36%.

Conclusion

An EPP is a necessary procedure for many patients with pleural mesothelioma. Therefore, learning more about the conditions most likely to cause serious side effects is a deeply important research program. While the complication rate of the procedure is still high, the authors have confirmed the results of a number of other studies which showed that mortality can be well-controlled. In this study here, only four patients were considered to have died postoperatively. The authors generally ruled out stage and gender as major risk factors, as well as induction chemotherapy itself, but they did identify right-side EPP and RBC transfusions of greater than four units as major factors. The authors specifically noted that those who received at least five RBC units saw an eightfold increase in the odds of death following surgery. They state theirs is the first analysis of RBC transfusion units for EPP and call for much more study on its surgical effects. Assuming these results will be replicated by other researchers, this study represents an important advancement in our knowledge of extraplerual pneumonectomy and our treatment of mesothelioma patients. If surgeons continue to increase the effectiveness and tolerability of EPP, the lives of thousands of patients would be improved.

Labels: mesothelioma

In mesothelioma research, as in most forms of disease research, the attempt to understand the basic biological features of tumor growth is one of the most active areas of contemporary study. Investigations in this area continue for nearly all forms of cancer with the ultimate goal being the development of therapeutic tools and strategies that allow doctors to precisely target the particular tumor-types involved with an individual’s cancer. If they can develop modalities that target the particular biological processes involved in tumor genesis and progression, they may be able to develop treatment tools that demonstrate both greater therapeutic efficacy and reduced side effects.

In the case of mesothelioma, this category of research has had scientists studying the relationship between a wide variety of tumor structures, malignant and non-malignant cell types and host-induced co-factors for insight into better treatments for mesothelioma. One of the most compelling of the recent research hypotheses has to do with the role that macrophages play in cancer growth. Previous studies have noted some correlation between macrophage density and tumor burden—especially with epithelial cancers, where 80% of the studied cancers demonstrated a correlation between greater macrophage density, tumor stage and poor prognosis. In recognition of those findings, an international team of researchers endeavored to study this relationship further. Their recently-released results do note a significant relationship between a certain type of macrophage and tumor growth and this article is a summary of the findings as presented in their paper.

Overview of the Study

Macrophages are an important type of immune system cell. They are normally responsible for the removal of foreign antigens and invading organisms through a process known as phagocytosis, where they engulf and essentially digest the antigen. They originate from monocytes(one of the immune system’s fundamental cell types) and in the transition from monocyte to macrophage undergo an activation process that is regulated by the presence of specific proteins which then dictate its final form. Two major forms of mature macrophages have been identified:

1. M1, known as “classically activated” macrophages; and
2. M2, known as “alternatively activated” macrophages.

In most cases, the mature form of the macrophage plays an important role in promoting the health and well-being of the body. However, research into these two phenotypes has shown that the M2 sub-type can also be associated with increased tumor burden in some forms of cancer. These macrophages, called tumor-associated macrophages (TAMs), have been implicated in the development of multiple forms of cancer and mesothelioma, including pleural mesothelioma and peritoneal mesothelioma. Not only have they been shown to have an overall immunosuppressive effect, which allows the growth of tumor tissue to proceed without restraint, they have also been implicated in angiogenesis (the process by which new blood vessels are formed and tumors are supplied with the blood necessary for their growth) and growth-factor overexpression that some feel is responsible for “cell survival, invasion and metastasis.”

In light of these previous findings, the authors of this study were interested in learning what, if any, effect a reduction in the density of TAMs would have on tumor growth and progression. To investigate this, they studied a mouse population with malignant peritoneal mesothelioma and used intraperitoneal injections of liopsome-encapsulated clodronate (CLIP) to trigger apoptosis in the macrophages. Their injections were targeted at just the macrophages and not the actual mesothelioma cells and their testing confirmed this targeting was successful. Their results showed a clear benefit to macrophage depletion.

Results

In nearly all cases of mice treated with CLIP versus the control therapies utilized, CLIP-treated mice showed significant reductions in tumor burden, tumor growth and tumor progression. Whether the test was looking at the future development of tumor tissue after having been exposed to the mesothelioma cell lines or in those mice who exhibited mesothelioma tumor tissue when the testing began, the depletion of TAMs showed a positive effect in the treated mice. The authors report that mice injected with CLIP showed a 4-fold reduction in the number of tumors and a 17-fold reduction in overall tumor burden. They also showed that the metastatic potential for mice treated with CLIP was significantly lowered than in mice for the control groups. For those mice who received CLIP after having already developed mesothelioma tumors, they too showed a marked reduction in tumor size and burden, although they did not show a reduction in metastatic potential as compared to the control groups.

Conclusion

The authors clearly state that their mouse studies show that TAMs are an important factor in the growth of mesothelioma. These macrophages seem to have important effects on growth factor expression, angiogenesis and tumor immunity and their reduction, using intraperitoneal CLIP injections, has been shown to have positive effects on reducing tumor burden and progression. In light of these findings, the authors call for the beginnings of human trials in patients who are unable to tolerate multimodal treatments.

Labels: mesothelioma

Belluck & Fox is proud to announce that partner Joseph W. Belluck is a speaker at the upcoming New York State Bar Association event “Practical Skills: Basic Tort and Insurance Law Practice.” The event is a full-day practical skills program designed for attorneys “who want to learn or review the types of issues confronting those who litigate cases involving personal injury incurred on the premises, in the construction environment, or in automobile accidents.”

Mr. Belluck will be speaking on a panel discussing the fundamentals of litigation.

Labels: Press Releases

Belluck & Fox is proud to announce that New York Governor David A. Patterson has appointed partner Joseph W. Belluck to the New York State Commission on Judicial Conduct, the state agency responsible for investigating complaints of judicial misconduct. Mr. Belluck began his four year term on the Commission on April 1^st 2008.

The Governor is only allowed to appoint one attorney to this commission.

Labels: Press Releases

Full Title: Phase III Trial Of Pemetrexed Plus Best Supportive Care Compared With Best Supportive Care In Previously Treated Patients With Advanced Malignant Pleural Mesothelioma

A number of chemotherapy regimens have been deployed in the treatment of mesothelioma, although none of them have yet to demonstrate the efficacy seen in other forms of cancer. From the earliest studies on single-agent treatments utilizing drugs such as doxorubicin and ifosfamide to the recent multi-agent combination therapies using pemetrexed (Alimta®) along with platinum agents such as cisplatin or carboplatin, the use of chemotherapy in the treatment of pleural mesothelioma has often focused only on first-line use for chemo-naive patients. There has not been much study on the efficacy of second-line chemotherapy for patients with a favorable, but still incomplete, response to first-line therapy. To address this issue, an international team of researchers conducted a multicenter, Phase III study which compared the effectiveness of pemetrexed with best supportive care in patients with advanced malignant mesothelioma to a similar cohort of patients with advanced disease who only received best supportive care. The results from this study have recently been released and what follows here is a summary of their findings.

Overview of the Study

The researchers initially entered 252 patients from 45 international institutions into this study. All of the patients had histologically-confirmed mesothelioma, with advanced progression, and had previously undergone first-line chemotherapy. At the time the study began, pemetrexed had yet to be approved, so no one received this drug during his or her initial chemo treatment. Patients also had to meet a number of other important health criteria to stay enrolled, some of which included good performance status, measurable disease and a life expectancy greater than two months. Of the 252 patients initially enrolled, 9 were subsequently excluded, so the final sample size was 243. The patients were then randomly assigned to either the pemetrexed with best supportive care (P+BSC) group or to the group only receiving best supportive care (BSC). The P+BSC group had 123 patients and the BSC group was assigned 120.

The BSC group received the best palliative care the centers could provide. The goal was to maximize quality of life, but to not treat the underlying cancer at all. Along with receiving the same in supportive treatment, patients in the P+BSC group received a pemetrexed dose of 500mg/m² on the first day of a three week period and were scheduled for a period of eight cycles. They also received supplements of folic acid and vitamin b₁₂, which are standard for pemetrexed therapy. Doses and delivery were adjusted in response to specific patient reactions.

The primary endpoint of the study was overall survival, which the authors defined as the period from group assignment to death. They also setup a number of secondary endpoints as well, some of which included time to progression (TTP), progression-free survival (PFS), time to treatment failure (TTF), interval from group assignment to first signs of progressive disease, and interval from progressive disease to death.

Results

In terms of overall survival, the results did not show a statistically significant difference between the two groups, with the P+BSC group demonstrating a median survival time of 8.4 months and the BSC group demonstrating a figure of 9.7 months. The authors specifically note that their use of the statistical method used to compute these averages could possibly be thrown off by specific aspects of the study—aspects that may have obscured the overall survival numbers.

Unlike the overall survival numbers, all of the secondary endpoints showed a clear benefit to the P+BSC group. Progression-free survival, time to progression and time to treatment failure for this group all demonstrated median values of 3.6 or 3.7 months compared to 1.5 months for the BSC group. Response rate also significantly favored the P+BSC group, with 18.7% of the patients (23 out of 123) showing some partial treatment response while only 1.7% (2 of 120) of the other cohort showing partial response. The duration of response for the pemetrexed group demonstrated a figure of 3.5 months, and, when one looks at the overall survival figures in those patients who did show a response to treatment, median survival jumps from 8.4 months to 20.5 months.

Conclusion

The results as presented by the study clearly demonstrate the benefits of second-line therapy for at least some patients. Toxicity for this second-line administration was generally well-controlled and the P+BSC group showed significantly greater antitumor activity than did the BSC group. Further research is, of course, necessary to confirm the study’s positive finding, as well as to investigate why the overall survival figures were actually lower for the chemotherapy group than for the supportive care group, but these initial results are quite promising for future chemotherapy treatment for persons with mesothelioma.

Labels: mesothelioma

Alfacell Corporation has begun the process of conducting the formal statistical analysis of the results of its Phase IIIb Clinical Trial on the use of ONCONASE® in patients with unresectable malignant mesothelioma. The trial was designed to show that multi-agent use of ONCONASE and doxorubicin for patients with pleural mesothelioma not amenable to surgery is more effective than the use of doxorubicin alone. The statistical analysis is required to complete the final section of ONCONASE’s rolling New Drug Application.

ONCONASE is an anti-cancer compound developed using Alfacell’s proprietary ribonuclease (RNase) technology. Previous laboratory studies have shown that ONCONASE triggers apoptosis in cancer cells while leaving normal cells alone. The mesothelioma trial is the furthest along in the therpeutic use of ONCONASE, but Alfacell is also conducting a Phase I/II trial on the efficacy of ONCONASE for the treatment of non-small cell lung cancer and other solid tumors.

Labels: mesothelioma

The search for more effective treatment regimens is probably the most active area of current mesothelioma research. Even as our overall knowledge of the disease has increased during the last few years, it has only had a limited effect on the efficacy of the available treatments—increasing their effectiveness in degree, but not really in kind. Mesothelioma, especially its most common form, pleural mesothelioma, still ranks among the most difficult of all cancers to treat. While peritoneal mesothelioma, which is the second most common form of the disease, often presents with a better prognosis than does the pleural form, its historical survivability figures have also been disappointing.

In terms of total number of diagnoses, peritoneal mesothelioma accounts for somewhere between twenty and twenty-five percent of all mesothelioma diagnoses. The FDA has not yet recommended a standard of care for its management and all of the current treatment modalities and staging guidelines for mesothelioma have been developed for pleural mesothelioma. In response to this situation, a number of treatments specific to the peritoneal form have been proposed and some of them have demonstrated excellent results in small-scale studies. Doctors from the Columbia University Medical Center in New York City have recently released the results of a study they conducted for the treatment of peritoneal mesothelioma and their findings are quite promising. Utilizing a comprehensive, multimodal treatment regimen that incorporated surgery, multiagent intraperitoneal chemotherapy and radiation of the entire abdomen, they achieved a median overall survival of 70 months and demonstrated a three-year survival figure of 67%.

This article is a description of their study and findings.

Overview of the Study

The study enrolled 27 patients with histologically-confirmed peritoneal mesothelioma. Patient requirements included good performance status (identified as a Southwest Oncology Performance Status of 0 or 1), life expectancy greater than 2 months, no prior radiation therapy and up to two previous systematic chemotherapy regimens or 1 intraperitoneal chemo treatment. The average age of the patients was 53, with the youngest at 31 and the oldest at 75. There were twenty males and seven females. Histologically, 23 patients presented with epitheloid mesothelioma, while 4 presented with sarcomatoid mesothelioma.

The study defined a single primary endpoint and two secondary endpoints. The primary endpoint was overall survival. The doctors were interested in how effective the treatment was for the actual lifespan of the patient and they defined this figure as “the time from consent until death from any cause or last follow-up.” Of the secondary endpoints, the first was disease-free survival, defined as “the time from consent until diagnosis of recurrent disease, death from any cause, or last follow-up,” and overall safety.

The treatment protocol involved abdominal surgery (laparotomy) with omenectomy (removal of the omentum, the fatty tissue that surrounds the peritoneum) and the removal of all visible malignant tissue greater than 0.5cm in thickness. A few weeks after the surgery, chemotherapy was begun. The first chemo regimen involved weekly intraperitoneal infusions of cisplatin that alternated with doxorubicin administration. This continued over eight weeks, so each agent was delivered a total of four times. After this dosing scheme was completed, the next phase of chemotherapy, involving intraperitoneal infusions of gamma interferon-1b, was begun. During the first week of treatment, nine million units were delivered twice. The dose was increased to thirty million units twice a week for the next three weeks. A few weeks after completing interferon administration, another laparotomy was performed to examine the effectiveness of the treatments. If residual tumor tissue was present and deemed resectable, surgery was once again performed to remove the tissue. If no tissue was present or only small nodules, another round of chemotherapy was begun. This time, heated chemo using mitomycin and cisplatin were delivered. For patients whose laparotomy identified tissue that was malignant and non-resectable, systematic chemotherapy was considered instead of the heated intraperitoneal chemotherapy.

For patients who completed both second round surgery and intraperitoneal chemotherapy, whole abdomen radiation was the next, and final, stage of treatment. Total radiation dose was 3000 or 3080 cGy, i.e., the standard unit of measure for radiation used for medical purposes, with kidney blocks utilized after 1400–1550 cGy.

Results

The overall results of the study as presented were excellent.

Median overall survival for the entire group was 70 months, with a three-year survival figure of 67%. Median disease-free survival for the whole group was listed at 30 months, with a 50% three-year probability of survival figure. As expected, there was a significant difference between the cohort who presented with epitheloid mesothelioma and the one who presented with sarcomatoid mesothelioma. The epithelial group had a three-year probability of survival figure of 78%, while none of the patients from the other group survived longer than 11 months.

Other grouping structures revealed findings in line with other studies. Patients with bulky disease are considered to have a worse prognosis than patients with a smaller tumor burden and this study confirmed this as well. The five-year probability of survival figure for those with bulky disease was only 50%, while those without bulky disease demonstrated a five-year figure of 75%. While women were identified as responding to treatment as slightly better than men were, controlling for the four cases of sarcomatoid mesothelioma (all of whom were men) effectively removed the gender difference.

Conclusion

The results of this study clearly demonstrate that treatments for peritoneal mesothelioma are improving for at least some types of patients. While much more research is still needed to verify these results, the overall efficacy of the treatment regimen as presented in this study is quite promising and certainly deserves more study.

Labels: mesothelioma