Evan as advancements in medicine’s ability to diagnose and treat mesothelioma have had a positive impact in the lives of many people, the disease is still often diagnosed only in its advanced stages where the common treatments for mesothelioma are not considered effective. In the push to develop more effective therapies, there has been considerable research into the discovery of which disease factors are indicative of a good prognosis vs. a poor one, with many of these studies identifying positive surgical margins, where malignant cells are discovered in the margins of resected tissue, and mediastinal lymph node involvement, where the lymph nodes in the mediastinum show evidence of metastasis, as poor prognostic indicators. However, the fact that a number of patients with pleural mesothelioma do not show any evidence of these factors and still experience poor treatment response and limited survival time has puzzled physicians and saddened many a patient and his or her family.

In response to this issue, a group of Italian researchers conducted a retrospective study on a number of pleural mesothelioma patients that investigated if occult disease was at work, that is, if mesothelioma was present, but remained hidden from the available diagnostic procedures. Using improvements in the ability of immunohistochemical staining to identify microscopic disease, these researchers discovered just that.

Overview of the Study

The researchers conducted a retrospective analysis of the results of 41 patients who were treated with trimodal therapy for pleural mesothelioma. Within the cohort, there were 30 men and 11 women and the average age was 58 years-old. The treatment protocol specified that each patient would undergo surgery, in this case, extrapleural pneumonectomy, followed by adjuvant chemotherapy and radiation.

The EPP was the first step in the protocol. There were 24 right-side EPPs performed, as well as 17 left-side EPPs. After surgery, the patient was examined for any macroscopic evidence of residual tissue in the margins. If an area was suspected, a sample was taken, analyzed microscopically with hematoxylin and eosin (H&E) staining and then preserved and archived. There were also a number of random samples taken from the areas surrounding the surgery and from local and medinstinal lymph nodes. These, too, were analyzed with H&E staining for the presence of malignant cells and then preserved and archived for future re-analysis. In cases where margins were found positive for mesothelioma, part of the subsequent radiation therapy would be directed to these areas.

The chemotherapy regimen included cisplatin + etoposide or gemcitabine and was given four to 10 weeks after the EPP. The radiotherapy regimen was then delivered post-chemo. The total dose was between 30 and 40 Gy, and was delivered in 1.5 Gy fractions.

The results from the H&E staining were then compared with an analysis conducted using immunohistochemical (IHC) staining. In this phase, the samples were stained with anti-calretinin and anti-mesothelin monoclonal antibodies and then analyzed for each antigen’s presence. A sample was considered positive for mesothelioma if at least five cells reacted to both antibodies.

The single endpoint to the study was overall survival time and that was measured from the time of EPP to the last follow-up or to the patient’s death. Due to the nature of the study itself, disease-free interval and time-to-progression were not evaluated.

Results

Histological analysis revealed 34 cases of epithelial mesothelioma, four cases of biphasic mesothelioma and three sarcomatoid cases. Staging was completed post-operatively and the following results were returned: 14 cases of Stage I disease, 6 cases of Stage II disease and 21 cases of Stage III disease—a clear indication that pleural mesothelioma is often diagnosed in its advanced stages. Patients with Stage IV disease were expressly excluded from this study by design.

The median survival for the entire cohort was 13 months, but differences in the presence of certain prognostic variables resulted in a wide range of median survival times when these variables were accounted for. Overall, the authors identified the presence of the following factors as indicative of poor prognosis: non-epithelial histology, stage, positive resection margins and lymph node metastases.

The initial H&E analysis identified 16 patients with positive surgical margins. Their 2-year median survival was only 13%, while patients with negative margins demonstrated a median 2-year figure of 49%. 12 patients in the cohort were discovered to have lymph node involvement and their median 2-year figure was only 8%, while those without nodal involvement had a 44% 2-year figure.

IHC analysis revealed additional patients with microscopic occult disease, as well as additional patients with lymph node metastases. When these additional findings were included in the analysis, these variables became even more significant predictors of prognosis.

Conclusion

The authors conclude that IHC is definitely an effective tool for the identification of occult disease and microscopic lymph node metastases for patients with pleural mesothelioma. In the cohort under study, IHC identified a number of additional patients who were in fact positive for marginal and nodal malignancy, indicating its greater specificity over traditional H&E staining. Its use for the diagnosis and staging of mesothleioma is an important development, as it will give physicians a greater ability to properly identify each patient’s individual status.

Labels: mesothelioma

Although a number of studies have shown that multimodal approaches to the treatment of mesothelioma have achieved some measure of local disease control, there is still controversy surrounding a number of issues, including which protocols are the most effective, which patients are the most likely to benefit from therapy and just how effective any of these treatments are when it comes to overall survivability. The relative rarity of pleural mesothelioma and peritoneal mesothelioma in the general population has slowed the development of new treatment protocols because the small sample sizes of many mesothelioma research programs often limit the scope of the conclusions that can reasonably be drawn from the results. Thankfully, though, research into innovative therapies continues to be conducted and slowly, but surely, physicians are learning more about the disease’s behavior patterns and the various ways in which it responds to treatments.

Of the various multimodal treatments that have been proposed, trimodality therapy—where some form of radical surgery is combined with adjuvant or neoadjuvant chemotherapy and radiation—has been shown in a number of studies to be the most effective protocol in local control of disease spread. However, questions have been raised regarding its true effectiveness in sustaining survival. To answer this question, physicians from a number of hospitals in Istanbul, Turkey conducted a study on the efficacy of trimodality treatments and recently published their results in the Journal of Thoracic Oncology. The study definitively found a survival benefit to the treatment, for some patients at least, and in the article the authors describe the patient profile for those who may respond well to therapy and for those who are unlikely to demonstrate a signifcant response.

Overview of the Study

The authors treated 37 patients for mesothelioma between 2003 and 2007. All patients were examined using chest and upper abdomen CT, thoracic MRI and those treated after 2004 also received PET scans. Cardiac and pulmonary function tests were routinely performed. For those selected for the study, the surgical protocol stipulated extrapleural pneumonectomy (EPP) with the pleura, lung, diaphragm and pericardium totally removed. Tissue samples from the EPP were then examined at 20 different sites for evidence of malignancy. If each site examined was negative for malignant tissue beyond the identified surgical margins, the surgery was deemed a microscopic complete resection. Otherwise, it was considered a macroscopic complete resection with microscopic positive margins.

Four to six weeks after surgery, the treatment protocol stipulated adjuvant radiation of the affected hemithorax, i.e., the side of the chest in which the surgery was performed, as well as for the incision points and the sites of the chest drain. The radiation was delivered in 1.8 Gy fractions until a total dose of 54 Gy was received. Some patients with residual disease received an extra 9 Gy of radiation.

The final section of the protocol stipulated adjuvant chemotherapy using a cisplatin-based treatment regimen. This was to be delivered four to six weeks after the cessation of radiation. For patients treated between 2003 and 2005, cisplatin was used along with gemcitabine. For those patients who were treated after 2005, pemetrexed (see Alimta Therapy) replaced gemcitabine.

Results

Of the 37 patients treated for mesothelioma, 20 were selected for inclusion into the authors’ trimodality treatment study. There were 12 males and 8 females, with 11 patients presenting with right-side disease and 9 patients presenting with left-side disease. Histological analysis revealed 17 patients with the epithelial subtype of the disease, two patients with the biphasic subtype and one with sarcomatous mesothelioma. The median age for the cohort was 56 years-old.

Of the 20 patients selected, 16 received the EPP, with four disqualied due to more extreme tumor invasion or lung weakness. Of these sixteen patients, 8 received a right-sided EPP and 8 a left-sided EPP. One patient died in the hospital and eleven others suffered some treatment morbidity. Only 12 of the 16 patients who received an EPP received the radiation and chemotherapy portions of the protocol. The radiation was well-tolerated overall, as was the chemotherapy portion. With the chemotherapy regimen, a number of patients experienced significant nausea and vomiting at the beginning of treatment, but this was eventually controlled through the use of ondansetron, an antiemetric agent used for control of these symptoms.

The authors report an overall median survival figure of 17.2 months. For the 16 patients who underwent an EPP, this figure rose to 19.6 months and to 23.9 months for the 12 who completed the full trimodal protocol. When the authors examined their findings for patients who demonstrated extrapleural lymph node involvement, they found that 8 were positive for it and their median survival figure dropped to 13.3 months. The 13 patients without extrapleural nodal involvement demonstrated a median survival figure of 23.9 months. These patients had a three year survival figure of 56%.

Conclusion

The authors conclude their article by stating that trimodality therapy is definitely an effective treatment protocol for pleural mesothelioma patients who present without extrapleural lymph node involvement, but its use for these latter patients is still questionable. To better make this differentiation, they call for the development of more effective staging methods. The protocol can be difficult to tolerate and it does take a significant time to complete, but for those who can benefit from it and who can tolerate it, trimodal therapy seems to represent a real breakthrough in the effectiveness of mesothelioma treatments.

Labels: mesothelioma

Mesothelioma is one of the most difficult of all cancers to treat effectively. A patient is often diagnosed only after the disease has progressed to a more advanced stage and the malignancy has invaded a large tissue area, as well as the lymph nodes. In these situations especially, the standard treatments for pleural mesothelioma or peritoneal mesothelioma, such as surgery and chemotherapy, have not proven effective in managing the disease and median survival time generally averages under a year. Studies have shown that to achieve the best prognosis it is imperative that patients receive a diagnosis and begin mesothelioma treatments as early within the course of the disease as possible. Historically, however, this has proven difficult to realize because the multiple phases involved with imaging, biopsy, histological analysis and lymph node staging are often completed in serial, with one coming after another until weeks or months have passed before the series is completed and treatments begin. In light of this, a number of doctors and researchers are currently exploring the development of more effective and efficient techniques for the determination of disease diagnosis and stage in the hopes of reducing this crucial time-to-treatment factor. Doctors from the United Kingdom have recently published an article in the European Journal of Cardio-Thoracic Surgery where they describe their use of a new technique they’ve developed called Video-assisted Cervical Thoracoscopy (VACT), which, they claim, allows histological diagnosis and staging, as well as an intraoperative talc pleurodesis, during the same procedure.

Overview of the Study

The authors describe the VACT procedure in the following manner:

“Patients are intubated with a double lumen tube to allow collapse of the lung on the diseased side. They were placed supine on the operating table with a sandbag between the shoulder blades and the head supported on a head ring. They were prepared and draped in standard fashion with the diseased side exposed to allow thoracoscopy should access to the pleura from the neck be unfeasible. A conventional cervical video-assisted mediastinoscopy was performed. Biopsies were taken from left and right paratracheal lymph nodes (stations 2 and 4) and subcarinal lymph node station 7. Following this, the video mediastinoscope was partially withdrawn and directed owards the diseased side. Aspiration of the pleural space was performed (above the superior vena cava [SVC] on the right) and if successful, a mediastinal pleurotomy was fashioned. A 5 mm thoracoscope was inserted through the mediastinoscope and mediastinal pleurotomy into the pleural cavity and visualised on a second video-assisted thoracoscopic (VATS) system. Pleural biopsies were then taken under direct vision, the pleural effusion aspirated and pleurodesis performed using 8 g of medical talc. A 28 Fr chest drain was inserted into the pleural space via the mediastinoscope and tunnelled caudal to the collar incision through the pre-sternal tissues . The mediastinoscopy wound was closed and the drain placed on 5 kPa suction. When unable to enter the diseased hemithorax through the neck, a conventional single port VATS biopsy was performed with the patient supine, the effusion was drained and talc pleurodesis performed. A 28 Fr intercostal drain was inserted through the VATS port site.”

The authors attempted VACT on 15 patients who presented with pleural mesothelioma, or a high suspicion of the disease. There were 13 males and 2 females, with an average age of 57 years-old. 13 patients had right-side disease and 2 presented with left-side disease. This study group was compared to a cohort of 26 patients who underwent the standard preoperative workups.

Results

The authors state that VACT was successfully performed on 10 of the 15 patients it was attempted on. For those patients, average time of surgery was 71 minutes and the average hospital stay was 4 days. 6 patients went on to receive an extrapleural pneumonectomy, while four received a pleurectomy/decortication.

There were a total of five failures in the VACT group: three in patients with right-side disease and both of the patients with left-side disease. Regarding the former group, one failure was due to a large amount mediastinal fat which obscured the pleura, while the other two were due to disease-thickened pleura, which prevented the hemithorax from being safely entered. In the left-side patients, the reason for procedure failure was the same: disease-thickened pleura surrounding the aortic arch. After VACT failure, these patients underwent a conventional VATS biopsy with staging completed during a subsequent mediastinoscopy.

When comparing the results of the VACT group vs. the VATS/mediastinoscopy group, the most impressive result was found in the median time-to-surgery figure for each group: just 28 days for VACT patients, compared to 87 days for the latter group. These figures represent an almost two month improvement upon time-to-treatment for the VACT group, indicating that for those who are eligible for it, VACT is definitely a great advance upon conventional diagnostic and staging procedures.

Conclusion

The authors conclude their paper by recommending the use of VACT for mesothelioma patients with right-side disease. They do not, however, recommend the procedure for those patients who present with left-sided disease, due to the particular anatomy of this area of the body. Certain patients with right-side disease, such as those with extensive pleural thickening, may not be candidates for the procedure, but for those who are, the authors state that VACT can have a positive effect on survival time because it greatly reduces the time-to-treatment over conventional diagnostic procedures. With a disease as aggressive as pleural mesothelioma can be, the results as presented here definitely represent an advancement upon our current procedures. While more research is of course necessary to confirm these results, VACT remains a promising new technique in the fight against mesothelioma.

Labels: mesothelioma

Improvements in the traditional therapeutic options available to mesothelioma patients have led to longer median survival times for a subset of these individuals, but the overall effectiveness of these treatments is still quite disappointing—especially when compared to the great advances that have been made in the treatment of other forms of cancer. Because of this, a number of researchers are actively investigating the development of alternative treatment strategies in the hope that more effective therapeutic management of the disease will one day be available to people diagnosed with pleural mesothelioma and peritoneal mesothelioma. One of these alternative strategies involves the use of gene therapy to combat tumor genesis.

Gene therapy is a disease-fighting technique where genes are inserted into a patient’s cells to replace defective or mutated alleles with functional ones. Although a relatively recent invention, it has already shown great promise in the treatment of a variety of disorders. It is an active area of research for mesothelioma treatments and this research is being conducted in a number of institutions around the world. One of the latest articles in the field, which describes a study on the efficacy of “suicide gene therapy” on individual mesothelioma cell lines, was recently published in the journal Onkologie.

Overview of the Study

The article describes a study by German researchers who conducted a number of interesting investigations of three mesothelioma cell lines. Histologically, two of the lines presented with a biphasic subtype, while the histological type of the third line was not known. To analyze the individual lines’ genetic makeup and particular chromosomal structure, the authors utilized multiplex fluorescene in situ hybridization (M-FISH) analysis. They also studied the tumorgenicity of each line by injecting mice with the one of the cell lines and then tracking the course of its health after injection. The cell lines were then studied for their susceptibility to genetic changes introduced by a rAAV2-based vector (recombinant adeno-associated virus 2-based vector). In molecular biology, a vector refers to a piece of foreign DNA that is used to transfer gene sequences from one organism to another, so the authors were interested in the extent to which the mesothelioma cell lines were reactive to the gene sequences that were inserted into the lines. The final phase of the study was to investigate the feasibility of using in vivo therapy to precisely target and attack these rAAV2-transduced mesothelioma cell lines.

Results

M-FISH analysis of the cell lines revealed a number of aberrations in each of the individual cell lines’ chromosomal structures, as well as clear differences in the underlying structures between the cell lines themselves. One of the cell lines, H-Meso-1, exhibited more aberrations than did the other two lines, but all lines exhibited non-standard genetic structures. After H-Meso-1, the cell line MSTO-211H exhibited the most aberrations, while the cell line NCI-H28 exhibited the least. When the authors compared the particular aberrations within each of the lines, they sometimes found that two of the lines shared the same recurrent aberrations, but the exact aberrations were not found among all three lines.

When the authors investigated the tumorgenicity of each of the lines, they discovered that H-Meso-1 was also the most tumorgenic of them. The NCI-H28 line did not cause any tumors at all. All of the cell lines were found to be rAAV2 susceptible, with H-Meso-1, again, exhibiting the highest gene transfer and expression rate. To study the feasibility of the in vivo gene therapy, the authors injected mice with the H-Meso-1 cell line and then separated them into groups treated with GVC and NaCl. The GVC group was the study group in this setting, because it should activate the rAAV2-vector. This is just what the authors found. Their analysis showed that GVC-treated mice demonstrated a near doubling of median survival time as compared to the NaCl group. This is a statistically significant finding, with the authors noting that future optimizations of the protocol could likely give even better survival figures.

Conclusion

The authors conclude their article by calling for additional research into the development of rAAV2-based treatments for patients with pleural mesothelioma. The results as presented in their paper were designed as a proof-of-feasibility test, not as an official clinical modality. Much more work is necessary before more comprehensive studies could even be considered, but the encouraging results as presented here certainly warrant this further research. The question of whether these therapies will be effective for humans is still years from being answered, but this study, as well as the numerous other studies that are investigating the creation of novel treatments, is another sign that improving the efficacy of mesothelioma treatments remains a top priority for researchers the world over.

Labels: mesothelioma

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