AboutMesothelioma.Net

The efficacy and safety of weekly vinorelbine in relapsed malignant pleural mesothelioma

Friday, May 30, 2008

Source: Lung Cancer

Mesothelioma remains one of the most difficult cancers to treat effectively. Even as improvements to the standard therapies have led to small increases in overall survival time for some patients, the disease remains without a cure and most patients diagnosed with pleural mesothelioma will die within two years of diagnosis. The introduction of pemetrexed and cisplatin combination chemotherapy represented a real advancement in the effectiveness of chemotherapy for mesothelioma, but they are approved only as first-line therapy and their use for patients with relapsed mesothelioma is unclear. In fact, very few studies have been completed on second-line chemotherapy so the role of any agent for this purpose is unclear.

In light of this question, researchers from the United Kingdom conducted a study on the use of vinorelbine for second-line chemotherapy. Vinorelbine is a chemotherapy drug commonly used to treat breast cancer and non-small cell lung cancer that previous studies have shown has some clinical activity for mesothelioma. The goal of the study was to investigate if vinorelbine was effective and well-tolerated for treating mesothelioma.

Overview of the Study

To investigate the efficacy of vinorelbine as a second-line chemotherapy agent, the researchers selected patients with histologically-confirmed pleural mesothelioma for inclusion in their study. All patients must have previously undergone chemotherapy for mesothelioma, as well as demonstrate a current performance status between 0-2 and adequate lung and organ function. Patients also had to be free of other cancers.

At the time of enrollment, patients were given a CT scan to establish disease status. If a patient presented with a pleural effusion, the effusion would be drained before starting therapy. The treatment protocol stipulated vinorelbine would be delivered on an outpatient basis, once per week. The standard dose administered was 30 mg/m² of vinorelbine in 20mL of saline; the maximum dose delivered was 60 mg/m². The patients’ weekly progress would be monitored with blood cell counts and chemistry panels. 6 administrations were considered one chemotherapy cycle and at the end of every cycle, a CT scan was completed to track treatment response.

Results

The authors enrolled 63 patients with pleural mesothelioma into their study. The average age in the cohort was 59 years-old. Most patients were male (94%) and most presented with epithelial histology. The median time between first-line chemotherapy and the start of this second-line study was 6 months.

10 patients in the study group demonstrated a partial response to the treatment. 43 patients demonstrated stable disease, which was defined in the study design as 6 consecutive months without any evidence of progression. 10 patients experienced progressive disease, but the authors noted that these 10 patients did not complete the recommended number of cycles.

Median survival for the group averaged 9.6 months.

The treatment was generally well-tolerated, but a number of patients did experience strong side effects, with the most common being neutropenia, anemia, constipation, neuropathy and phlebitis.

The authors state that there were no statistically significant differences in response or survival when controlling for histological type, stage or performance status.

Conclusion

The results of this study indicate that vinorelbine is well-tolerated and moderately effective as second-line chemotherapy for pleural mesothelioma. The authors note that median survival time was greater than would expected and they cite a number of previous studies that have also shown vinorelbine’s activity for the treatment of pleural mesothelioma. The authors conclude their article by calling for more studies on the use of vinorelbine as both a first-line and as a second-line treatment for mesothelioma.

Labels: mesothelioma

posted by Belluck & Fox at 9:53 AM
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Efficacy and Safety of Pemetrexed in Combination with Cisplatin for Malignant Pleural Mesothelioma: A Phase I/II Study in Japanese Patients

Wednesday, May 28, 2008

Source: Japanese Journal of Clinical Oncology

Even though mesothelioma remains without cure, improvements in the traditional mesothelioma treatments have led to an increase in median survival times for many types of patients. The success of the chemotherapy agent pemetrexed, marketed as Alimta by Eli Lilly, has been one of these notable improvements. Whereas previous chemotherapy regimens had not demonstrated any real success in treating pleural mesothelioma or slowing disease progression, a number of studies have confirmed the efficacy of pemetrexed in combination with the platinum compound cisplatin in the treatment of the disease. The United States Food and Drug Administration (US FDA) approved pemetrexed and cisplatin for the treatment of malignant pleural mesothelioma in 2004 because of these studies and the combination remains the only FDA-approved treatment for mesothelioma in the United States.

Researchers from Japan began a study in 2005 about the use of pemetrexed and cisplatin for Japanese patients with malignant pleural mesothelioma and they have recently released their results. As with many of the other published studies, these researchers found moderate therapeutic activity and some survival benefit to the use of pemetrexed.

This article summarizes their findings.

Overview of the Study

The researchers began their study in 2005 with the identification of two phases of research: the first phase would investigate the recommended clinical dose of pemetrexed and cisplatin, while the second phase would analyze how effective the treatment at recommended dose was in controlling disease growth and progression.

To be eligible for study, patients had to meet a number of criteria. The major factors governing patient inclusion were:

• Chemonaive—patients were not allowed to have undergone a previous course of chemotherapy.
• Patients must have received histological confirmation of their disease.
• Patents must not have been eligible for curative surgery.
• Patient age between 20–74, performance status of 0 or 1, with adequate organ and lung function.

Results

A total of 25 patients were evaluated in the study. The majority of patients were male with an average age of 61. Most patients were Stage IV when the study began, with a performance status of 1. 60% of the patients presented with epithelial subtype.

The first phase of the study was an investigation of the recommended clinical dose. Four sets of dosing instructions were initially investigated and a fifth track at a smaller dose was also studied:

• Pemetrexed at 500 mg/m² with cisplatin at 75 mg/m² (Level 1)
• Pemetrexed at 700 mg/m² with cisplatin at 75 mg/m² (Level 2)
• Pemetrexed at 900 mg/m² with cisplatin at 75 mg/m² (Level 3)
• Pemetrexed at 1000 mg/m² with cisplatin at 75 mg/m² (Level 4)
• Pemetrexed at 500 mg/m² with a lower dose of cisplatin at 60 mg/m² (Level -1)

During the dose escalation phase, these various administrations were evaluated for causing toxicity events and the administrations which failed the study’s toxicity-evaluation algorithm were then removed from final consideration. The recommended dose was eventually decided as the Level 1 administration—pemetrexed at 500 mg/m² with cisplatin at 75 mg/m², which matches the average for pemetrexed treatment worldwide.

During the second phase of the study, the researchers investigated tumor response at the recommended dose level of 500 mg/m², with cisplatin at 75 mg/m². 19 patients received the Level 1 dose during this phase of the trial. 6 patients completed the smaller-dose Level -1 administration during the first phase and their results were also reported. The authors list the individual group statistics and a set of combined statistics. The Level -1 group scored better than the Level 1 group in nearly all categories, but the researchers speculate the cause of this was that all of those patients presented with epithelial mesothelioma, while only about half of the recommended dose cohort presented with epithelial histology.

Of the 19 patients who received the recommended dose, 7 patients experienced a partial response to treatment, 5 patients had stable disease, six had progressive disease and one was not evaluated. Thus, the response rate for the Level 1 cohort was 36.8%, or 7/19. Each member of the Level -1 group showed some partial response, so the overall response rate was 52%, or 13/25. The median duration of response for both groups was 5.2 months, while progression free survival was 4.7 months for the Level 1 cohort and 10.1 months for the Level -1 group, for a combined figure of 4.8 months. The 1-year survival rate for the Level -1 group was 66.7%, while the 1-year rate for the Level 1 group was 36.8%.

The overall median survival time was 9.2 months for both groups.

Conclusion

Pemetrexed and cisplatin represent the chemotherapy standard of care in the treatment of pleural mesothelioma. This study is the latest to show the treatment’s efficacy for extending survival times, even if the treatment—as all mesothelioma treatments do—falls short of being a true cure. However, these results do show treatments have improved and they offer hope that the improvements will continue in the future.

The authors report that Japan approved the use of pemetrexed and cisplatin in 2007.

Labels: mesothelioma

posted by Belluck & Fox at 9:21 AM
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Malignant peritoneal mesothelioma as a rare cause of ascites: a case report

Monday, May 19, 2008

Source: Journal of Medical Case Reports

Due to its relative rarity among the general population, mesothelioma is often misdiagnosed or remains entirely undiagnosed until its more advanced stages, when the disease’s outward form is likely to be the cause of significant physiological distress. Problems with mesothelioma diagnosis are especially likely for individuals who present without obvious asbestos exposure, such as women and those who did not work directly with the mineral, because these individuals do not meet the standard patient profile for people with pleural mesothelioma or peritoneal mesothelioma. However, we do know that environmental and secondary exposures are also proven causes of the disease, so patients who present without known exposures should still be taken seriously as potential candidates for mesothelioma. The literature on the disease is full of examples of these kinds of cases and doctors from the United Kingdom have recently added to the available articles on the subject.

In an article recently published in the Journal of Medical Case Reports, doctors presented a case study of a 75 year-old woman who presented with abdominal pain and ascites, which is an accumulation of fluid in the abdomen, but without any known asbestos exposure, which complicated their differential and extended the time before a diagnosis of peritoneal mesothelioma was returned.

Case Study

The article describes the presentation of a 75 year-old woman who suffered from dyspnea, ascites, leg edema and lethargy for at least five weeks prior to admission. The first round of blood tests and radiological examinations did not turn up anything remarkable in the abdominal area, but the ascites kept returning—even after multiple drainings—so more rounds of tests were scheduled to determine their cause. Subsequent CT scans revealed the existence of nodules along the abdominal surfaces, which a laparoscopy and biopsy eventually revealed to be malignant. Immunohistochemical staining then confirmed a diagnosis of peritoneal mesothelioma.

Conclusion

This case study highlights the importance of a physician’s mind remaining open to multiple possibilities during the differential diagnosis. Even as mesothelioma is a disease that is caused only by exposure to asbestos, in many cases, an individual may not have been aware of when this exposure was occurring, so he or she will not generally be considered a likely candidate for its development. This does not mean, however, that the patient’s unawareness will somehow save him or her from developing mesothelioma at some point after the exposure has ceased. In all cases, mesothelioma remains a very difficult disease and patients who present with symptoms related to it should be carefully worked-up to return as accurate a diagnosis as possible.

Labels: mesothelioma

posted by Belluck & Fox at 4:12 PM
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Individual versus standard quality of life assessment in a phase II clinical trial in mesothelioma patients

Monday, May 12, 2008

Source: Lung Cancer

Full Title:Individual versus standard quality of life assessment in a phase II clinical trial in mesothelioma patients: Feasibility and responsiveness to clinical changes

With cancer research so often dominated by talk of scientific programs and technological advances, it is often easy to forget that this research exists for one reason only: to save people’s lives. While improvements in the science behind cancer treatments have been the primary reason for the great advances made in cancer therapies during the last ten years, we must always remember that an individual person is at the center of this process and so we must remain dedicated to listening and responding to his or her needs as he or she undergoes treatment. To accomplish this, doctors have developed a number of scales and questionnaires that attempt to track patient progress, but these assessments have rarely received the same level of study that the actual treatment experiments have received, so questions regarding which of the assessments is most effective in diagnosing quality-of-life issues remain unanswered.

These kinds of questions are important for the treatment of all forms of cancer, but they are especially important to track how patients with mesothelioma respond to their treatments because of the aggressive nature of the protocols themselves. Even though truly curative treatments for pleural mesothelioma and peritoneal mesothelioma have not been developed, recent research has indicated that trimodal therapy—consisting of surgery, chemotherapy and radiation—is the most effective way to manage the disease in some patients. However, trimodal therapy often leaves the patient quite weakened and a full recovery can take months, so the development of effective quality-of-life (QoL) scales for these patients is an important aspect to their overall recovery. To asses the efficacy of some of these competing QoL scales, researchers from Switzerland conducted a study on patients undergoing a Phase II clinical trial for the treatment of pleural mesothelioma and they have recently released their results. The study compared the effectiveness of a standardized quality-of-life assessment scale with a personalized one based on patient interviews.

Overview of the Study

The authors enrolled 61 patients undergoing treatment for pleural mesothelioma into their study. These patients were participating in a Phase II clinical trial involving trimodality therapy. The treatment protocol stipulated 3 cycles of neoadjuvant chemotherapy, followed by extrapleural pneumonectomy and then adjuvant radiotherapy. The quality-of-life assessment was tracked according to two different systems and the comparison of these systems was the endpoint of the study under discussion.

The first QoL system the patients responded to was the Rotterdam Symptom Checklist (RSCL), a standardized assessment that tracks a patient’s response to clinical treatment along a number of defined axes. The authors describe RSCL as “a cancer-specific self-report questionnaire consisting of subscales for physical symptom distress, psychological distress, activity impairment and an overall evaluation of QoL.” The main thrust of RSCL tracks responses to 23 physical symptoms and 7 psychological symptoms.

The second system was known as the Schedule for the Evaluation of Individual Quality of Life (SEIQoL). This system is a personalized system that begins from the premise “quality of life is what the individual determines it to be,” and proceeds through an individual interview to determine one’s own personal meaning regarding “quality of life.” Here, a trained research nurse interviews the patient in three stages. During the first stage, the patient identifies the most important areas of his or her life at the time; during the second stage, he or she then rates his or her overall level of functioning for each of these activities, while in the third stage the patient has to determine the relative weight his or her previous answers are given to determining an overall quality-of-life.

The answers to each of these two scales were then converted to a numerical system and a single overall score was then developed.

Patients underwent the QoL assessments five times during treatment: at registration, at the start of the third chemotherapy cycle, at four weeks after surgery, and then again at 3 months after surgery and 6 months after surgery.

Results

Of the 61 patients, 58 completed three cycles of neoadjuvant chemotherapy, 45 then went on to receive an extrapleural pneumonectomy, while 36 of these patients then completed the radiotherapy section of the protocol. Of these patients, more completed the RSCL assessment (95%), than did the SEIQoL assessment (82%).

When analyzing the results, the authors determined that the two systems did not correlate over the same domain and concluded that this was because they were measuring different things: the RSCL assessment was focused on tracking particular aspects of treatment response and because of this, was more effective at diagnosing a patient’s individual reactions to the therapy than was SEIQoL, while the SEIQoL assessment was more effective at determining individual patient needs and revealing more about the patient’s psychological state than was the RSCL assessment.

While the RSCL only took on average 8 minutes to complete, the SQEIQoL averaged 24 minutes to completion because of its personalized nature. The authors felt this was generally acceptable because it did reveal important information regarding the patient’s needs.

Conclusion

The author’s feel that using both systems would be an effective method of determining patient quality of life because their combination returns a wider domain of patient response than using either method in exclusion of the other does: RSCL is effective for individual response assessment, while SEIQoL is effective for determining patient needs. The incorporation of these assessments into treatment protocols are important steps in the determination of a patient’s treatment needs—both physical and emotional. This is especially so for mesothelioma patients, both because mesothleioma is very difficult to manage medically and because the treatments themselves are physically demanding. RSCL and SEIQoL can both play an important role in the treatment of the disease.

Labels: mesothelioma

posted by Belluck & Fox at 4:56 PM
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The value of occult disease in resection margin and lymph node after extrapleural pneumonectomy for malignant mesothelioma

Thursday, May 8, 2008

Source: The Annals of Thoracic Surgery

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

posted by Belluck & Fox at 5:42 PM
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Trimodality treatment of malignant pleural mesothelioma

Wednesday, May 7, 2008

Source: Journal of Thoracic Oncology

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

posted by Belluck & Fox at 5:20 PM
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Video-assisted cervical thoracoscopy: a novel approach for diagnosis, staging and pleurodesis of malignant pleural mesothelioma

Tuesday, May 6, 2008

Source: European Journal of Cardio-Thoracic Surgery
(Chamberlain MH, et al., Video-assisted cervical thoracoscopy: a novel approach for diagnosis, staging and pleurodesis of malignant pleural mesothelioma, Eur J Cardiothorac Surg (2008)

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

posted by Belluck & Fox at 12:32 PM
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Characterization of Human Mesothelioma Cell Lines as Tumor Models for Suicide Gene Therapy

Thursday, May 1, 2008

Source: Onkologie

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

posted by Belluck & Fox at 5:35 PM
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