AboutMesothelioma.Net

Systemic Treatments for Mesothelioma: Standard and Novel

Tuesday, September 30, 2008

Source: Current Treatment Options in Oncology

The medical journal Current Treatment Options in Oncology has recently published a number of articles on the biology, diagnosis and treatment of mesothelioma. In a report published last week, we covered their article, “Diagnosis, Staging, and Surgical Treatment of Malignant Pleural Mesothelioma,” which provided an overview of the diagnostic procedures used to identify the disease, the system that has been developed to analyze the disease’s stage in an individual patient and an introduction to the surgical procedures that are used to treat pleural mesothelioma. Surgical invention is one of the key elements in the multimodal treatment of the disease, but many patients are not eligible for radical surgery because their diagnosis only came after the disease had progressed to an advanced stage. For these patients, chemotherapy represents their best chance to extend survival. In recognition of its importance to overall mesothelioma treatment, Current Treatment Options has also published an article describing the current use of chemotherapy in the treatment of the disease.

“Systemic Treatments for Mesothelioma: Standard and Novel” provides an historical overview of the chemotherapy treatments deployed before the introduction of pemetrexed, as well as a description of the current use of pemetrexed and an overview of other avenues in contemporary mesothelioma research. The article closes with a discussion of novel therapeutic agents that have been proposed for mesothelioma treatment.

Cytotoxic Chemotherapy Before Pemetrexed

The article begins with reference to a report published in the Journal of Clinical Oncology from 1988 entitled “Malignant Mesothelioma, a disease unaffected by current therapeutic maneuvers,” which noted that chemotherapy, like every other then-current cancer treatment, was simply not effective for management of the disease. Since that time, however, much has changed for the better. Even though the disease is still without a cure, current treatments have definitely led to improvements in both median survival time and symptom management.

Before the introduction of pemetrexed in 2004 a number of different chemotherapy drugs had tried–and failed—to treat mesothelioma. Anthracyclines, such as doxorubicin, were once hailed as a promising new therapeutic avenue for the disease, but subsequent radiological analysis showed limited response rates to these agents. Even though a number of these drugs were also tried, they only offered limited value at disease control.

Along with the use of single-agent treatment regimens, combination therapies were also used, but they, too, demonstrated limited efficacy. A meta analysis was then conducted on the different chemotherapy clinical trials performed between 1965 and 2001 and this showed that the platinum agent cisplatin was the most active single drug for mesothelioma treatment. Because of this, cisplatin became the focus of a number of new treatment regimens. Along with it, other platinum agents, such as carboplatin and oxaliplatin, were also investigated for their efficacy in mesothelioma treatment.

The Antifolates

Antifolates are the most active class of chemotherapy agents that have been used to treat mesothelioma. These drugs inhibit the ability of cells to metabolize folate (folic acid), which is an essential ingredient in the process of DNA replication. Thus, an antifolate’s fundamental mechanism of action is disrupting a tumor’s ability to continue to replicate. Methotrexate is one of the most common antifolates deployed for cancer treatment and studies that investigated its use for mesothelioma showed a higher response rate (37%) and a longer median survival (11 months) than many of the previous mesothelioma trials had shown. These results gave great hope to mesothelioma physicians, but it was with the introduction of pemetrexed that chemotherapy turned a corner in its effectiveness for mesothelioma treatment.

The FDA approved pemetrexed in 2004 after the largest clinical trial that had ever been conducted on a mesothelioma treatment showed clear advantages to combination therapy using pemetrexed and cisplatin than the use of cisplatin alone. Not only did this study achieve one of the highest response rates (41%) and the longest median survival time (12.1 months) when compared to other trials, study participants also reported significant increases in symptom control and quality of life issues. The combination of cisplatin and pemetrexed is now the world-wide chemotherapy standard of care for pleural mesothelioma and the investigations into its activity for peritoneal mesothelioma are also promising. In some cases, cisplatin may be replaced with carboplatin, which has demonstrated similar—though slightly less effective—response rates to cisplatin, but is associated with a less severe toxicity profile. Because of this, weak patients are sometimes given carboplatin in place of cisplatin.

Even as pemetrexed has achieved “standard of care” status, the article notes that a number of questions regarding its use remain unanswered. One of the most important of these questions has to do with onset of treatment: is it better to begin treatment at time of diagnosis, at the onset or progression of symptoms or at signs of radiological disease progression? For patients who are diagnosed in the disease’s later stages, this question is not applicable because symptoms have usually become quite difficult at that time, but for patients who are diagnosed in its early stages and with the epithelial subtype of the disease—which is associated with the best prognosis—this question is still opened. Physicians are waiting for the results of a large trial before they can answer this question with any certainty.

Another question the article brings up revolves around the optimum length of treatment: four to eight cycles of combination therapy are typically given to patients, but many people are not able to tolerate more cycles, so the question of the long-term management of the disease with chemotherapy remains open. There is some indication that pemetrexed can be given as a single agent after the full combination course has been completed, but, again, physicians are waiting for trial results before any definitive answers are given.

Another antifolate that has shown some activity in the treatment of mesothelioma is raltitrexed. It has not yet matched pemetrexed’s efficacy when combined with a platinum agent, but some research is still being conducted on this agent.

Other Active Cytotoxic Agents

Gemcitabine and vinorelbine are two other chemotherapy agents that have demonstrated some activity in the treatment of mesothelioma. Studies investigating gemcitabine in both single-agent regimens and in combination regimens with cisplatin, carboplatin and oxaliplatin have shown a wide variety of response rates. Prior studies on pemetrexed and gemcitabine have not found any synergistic effect in their combination, but they have shown increased toxicity profiles. However, investigations of this regimen do continue.

Vinorelbine is a chemotherapy drug in the class of drugs known as vinca alkaloid agents. While other vinca alkaloids have not shown much activity for mesothelioma, studies involving vinorelbine have shown some of the highest response rates besides pemetrexed. A number of recent studies have reported promising indications for its use in both first-line and second-line therapy and larger scale studies investigating its overall efficacy are currently being planned.

Novel Agents

Investigations into the biological substrates of mesothelioma genesis have identified a number of proteins that may be overexpressed by the disease. In identifying these elements, the studies opened up the possibility that highly targeted treatment agents could possibly be developed that would inhibit the growth of the malignancy at a cellular level. Some of the areas targeted for therapy include EGFR, PDGF and VEGF. Initial studies on agents targeted at these growth factors have not shown much clinical efficacy to the treatments under investigation, but the agents are still quite new and many physicians still believe that the more we understand the molecular composition of mesothelioma, the more effective our treatments of it will become.

A number of other agents besides the ones mentioned in this article are also under investigation, although definitive results for many of these studies will not be available for years. Even as the disease’s still-poor response rate to most treatments is frustrating when seen against the background of great successes that have been achieved in the management of other cancers, the number of studies under active investigation for mesothelioma is an indication that treatments are improving and that hope for the development of future treatments is well-placed.

Labels: chemotherapy, mesothelioma, treatments

posted by Belluck & Fox at 4:47 PM
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Phase I Trial of Cisplatin, Pemetrexed, and Imatinib Mesylate in Unresectable or Metastatic Malignant Mesothelioma

Wednesday, September 24, 2008

Source: Clinical Trials.Gov

The MD Anderson Cancer Center in Houston, TX is currently recruiting participants for their ongoing chemotherapy study entitled Phase I Trial of Cisplatin, Pemetrexed, and Imatinib Mesylate in Unresectable or Metastatic Malignant Mesothelioma.

As a Phase I trial, the study’s primary endpoint is the determination of the maximum tolerated dose for a chemotherapy regimen using pemetrexed, cisplatin and imatinib for mesothelioma patients. Along with this objective, the study has designated a number of secondary endpoints as well, including the exploration of the biologic effects of this regimen on tumor tissue and on surrogate serum markers and an assessment of the therapy’s overall rate of response. Other secondary endpoints have been defined as well and can be viewed at the trial’s home page on www.clinicaltrials.gov.

Patients will have to meet a number of specific requirements for enrollment in the study. These requirements include a number of positive indications that must be met, as well as a number of exclusion criteria that will disallow the patient from enrolling in the study if he or she satisfies any of them. If the patient meets these criteria and his or her initial workup is positive, the patient will then be enrolled in the study and will start on imatinib right away. A week after this, the patient will then commence the first of six cycles of cisplatin and pemetrexed administration. Each of these cycles will last 28 days. Every four weeks physical examinations will be given and then CT or MRI will be given every eight weeks to measure tumor response. After these 6 cycles, the patient will stop cisplatin and pemetrexed, but will continue the imatinib for up to a month. When treatment is completed, the patient will have his or her end-of-study visit, where a final set of tests and scans will be conducted.

This study is being conducted by Anne S. Tsao, MD, at the MD Anderson Cancer Center in Houston, TX. The contact information is the following:

Anne S. Tsao, MD
U.T.M.D. Anderson Cancer Center
Houston, Texas 77030
713-792-6363

Cisplatin, Pemetrexed, and Imatinib Mesylate in Malignant Mesothelioma

Labels: chemotherapy, mesothelioma

posted by Belluck & Fox at 4:56 PM
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Diagnosis, Staging, and Surgical Treatment of Malignant Pleural Mesothelioma

Tuesday, September 23, 2008

Source: Current Treatment Options in Oncology

Advances in diagnostic technologies and treatment-related procedures for mesothelioma patients have led to enhanced survival times for a number of different patient classes. These advances have allowed physicians to diagnose the disease sooner than they’ve previously been able to diagnose it, which allows treatments for mesothelioma to begin at an earlier time as well. However, not all patients are eligible for these new procedures and most still receive a diagnosis in the disease’s later stages when radical surgery is not an option. Because of this, research into pleural mesothelioma and peritoneal mesothelioma continues on a number of important fronts.

A series of articles on mesothelioma have recently been published in Current Treatment Options in Oncology, an important medical journal that features expert commentary on contemporary treatment practices for a number of different cancers. One of these recent articles is a report on the diagnosis, staging and surgical treatment of pleural mesothelioma. The article describes the current thinking on these topics and provides a detailed overview of the current mesothelioma staging system.

Overview of the Article

The article is divided into three basic sections: Diagnosis, Staging and Surgical Management. The section on mesothelioma diagnosis describes the “clinical and radiological presentation” of the disease, as well as some of the steps and procedures involved with pathology analysis. The section on staging describes, in detail, the current staging system used for pleural mesothelioma patients. The final section describes various treatment protocols featuring surgical intervention.

Mesothelioma Diagnosis

When the disease is in its earliest stages, the results of physical examinations are “non-specific,” but they quickly become more serious as the disease progresses. CT (computed tomography) scans are the preferred imaging modality for most cases of mesothelioma. MRI features enhanced resolution and soft-tissue contrast over CT, but for basic diagnostic purposes the images provided by CT are more than adequate. CT’s principal failing is poor presentation of chest wall involvement and tumor infiltration of certain pleural structures, so MRI may be indicated for these particular purposes, but CT is adequate for most cases of preoperative staging.

The article also discusses a study conducted by Dr. Harvey I. Pass that showed how three-dimensional CT imaging can be used to conduct pre-operative tumor volume analysis. Dr. Pass found that CT was able to measure tumor bulk and to predict survival times among patients with different levels of tumor volume, so CT is said to have both diagnostic value and prognostic value.

Another common imaging system in mesothelioma diagnosis is PET (positron emission tomography). PET is an important diagnostic modality because it specializes in the identification of distant metastases, something that CT is simply unable to do. Because radical surgery requires patients to be in the best overall health, any evidence of distant tumor seeding is a negative indicator for this kind of procedure. Even as staging is PET’s primary function in mesothelioma treatments, there is evidence that indicates PET can also be used to predict median survival in some patients.

Imaging technologies are the standard non-invasive diagnostic procedures, but a definitive diagnosis requires pathology assessment. The most common procedures that physicians deploy for sample extraction and analysis are thoracentesis, thoracoscopy and VATS. Due to its highly invasive nature, thoracotomy is not indicated for exploratory surgery.

When the sample has been removed, a pathologist must examine the specimen for malignant indications. Immunohistochemistry analysis is the standard testing methodology to determine a diagnosis. Because no single marker is 100% positive for mesothelioma, most of these analyses test against a panel of antibodies and use a combination of positive stainings and negative findings to determine a complete diagnosis.

For more information, please read mesothelioma diagnosis.

Mesothelioma Staging

A variety of staging systems have been proposed for mesothelioma, but all of them have had some notable downsides. The current system in use was developed by the International Mesothelioma Staging Systems group and is a 4-stage system that is based on a TNM model that represents an individual’s present state of tumor spread (T), lymph node status (N) and existence of metastases (M). Within each of these designations, there are individual status designations and the final staging decision is based on combining the statuses of each of the constituent models. The T value measures the extent of tumor bulk and spread, and has 5 possible values: T1a, T1b, T2, T3, T4, with T1a the best case scenario for mesothelioma patients, meaning limited tumor bulk, with no involvement of the visceral pleura. The N status has 4 possible values: N0-N3, again with N0 the best case, meaning no lymph node involvement. The M status is a value of 0 or 1, meaning no distant metastases or any evidence of distant metastases.

These designations are then put together to determine an individual patient’s current stage. The staging system is as follows:

For more information, please read: mesothelioma stages.

Surgical Management of Mesothelioma

Most patients who are diagnosed with mesothelioma receive a diagnosis later in life. Because of this, accurate staging of patients is an important element in developing a treatment plan, especially a plan that can include surgery. Older patients are less likely to tolerate the invasive surgery and extensive recovery associated with mesothelioma surgeries. Patients with no evidence of metastases and limited tumor involvement are the target patients for surgical intervention and multimodal therapy. Those with M1 status are immediately not considered for radical surgery. For patients who are between the best and worse cases though, a judgment call must me made by their physicians as to appropriate an treatment course.

Multimodal protocols featuring surgery, chemotherapy and localized radiotherapy remain the best way to extend median survival for eligible patients, but there is still much research being conducted on which combination of modes is the most effective in treating mesothelioma, so definitive statements on treatment methods are not yet possible. The role of pleurectomy/decortication vs. extrapleural pneumonectomy is one of the most controversial questions among mesothelioma physicians. A number of studies have been done, but the choice often comes down to the choice of individual surgeons. There are a number of other controversial questions as well, such as the the question of whether chemotherapy should be deployed in an adjuvant or a neoadjuvant manner for greatest treatment efficacy.

For more information on mesothelioma treatments, please read: Mesothelioma Treatments: Surgery and Mesothelioma Treatments: Chemotherapy and Radiation.

Conclusion

Even as research as improved the efficacy of our treatments, mesothelioma still remains one of the most difficult of all cancers to treat effectively. The work that is currently being conducted by physicians and researchers is an important step in changing the dynamics of mesothelioma treatment and diagnosis.

Labels: diagnosis, mesothelioma, staging, surgery, treatments

posted by Belluck & Fox at 4:03 PM
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Mesothelioma Articles in Current Treatment Options in Oncology

Monday, September 22, 2008

A number of articles on malignant mesothelioma have recently appeared in Current Treatment Options in Oncology, an important medical journal that features reports on the latest in oncology medicine. The journal was “developed out of the recognition that it is increasingly difficult for specialists to keep up to date with the expanding number of treatment options published in their subject,” so it features case reports and detailed descriptions of the latest treatments and other research on individual cancers.

The recently-published articles on mesothelioma encompass a variety of important topics in mesothelioma research, including the latest data on pleural mesothelioma and peritoneal mesothelioma, as well as descriptions of cutting-edge mesothelioma treatments and diagnostic procedures.

We will be publishing individual summaries of the following articles within the next week:

• “Mesothelioma Epidemiology, Carcinogenesis, and Pathogenesis” provides an overview of the latest research on the biological factors responsible for mesothelioma genesis. One of the authors of the article, Michele Carbone, MD, PhD, is an internationally-regarded researcher on mesothelioma.
• “Diagnosis, Staging, and Surgical Treatment of Malignant Pleural Mesothelioma” is an article written by physicians at Memorial Sloan – Kettering Cancer Center in New York City, one of the country’s most well-regarded cancer centers. The article features the latest information on mesothelioma diagnosis and a detailed description of the current mesothelioma staging system. It also provides an overview of the main surgical treatments for mesothelioma.
• “Systemic Treatments for Mesothelioma: Standard and Novel” describes how chemotherapy is used for the treatment of mesothelioma and it provides detailed information regarding combination therapy using pemetrexed and cisplatin, which is the chemotherapy standard of care for treatment of pleural mesothelioma, as well as information on newer agents that are being investigated for treatment of the disease.

Labels: mesothelioma

posted by Belluck & Fox at 5:07 PM
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Consensus Statement on Peritoneal Mesothelioma

Friday, September 19, 2008

Journal of Surgical Oncology

5th Biannual Peritoneal Surface Oncology Workshop

The 5th Biannual Peritoneal Surface Oncology Workshop was held in Milan, Italy during December 2006. The title of the workshop was “Integrating Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy into the management of Peritoneal Malignancies: a Consensus Meeting,” and included sessions on a number of peritoneal malignancies, including peritoneal mesothelioma. In the hope of developing a consensus statement on the diagnosis and treatment of this disease, a questionnaire was placed on the workshop’s website and members were asked to complete the questions based on their professional experience and opinions. The submitted answers were then debated during the workshops and general principles were developed in response to these debates.

An article reporting the results of this workshop has recently been published in the Journal of Surgical Oncology. The authors describe the findings on both the questionnaire and the workshop sessions and they include information on areas of significant agreement, as well as on areas where important questions still remain.

The following article is a summary of the “Consensus Statement on Peritoneal Mesothelioma” that appears in the Journal. We are not covering the entire report, but are instead highlighting specific parts of it. A copy of the article can be purchased from Journal of Surgical Oncology and a spreadsheet of the official results of the questionnaire can be downloaded from the website of the 5th Biannual Peritoneal Surface Oncology Workshop (this link will take you to the download page, while the link that is below the title will take you to the workshop’s home page).

Introduction

Peritoneal mesothelioma is the second most common form of mesothelioma and is diagnosed in 10% to 20% of all cases. It is, however, still a relatively rare disorder. There have not been any large-scale Phase III studies on treatment protocols and, because of this, a standard of care has not yet been developed for it, nor has a specific staging system been deployed. There are, however, a number of small scale studies and some anecdotal reports that point to the efficacy of a multi-modal approach to disease treatment involving surgery and chemotherapy. In patients who are eligible for “curative” cytoreduction surgery, the combination of aggressive surgery and hyperthermic intra-peritoneal chemotherapy (HIPEC) has demonstrated survival figures approaching 5 years. In patients who are treated with palliative surgery and systemic chemotherapy and/or intra-peritoneal chemotherapy, the median survival figures range from 9 months to 15 months.

Preoperative Evaluation

As is true with all forms of mesothelioma, early diagnosis of peritoneal mesothelioma is quite difficult due to its rarity and “unspecific presentation.” It is often misdiagnosed as another disorder, which can lead to “treatments” that are not only ineffective, but potentially dangerous: because the disease has a strong tendency to invade instrumentation sites, such as drainage points and incision areas, beginning therapy without a knowledge of mesothelioma as the underlying condition can complicate future treatments and start the patient off at a significant disadvantage.

The experts surveyed at the workshops voted CT as the imaging technology of choice for pre-operative workups of the disease and they indicated that laparoscopic biopsy techniques were preferred over surgical exploration of the peritoneum, should CT suggest the presence of mesothelioma. As is the case with pleural mesothelioma, pathological analysis of the biopsy samples remains the principal means of achieving a definitive diagnosis. Peritoneal mesothelioma has been shown to stain positive for calretinin, epithelial membrane antigen (EMA), Wilms tumor 1 antigen (WT1), cytokeratin 5/6, human mesothelial cell 1 (HBME-1) and mesothelin, while staining negative for CEA, B72.3, MOC-31, TTF-1 and Ber-EP4. Within this context, the article states that “positive calretinin and EMA with negative CEA is highly suggestive” of peritoneal mesothelioma.

As with pleural mesothelioma, the histological subtype of the disease is an important finding in developing a treatment plan. Epithelial mesothelioma is the most common subtype of the disease and is present in upwards of 88% of peritoneal mesothelioma diagnoses. Sarcomatous mesothelioma and the biphasic subtype are each found about 6% of the time. There is also a form of peritoneal mesothelioma that is characterized by a low-malignant potential, but its incidences are quite rare.

Patient Eligibility to Cytoreductive Surgery and PIC

Even though peritoneal mesothelioma does not have a cure, a treatment protocol featuring cytoreductive surgery and some form of peri-operative intraperitoneal chemotherapy (PIC) remains the most effective methodology for long-term management of the disease. This protocol is, however, expensive to deploy and features a significant recovery period, so patient selection is an important element in developing a treatment plan. Patients who are eligible for this protocol must be medically fit and their disease must not demonstrate any extra-abdominal metastases. One of the most important determinations involving patient eligibility is the histological type of the disease: patients with the rare form of low-malignant disease are the best candidates for treatments, followed by patients who present with the epithelial subtype. Patients with biphasic or sarcomatous mesothelioma, just as in pleural mesothelioma, are rarely good candidates for long term treatment success. Other indicators for reduced prognosis and treatment response include male gender, incomplete cytoreduction and aggressive malignant potential.

The use of systemic chemotherapy in adjuvant or neoadjuvant settings may be combined with surgery and PIC, but there is not a consensus on the precise conditions in which it should be carried.

For patients who are not eligible for cytoreductive surgery and PIC, the most commonly prescribed treatments included debulking surgery for cases of low malignant potential. For cases of epithelial mesothelioma (and possibly the more aggressive histological types) neoadjuvant systemic chemotherapy is often attempted and is then followed by revaluation for surgery and PIC.

The article also proposes a staging classification for cases of peritoneal mesothelioma. The staging system in use for pleural mesothelioma is not applicable to cases of peritoneal disease, so the authors propose the following staging system for trial study:

State of the Art of the Methodology

In this section of the article, the authors provide an overview of the goals and the techniques deployed for cytoreduction and chemotherapy.

The most important factor in developing a cytoreductive surgical plan is the accurate mapping of the extent of tumor invasion. Complete macroscopic cytoreduction can only be achieved if the full surface area of the malignancy has been identified. While most of the experts surveyed felt that the key to the surgery was removal of the visibly malignant tissues, a small majority (58%) felt that complete peritoneal pleurectomy–even when tumor spread was limited and not extensive of the entire surface–was necessary to help prevent microscopic disease spread.

A number of variations on the HIPEC procedure have been deployed for peritoneal mesothelioma and a number of different chemotherapy agents have been delivered as well. While questions regarding specific techniques of perfusion and delivery remain unanswered, most of the experts surveyed for the article agreed that cisplatin and doxorubicin were the best chemotherapy agents for peritoneal mesothelioma treatment. They also agreed that 42 degrees Centigrade is the optimal temperature to deliver the drugs at.

Follow-up

As they had for diagnosis and pre-op evaluation purposes, the experts agreed that CT was the best imaging technology to be used for testing and tracking treatment response. Regular clinical exams and lab tests were also recommended as part of the standard follow-up procedures. The physicians felt that during the first two years post-op, asymptomatic patients should receive a workup every three to four months. After two years, the workups should occur every six months. Early surgery and/or chemotherapy were recommended by most physicians should any of these tests indicate recurrence of the disease.

Future Perspectives

The authors close the article with descriptions of technologies and other tools that the physicians hope will impact diagnostic efficiency and treatment efficacy in the near future. Integrated PET/CT is a potential advance on the individual use of both CT and PET in cancer diagnostics. CT is known for its ability to provide adequately high resolution scans of internal surfaces for visualization and diagnostic purposes, but—unlike PET—is not able to provide any indication of concurrent and distant metastases. Even as more research needs to be conducted to validate the results of this new technology, the combination of these imaging systems has great potential for the diagnosis of mesothelioma and a number of other cancers as well.

Serum analysis tests and gene microarray analysis techniques are two other cutting-edge technologies that may enhance a physician’s ability to provide earlier and less invasive strategies for diagnostic purposes, but their efficacy for peritoneal mesothelioma is still under investigation.

The investigation of new treatments for peritoneal mesothelioma, just as it is for pleural mesothelioma, is one of the most exciting areas of research. The development of targeted therapeutic agents, such as agents that focus on growth factor signaling pathways, is an area of heavy research right now. Even as the first studies on this subject are not showing much, if any, treatment efficacy to growth-factor targeting agents, there is hope that our growing understanding of the biological substrate at work in mesothelioma genesis will reveal more potential treatment targets.

Other areas of therapy that experts identified as promising were immunotherapy, gene therapy, anti-angiogenic drugs and agents that promoted apoptosis.

Labels: mesothelioma, peritonealmesothelioma, treatments

posted by Belluck & Fox at 3:17 PM
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MVP and Vinorelbine for Malignant Pleural Mesothelioma

Thursday, September 18, 2008

Source: Lancet

In July of this year, The Lancet published an article describing the results of a study that compared the efficacy of a chemotherapy regimen utilizing mitomycin, vinblastine and cisplatin (MVP) or vinorelbine to a treatment regimen featuring best supportive care and active symptom control for patients with mesothelioma. The study showed that neither the MVP regimen nor the vinorelbine regimen showed any statistically significant improvement in extending patient life over the symptom control regimen. However, the authors concluded that vinorelbine deserves more study because there was some evidence to indicate a possible survival benefit to the treatment, even though it did not achieve statistical significance.

The latest edition of The Lancet has published a letter criticizing that study and its conclusions, as well as a reply by the authors of the original study. The letter attacked the design of the study and the pathology analysis conducted during it, as well as the authors’ conclusion that the use of vinorelbine to treat pleural mesothelioma deserved more research. The letter noted that while active symptom control and vinorelbine were more tolerable than pemetrexed (Alimta), the latter is still the only chemotherapy agent to demonstrate statistically significant improvements in median survival times for mesothelioma patients, so patients who can tolerate it should be treated with pemetrexed.

In their reply, the authors’ defend their study and their conclusion that vinorelbine warrants more research. They state that the recommendation to continue research on vinorelbine is warranted by their demonstration of some survival benefit, even though their results were not conclusive and were not presented as such. The authors state that a two month survival benefit in some of the patients treated with the chemo agent alone justifies the call for more research, especially considering how so few therapies have shown any benefit for the treatment of mesothelioma. They conclude that the future of mesothelioma diagnoses and treatment regimens is the identification of specific biomarkers and the development of truly targeted therapies.

Labels: chemotherapy, mesothelioma, treatments

posted by Belluck & Fox at 3:21 PM
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Prevention of Malignant Seeding at Drain Sites after Invasive Procedures … by Hypofractionated Radiotherapy in Patients with Pleural Mesothelioma

Wednesday, September 17, 2008

Full Title: Prevention of Malignant Seeding at Drain Sites after Invasive Procedures (Surgery and/or Thoracoscopy) by Hypofractionated Radiotherapy in Patients with Pleural Mesothelioma

Source: Acta Oncologica

Radiotherapy is not a general modality in the treatment of mesothelioma because the diffuse nature of the disease’s invasion pattern rarely presents a localized malignancy for the radiation to be applied to. Due to mesothelioma’s widespread appearance, the radiation would have to be delivered over a very wide area at very high doses to be effective, but this would put vital organs such as the lungs, heart and kidneys at serious risk for radiation overexposure and sickness. There is, however, a very specific use of radiotherapy that has shown some efficacy in the treatment of pleural mesothelioma and peritoneal mesothelioma: localized application of radiation to drain sites and other instrumentation sites after treatment, or other medical intervention.

Metastases to areas of surgical intervention are a common problem in the treatment of a number of different cancers, but the problem seems especially acute with mesothelioma treatments. Different studies have reported different figures on the likelihood of this occurring, but most estimates report a 20-50% of chance of surgical site metastases following treatment. Prior studies have reported on the benefits of radiotherapy to prevent tumor seeding, but the treatment is still not deployed in many cases and research into this question continues on a number of fronts.

An article has recently been published in the journal Acta Oncologica that describes the results of a study conducted by Italian physicians on their use of radiation to prevent drain site metastases. That article will be summarized in the following sections.

Overview of the Study

To investigate the efficacy of radiation therapy for the prevention of tract site metastases in patients treated for pleural mesothelioma, the authors enrolled 32 patients with histologically-confirmed mesothelioma into their study. There were 24 men and 8 women, with the average age at diagnosis listed at 64 years-old. 25 patients presented with epithelial mesothelioma, 6 with sarcomatoid mesothelioma and there was 1 case of the biphasic subtype. When the patient cohort was analyzed by stage at time of diagnosis, the authors found that 2 patients were considered Stage IA, 3 patients were considered Stage IB, 20 patients were listed as Stage II, 4 presented as Stage III and 3 others as Stage IV.

The patients underwent a variety of procedures in their diagnosis and treatment: some were palliative in their intent, while others were curative, but all involved some type of surgical intervention, from the insertion of drainage tubes to radical pleurectomy to other procedures as well. After their wounds healed from the original operations, all of the patients then received radiation therapy to each area that was treated by the procedure. 21Gy were delivered in three daily fractions to each patient. After the completion of treatment, 20 patients received some form of chemotherapy.

Patients received clinical examinations every 3-4 months during the first two years of treatment and then at 6-8 months following the initial two-year period.

Results

The authors were quite pleased with the results of their study. They report that “after a mean follow-up of 13.6 months…from the end of radiation therapy, no patient developed subcutaneous nodules in the treated area.” They also report that the therapy was well tolerated, with 11 patients developing a temporary grade I erythema, which is a reddening and swelling of the skin, but seemingly nothing more serious and no late treatment effects were seen.

The one year survival for the patient cohort was reported as 68.9% and the two-year rate was reported as 30.3%—both of which are excellent results for pleural mesothelioma patients. 17 patients (52%) died of mesothelioma due to local progression after a mean survival of 12.6 months. The authors note that 13 patients (41%) are still alive after a 13.9 month mean follow-up and two others are alive “without evidence of disease after a mean follow-up of 16.5 months.”

Conclusion

Because of the results of their study, the authors conclude that radiotherapy following therapeutic treatment of pleural mesothelioma is an effective methodology to prevent tumor seeding in areas of surgical intervention. They note that although this procedure has not yet been incorporated into standard treatment protocols, their results, as well as the results of a number of other studies, demonstrate radiation therapy’s benefits for the treatment of mesothelioma and they propose that it be deployed as a standard therapy.

Labels: mesothelioma, pleuralmesothelioma, radiation, treatments

posted by Belluck & Fox at 4:40 PM
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Successful Palliation of Malignant Ascites from Peritoneal Mesothelioma by Laparoscopic Intraperitoneal Hyperthermic Chemotherapy

Tuesday, September 16, 2008

Source: Surgical Laparoscopy, Endoscopy & Percutaneous Techniques

The development of more effective treatment options for patients with mesothelioma remains the most pressing issue facing physicians and researchers who work with the disease. Pleural mesothelioma is the most common form of the disease, so the majority of research programs that are conducted for the study of mesothelioma are devoted to the study of its pleural form. However, nearly 20% of all mesothelioma diagnoses are for peritoneal mesothelioma, where the malignancy attacks the peritoneum, which is the lining of the abdominal cavity. Because of this situation, even less is known about effective therapies for peritoneal mesothelioma than is known about general mesothelioma treatments. Large scale studies have been impossible to perform for patients with this variety of disease, so the major ways in which information has been shared among physicians has been through case reports made in journal articles. Even though these reports cannot replace the validity of results achieved with large scale studies, they are still able to share important information about the treatment of the malignancy and of the experience that individual physicians have had with individual mesothelioma patients.

One such article has recently been published in the journal Surgical Laparoscopy, Endoscopy & Percutaneous Techniques. In it, the authors describe their experience treating a 49 year-old woman with pleural mesothelioma and peritoneal mesothelioma who presented with a painful ascites that was not responsive to any of the therapies attempted to treat it. Because of this, they treated the woman with a procedure known as laparoscopic hyperthermic intraperitoneal chemotherapy (LHIPEC). The journal article describes the women’s presentation and their successful treatment of her malignant ascites.

Mesothelioma, Ascites and LHIPEC

Ascites is a condition where fluid has built-up within the abdominal cavity. It is common to a number of disorders and is associated with a number of painful symptoms, such as dyspnea, abdominal pain and nausea. When the ascites are caused by an underlying malignancy, such as peritoneal mesothelioma or colon cancer, other symptoms may include reduced mortality and malnutrition. Many of the traditional treatments for ascites, such as paracentesis or some form of shunting to move the fluid into a different area, are not often associated with successful symptom management. Because of this, alternative therapies are being researched on a number of fronts.

The authors note that one of these therapies, laparoscopic hyperthermic intraperitoneal chemotherapy (LHIPEC), has achieved a 100% success rate in recently-published, retrospective studies involving the treatment of ascites. LHIPEC is a variant of traditionally-delivered heated intraperitoneal chemotherapy, but the chemo agents are delivered through laparoscopic entry techniques instead of a traditional laparotomy, which refers to a potentially large surgical incision that is made to facilitate open access to the abdomen. Because the use of laparoscopic techniques are associated with enhanced recovery time, LHIPEC is considered a potential option in cases where palliation is the primary concern.

Case Study

The authors describe the case of a 49 year-old woman who presented with “debilitating ascites” after pleural mesothelioma had spread to her abdomen. She initially received treatment for pleural mesothelioma in 2003 involving pleural decortication and adjuvant chemotherapy using pemetrexed and carboplatin. In 2006, CT scans showed a relapse of pleural mesothelioma, the spread of the disease to her peritoneum and the development of ascites. She was treated with further chemotherapy but integrated PET/CT showed gross spread of the disease and her mesothelioma symptoms continued to restrict her quality of life. Because of this, she underwent LHIPEC in January of 2007. Cisplatin and doxorubicin were the agents delivered.

After the operation, the patient was watched for 24 hours. During this initial period she developed a grade 4 hyponatremia, which is an abnormally low level of sodium in one’s blood, but this was treated upon discovery and soon corrected. She began taking food on the second post-op day, had the drains removed on the fourth day and was discharged on the seventh day after the surgery.

The procedure was a great success. The patient experienced noticeable improvements in symptom relief within a day of surgery, including a “complete remission of dyspnea and abdominal distension.” Her follow-up scans showed no signs the ascites were returning. She died six months after the procedure, but from a pulmonary embolism unrelated to her mesothelioma.

Conclusion

The authors feel that LHIPEC could be an important therapeutic option for the palliative treatment of malignant ascites. It seems to be well-tolerated and other recent studies have also shown its effectiveness for palliative purposes. The authors state that their article is only the second one to describe its use for the treatment of peritoneal mesothelioma and they call for more research into the use of LHIPEC. They also note that along with the symptom control they achieved—which the procedure was initially conducted for—their patient also demonstrated some therapeutic response to LHIPEC as post-op imaging scans showed a much lesser extent of ascites than before the procedure.

It is much too early to conclude that LHIPEC should be a regular option for the treatment of mesothelioma, but the results of this case report certainly point to the need for more research into the various forms of mesothelioma.

Labels: chemotherapy, mesothelioma, peritonealmesothelioma, treatments

posted by Belluck & Fox at 5:24 PM
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Review of Pemetrexed in Combination with Cisplatin for the Treatment of Malignant Pleural Mesothelioma

Monday, September 15, 2008

Source: Therapeutics and Clinical Risk Management

The current standard of care for the treatment of mesothelioma is combination chemotherapy using pemetrexed (Alimta) and cisplatin. The US FDA first approved this therapy in 2004, soon after the results of a large-scale, Phase III clinical trial were published that showed statistically significant improvements in median survival and time-to-progression for patients with pleural mesothelioma. Subsequent trials confirmed the clinical benefits this study found and the intervening years have seen approvals of the therapy from every other major nation’s health care regulatory agency. However, this treatment is still not a curative solution for mesothelioma, so research into improving its efficacy, along with additional research into the combination of these agents with other modalities of treatment, continues on a number of other fronts.

An article describing the history of pemetrexed use, from its earliest Phase I studies to the 2004 Phase III study that led to its approval, has been published in the journal Therapeutics and Clinical Risk Management. The authors provide a full literature review of these various trials and they describe pemetrexed’s mechanism of action and the initial studies that investigated its use, as well as a detailed description of the study design and results of the Phase III study that led to pemetrexed’s approval.

The following is a partial summary of that article, “Review of Pemetrexed in Combination with Cisplatin for the Treatment of Malignant Pleural Mesothelioma.”

Cisplatin and Pemetrexed

Cisplatin is a chemotherapy drug in the class of drugs known as platinum agents. Cisplatin was first introduced in 1978 and its efficacy for the treatment of a number of cancers has been shown time and time again. Pemetrexed is an antimetabolite chemotherapy agent, whose efficacy arises from its ability to inhibit folate (folic acid) from being metabolized.

Phase I and Phase II Clinical Trials

A number of different chemotherapy agents have been used to treat mesothelioma, but the results have been disappointing. Preclinical studies of cisplatin and pemetrexed showed efficacy for the treatment of non-small cell lung cancer, so researchers considered it possibly beneficial for mesothelioma treatment. In a Phase I evaluation, a number of patients with various cancers, including pleural mesothelioma, were given pemetrexed in combination with cisplatin. This trial investigated dosage recommendations and their relationship with treatment toxicities. The study concluded with a recommendation of 600 mg/m² of pemetrexed and 75 mg/m² of cisplatin and a call for more research.

A Phase II study of the combination chemotherapy was not conducted with mesothelioma patients, but was conducted for untreated patients with Stage IIIB or IV non-small cell lung cancer. In this trial, pemetrexed levels were reduced to 500 mg/m² and cisplatin levels remained the same. Overall response was 45% and the treatment was well-tolerated, so a Phase III trial was planned for mesothelioma patients.

EMPHACIS III Clinical Trial and FDA Approval

The Evaluation of Mesothelioma in a Phase III Trial of Pemetrexed with Cisplatin (EMPHACIS) enrolled 448 chemonaive patients into a trial that randomized patients into one of two groups: a group that received pemetrexed + cisplatin and a group that received cisplatin alone. Administrations were given every 21 days. When B12 and folic acid deficiency were discovered as common side effects, vitamin supplementation administrations were added to the trial design. This was the largest study of mesothelioma patents ever attempted.

The initial study results showed a median survival time for the combination arm at 12.1 months, compared to 9.3 months for the cisplatin only group. Although not statistically significant, subgroup analysis of the patient cohort showed that patients who received both the combination therapy and vitamin supplements had a 13.3 month median survival vs. 10.0 months for the cisplatin + vitamin crowd. Final results of the study were released in 2005, with a 12.8 month median survival noted for the combination therapy patients vs. only 9 months for the cisplatin-alone patients. These results also demonstrated improvements in pulmonary function tests.

This study led to the FDA’s approval of pemetrexed and cisplatin in 2004. The FDA could not fully confirm all of the results of the EMPHACIS trial, but they could confirm that this treatment arm was more effective than previous trials had been. The FDA’s dose recommendation also incorporated the recommendation for vitamin supplements, as well as the use of dexamethasone to prevent pemetrexed-caused rashes.

International Approval and Quality of Life Issues

The FDA was the first major regulatory agency to approve pemetrexed + cisplatin for the treatment of pleural mesothelioma. Since that time, most other national healthcare agencies have also approved its use. As was alluded to in our description of the Phase III trial, pemetrexed’s efficacy is not simply based on increased survival time, but is also based on real improvements in patient quality of life. A number of studies have shown statistically significant improvements in disease-related dyspnea, pain and cough.

Other Studies and Combinations

Even as this combination has proven the most effective chemotherapy treatment in clinical trials, research into other pemetrexed-based combinations also continues. In place of cisplatin, carboplatin is sometimes used because it typically has a more favorable toxicity profile. Overall response rates and efficacy tend to be higher with cisplatin, but carboplatin has demonstrated easier tolerability for many patients. However, Phase III trials have not been conducted for this combination.

Labels: chemotherapy, mesothelioma, treatments

posted by Belluck & Fox at 3:25 PM
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Molmed gets US FDA Orphan Drug Status for Malignant Mesothelioma Drug

Wednesday, September 3, 2008

Source: MolMed.com

Italian biotechnology company MolMed has recently announced that ARENEGYR, its experimental anti-cancer drug that is being investigated for the treatment of mesothelioma and a number of other cancers, has been granted orphan drug status from the US FDA. This announcement follows on a similar designation given by the EU’s pharmaceutical regulatory agency in June. Orphan drug status is available to investigational treatment agents that focus on uncommon and/or rare diseases, specifically defined as pathologies that affect less than 5 in 10,000 people, and it confers a number of benefits to the manufacturer to reward their research.

Malignant pleural mesothelioma remains a very difficult disease to treat effectively. Even though contemporary multimodal treatment protocols have increased median survival time, the disease is still not curable, so research into more effective therapeutics continues on a number of fronts. ARENEGYR represents one of the most promising avenues of contemporary research. It is a vascular targeting agent that selectively targets and binds with a tumor’s blood vessels. Its mechanism of action is governed by two major elements: NGR, a “tumor homing peptide” that allows this binding to occur, and TNF, a cytokine known for its ability to trigger apoptosis, which is the principal mechanism for ARENEGYR’s antitumor activity.

Along with its proposed use for mesothelioma treatment, ARENEGYR is being investigated in single agent therapy for the treatment of colorectal cancer, hepatocellular carcinoma and small-cell lung cancer. Molmed is also exploring ARENEGYR in combination with cisplatin for mesothelioma treatment and with Xelox for colorectal cancer.

Labels: chemotherapy, mesothelioma, pleuralmesothelioma, treatments

posted by Belluck & Fox at 10:52 AM
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Localized Malignant Mesothelioma in the Middle Mediastinum: Report of a Case

Tuesday, September 2, 2008

Source: Surgery Today

The most common clinical presentation of mesothelioma is diffuse malignant pleural mesothelioma, where the mesothelioma cells arise in the parietal or visceral pleura and then spread through the pleural surfaces. This form of the disease is seen in 70% or 80% of all cases and is often characterized by the aggressive spread of the malignancy to tissue structures adjacent to the pleura, such as the lungs and diaphragm. However, there are a number of other forms of the disease as well. Alternative forms typically arise among different origin sites, with peritoneal mesothelioma the next most common form of the disease after pleural mesothelioma. Even when the disease arises from these different origin sites, it’s normal behaviour pattern is described as a diffuse disorder where the cancerous cells spread throughout large surface areas. In very rare cases though, individuals may present with a localized version of the disease, where the histological analysis of the tumor cells reveals mesothelioma, but the presentation is characterized by a single, solitary tumor instead of a large malignancy. These cases rank among the rarest of all forms of mesothelioma and articles that describe these single presentations are often the only way that knowledge of these variants can be shared among physicians.

The newest case of localized mesotehlioma to appear in the literature was recently published in the journal Surgery Today. In the article, the authors describe the presentation, treatment and response to treatment of a patient who presented in their institution with very rare case of localized pericardial mesothelioma.

Overview of the Case

The authors report on a 52 year-old man admitted to their institution to discover the cause of an unexplained shadow on a chest x-ray that was incidentally found by the patient’s dentist during a dental examination. After receiving a follow-up chest radiograph, a contrast-enhanced CT disclosed the cause of the shadow: a middle mediastinal tumor, approximately 43 x 36mm in size. Further examination revealed a localized tumor, without evidence of metastasis or local spread, nor pleural or peritoneal effusion. The man then underwent surgery and the tumor was resected with surgical margins from the pericardium.

The tumor was then examined microscopically and histologically. Microscopic analysis revealed the presence of “large atypical epithelial tumor cells” that were “admixed with dense lymphoplasmahistiocytic infiltrates.” Histological examination revealed that the tumor cells were positive for calretinin, thrombomodulin and CAM5.2, which are part of the panel used in mesothelioma diagnoses, while negative for carcinoembryonic antigen (CEA) and LeuM1, which are common markers for adenocarcinoma. Based on these findings, the authors diagnosed the man with localized epithelial lymphohistiocytoid pericardial mesothelioma.

The tumor returned a year later and the follow-up thoracotomy also revealed a localized tumor, but in this case, the tumor had invaded the aorta and the superior vena cava. Because the tumor could not be resected, a bypass of the superior vena cava was performed instead and, pursuant to the patient’s request, he was treated solely with radiotherapy. Follow-up at 27 months from diagnosis revealed significant lung metastases. The patient attempted an alternative therapy, but this was not successful and he finally died three years after his initial thoracotomy.

Discussion

In this article, the authors describe a very rare presentation of mesothelioma. As we said above, the most common presentation of mesothelioma is diffuse malignant pleural mesothelioma, which accounts for 70% to 80% of all diagnoses. When pleural mesothelioma is not the case, peritoneal mesothelioma is the next most common diagnosis, with pericardial mesothelioma and mesothelioma of the tunica vaginalis considered very rare presentations. In the few cases of localized mesothelioma that have been described, most of them arise form the pleura. The authors note that localized forms of pericardial mesothelioma have only been described in five other cases, making their patient the sixth person in which this variant has been seen and described.

Due to their extreme rarity, localized mesotheliomas are easily misdiagnosed as different malignant developments than what they actually are. In these cases, immunohistochemical analysis is probably the best way to return a definitive diagnosis. Localized forms of the disease also seem to have a better prognosis than do the typical forms of the disease, but that conclusion could be based more on the small number of cases that have been reported on than on any actual prognostic differences between the various behavior patterns involved.

The authors also state that their patient’s presentation was quite rare for another reason as well: lymphohistiocytoid mesothelioma is a proposed term for a variant of sarcomatoid mesothelioma that has only been identified in 10 other cases besides the present case.

Conclusion

Mesothelioma remains a difficult to understand disease. Even as more is being learned about its most common forms, it continues to evade effective treatment. When it comes to management of the disease’s rarest forms, physicians must deploy whatever treatments are available, or what their patients request, because so little is known about them. Journal articles remain the primary way in which knowledge of these rare forms can be shared.

Labels: mesothelioma, pericardialmesothelioma

posted by Belluck & Fox at 4:06 PM
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