Peritoneal mesothelioma is the second most common form of mesothelioma, appearing in 20% of all cases. The disease typically presents as a diffuse malignancy that can spread throughout large areas of the peritoneum. In its advanced stages, the disease can infiltrate the outer layers of the GI tract, as well as metastasize to abdominal organs, but the first indication of the disease as a metastatic event is quite rare. Researchers from Italy have recently published an article in the International Journal of Surgical Pathology where they describe a case report of a 64 year-old man who presented with gastric metastases as the first sign of peritoneal mesothelioma.

The authors describe this as the first such case report in the literature on mesothelioma.

Case Report

The authors describe a 64 year-old man who presented with abdominal pain and distension, with corresponding ascites and significant weight loss within the year. At time of presentation, he has awaiting a liver transplant due to liver cirrhosis and suffered from esophageal varices as well. His physicians first assumed a bacterial infection was the cause of the abdominal pain, but the standard treatments were not effective. After serum markers returned negative, the patient underwent an esophageal gastric endoscopy, which revealed a lesion in the antral mucosa, which is a lining of a specific area (gastric antrum) in the stomach. A biopsy of the lesion was performed and subsequent analysis showed peritoneal mesothelioma, epithelial sub-type. After these results were returned, a high resolution abdominal CT showed thickening of the parietal pleura. The patient was treated with single-agent pemetrexed(Alimta) and was still alive 7 months after diagnosis.

Conclusion

The authors report their article as the first description of a case of gastric metastasis as the first indication of peritoneal mesothelioma. In the disease’s later stages, metastases to abdominal organs are common, but the authors describe discovering peritoneal mesothelioma during an endoscopic GI biopsy as “exceptionally rare.” Because of this, they note serious diagnostic challenges to the clinician who encounters such a case.

Labels: mesothelioma, peritonealmesothelioma

Malignant Mesothelioma is most commonly a disease of the older and the elderly. The vast majority of all mesothelioma diagnoses are for men and women (although, mainly men), older that 55 or 60. However, the disease can, albeit very rarely, affect teenagers and young adults. Because mesothelioma is so rarely seen in these populations, studies are impossible to perform and little is understood about the best treatment regimens or the prognostic indicators involved in determining overall treatability. The only way to share information about these cases is through the publication of individual case reports in medical journals.

Physicians from the Dana-Farber Cancer Institute and from Brigham & Women’s Hospital have recently published an article on their treatment of four pediatric peritoneal mesothelioma cases. The case reports describe how the physcians treated these patients and how each responded to these therapies. They close the article with a number of recommendations regarding the future treatment of pediatric mesothelioma cases.

Case Reports

The authors report on four cases of pediatric mesothelioma:

1. A previously healthy 17-year-old female with a number of symptoms, including deep vein thrombosis of the left arm, a left-side pleural effusion and an unknown pelvic mass. Fluid in her peritoneum tested positive for mesothelioma.
2. A previously healthy 16-year-old male with pelvic pain and weight loss, among other symptoms, had a biopsy of a diffuse tumor mass in his pelvis which revealed peritoneal mesothelioma.
3. A previously healthy 20-year-old male with a Klebsiella pneumonia, pleural effusion and a mass in the tissue surrounding his kidneys tested positive for peritoneal mesothelioma.
4. A 16-year-old female with a prior cancer history (neuroblastoma at 12) who had achieved complete remission, presented with abdominal pain that was discovered to be caused by peritoneal mesothelioma.

None of the patients had any personal risk factors for mesothelioma, and none were smokers. However, three of them had fathers who were likely exposed to asbestos during their work in construction. None of the men had any evidence of pleural mesothelioma or peritoneal mesothelioma, but we know that the disease can affect the children and spouses of exposed workers before they are diagnosed, or even if they are never diagnosed.

Treatment Regimen and Response

After the patients were diagnosed with peritoneal mesothelioma, they all received the same basic treatments as an adult would receive. All of the patients received systematic chemotherapy using pemetrexed and cisplatin; two of the patients received surgical debulking prior to their chemotherapy.

The median survival for the group was 40.3 months. At the time the article was published, three of the four were still alive. Two of these were progression free at 45 and 57 months, respectively, while the third demonstrated some progression at 22 months, but will still alive at 24 months.

Conclusion

The authors conclude their article by raising the question as to the relationship between asbestos exposure and the development of either pleural mesothelioma or peritoneal mesothelioma, especially in pediatric cases. They note that while the incidence of the pleural disease is to be expected based on the way in which these exposures occur, the reasons for the development of peritoneal mesothelioma are still unknown. They wonder if the precise nature of the exposures—whatever they may be, as the question remains totally open for these four patients—may explain the development of peritoneal disease in place of pleural disease.

They also conclude that, where applicable, pediatric cases should be treated in the same manner as adult cases are treated: they should receive debulking surgery if possible and intravenous systemic chemotherapy. The authors also believe that these patients should be eligible for enrollment in adult-focused clinical trials.

Labels: mesothelioma, peritonealmesothelioma, treatments

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

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

Mesothelioma is an asbestos-caused cancer of the lining that surrounds many of the body’s vital organs. Pleural mesothelioma is the most common form of the disease and is diagnosed in 2000-3000 people every year. Peritoneal mesothelioma is the next most common form of the disease, but it is relatively rare and is diagnosed in only a few hundred cases per year. Because of this situation, detailed clinical trials and other treatment-related studies are difficult to perform and no standard of care yet exists for peritoneal mesothelioma.

Chemotherapy with pemetrexed is the standard of care for the treatment of pleural mesothelioma and many of the studies investigating effective therapies for peritoneal mesothelioma have incorporated pemetrexed into their treatment plans as well. An article was recently published in the Journal of Clinical Oncology that describes an open-label, multicenter study of the use pemetrexed in combination with gemcitabine for the treatment of peritoneal mesothelioma. This was the first study to investigate combination chemotherapy using these two chemo agents and the initial results, while limited, do show some efficacy for the treatment of peritoneal mesothelioma.

Overview of the Study

In order to evaluate the therapeutic efficacy of pemetrexed in combination with gemcitabine, the researchers enrolled 20 patients with histologically-proven peritoneal mesothelioma into their study. As is the case with most diagnoses of mesothelioma, the majority of patients were Caucasian men and epithelial mesothelioma was the most common histological sub-type of the disease. Enrollment criteria included good performance status (0-2), adequate organ function, and a malignancy not currently eligible for curative surgery. While some patients had previously undergone some form of cytoreductive surgery, patients were excluded from the study if they received prior systemic chemotherapy or radiotherapy to the target area, or they presented with evidence or suspicion of metastatic spread to the brain.

The study design indicated at least six chemotherapy cycles, with each cycle defined in 21-day increments. On Day 1 of the cycle, 1250mg/m² of gemcitabine would be delivered intravenously for 30 minutes. On Day 8, 500mg/m² of pemetrexed would be delivered over IV for 10 minutes, immediately followed by another IV administration of gemcitabine at the same dose as before. Because of previously reported toxicities related to pemetrexed delivery, a number of supplements were also given to patients. Folic acid was orally administered a week or two prior to beginning pemetrexed and was then given daily for the remainder of the patient’s enrollment in the study. Vitamin B12 was delivered by injection 1 or 2 weeks prior to beginning the first cycle and then subsequently delivered every 9 weeks the patient stayed enrolled. Dexamethasone was given one day before pemetrexed and was continued for three days per cycle.

Adjustments to the study design in terms of dose reductions and/or cycle delays could be made in response to individual patient treatment effects, but patients who received dose reductions would not be eligible for subsequent dose escalations and any patients whose cycle delay exceeded the cycle-length of 21 days were removed from the study. Physicians were able to add additional cycles if patients could tolerate them, or were able to remove patients from the study for other treatment effects as well. Any patient who demonstrated progressive disease during intracycle assessment was also removed from the study.

The principal endpoint of the study was determining tumor response rate, with secondary end points identified as disease control rate, overall survival, time to progression and response duration.

Results

10 patients completed the treatment course, while 10 others did not complete the study. 1 patient died in response to the chemotherapy, 5 were removed due to severe toxicity-related treatment effects, 3 patients experienced progressive disease during treatment and 1 patient dropped out of the study for “personal reasons.” 15 patients (75%) completed four chemotherapy cycles, while 12 patients (60%) completed at least six cycles.

The primary endpoint of the study was the determination of overall tumor response and even though not every patient completed the treatment plan, all were included in the determination of overall response rate. No patient experienced a complete response to the treatment, while 3 experienced a partial response and 7 others achieved stable disease (for a time). This leaves a tumor response rate of 15%. Disease control rate, a summation of all patients who achieved a partial response or stable disease, was a much higher 50%. 5 patients could not be fully evaluated for tumor response, either because of early removal from the study or because response data could not be independently-validated, so when these patients were excluded from the results, tumor response rate rose to 20% and disease control rate rose to 67%.

Median survival for the patient cohort was 26.8 months, with a one-year survival rate of 67.5% and a median time to progression of 10.4 months. The two-year survival figure was reported at 50%.

Treatment-related side effects were experienced by a number of patients, with neutropenia and fatigue the most commonly experienced effects. Neutropenia is a serious condition where the body has an abnormally low level of neutrophils, which are a type of blood white cell responsible for fighting infections in the body. 12 patients experienced grade 3 neutropenia and eight experienced grade 4 neutropenia. These figures are significantly higher than some of the earlier studies featuring pemetrexed and cisplatin, which reported neutropenia rates at under 5%.

Conclusion

The authors conclude their article by stating that the combination of pemetrexed and gemcitabine shows clear activity in the treatment of peritoneal mesothelioma and they call for more research into the use of this therapy for patients with peritoneal disease. While objective response rate was low, their statistics demonstrated an overall survival time of 26.8 months, which is longer than some of the figures reported in studies of pemetrexed and cisplatin combination therapy. However, they also state that treatment-related side effects were higher in this patient cohort than in previously-reported on cohorts, and they suggest that future studies should look to a reduction in gemcitabine dosage levels to counter these toxic events.

Studies of peritoneal mesothelioma are few and far between, so this article represents an important addition our knowledge of this rare form of mesothelioma. For patients who are diagnosed with peritoneal mesothelioma and who are not eligible for multimodal treatment plans involving significant cytoreductive surgery, combination chemotherapy using pemetrexed and gemcitabine may be an important new avenue of treatment.

Labels: mesothelioma, peritonealmesothelioma, treatments