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