Cytoreductive Surgery for Mesothelioma Cancer

History of cytoreductive surgery for Mesothelioma Cancer

Mesothelioma is a rare tumor that develops from cells lining the pleural space (chest cavity) and abdominal cavity (peritoneal space) and can rarely present as a soft tissue mass or growth. Malignant peritoneal mesothelioma (MPM) is a type of mesothelioma characterized by the presence of a number of internal organs, such as the intestine, liver, spleen, omentum, and surface lining of the inner abdomen. Other malignancies that grow and metastasize in the peritoneal cavity with high frequency include tumors of the appendix, colon, and ovaries. 

Peritoneal metastases are one of the most common types of cancer that can be found in the liver, lungs, bones, or brain. Patients with peritoneal metastases often experience symptoms related to their cancer metastases, and common symptoms include flatulence, ascites, pain, loss of appetite, early satiety, fistulas, and infection. Untreated peritoneal metastatic disease has a poor prognosis with mean and average overall survival of 6 and 3 months, respectively (Sadeghi et al. 2000). During this short survival time, patients often experience a poor quality of life from the tumor symptoms and malnutrition that accompany the development of peritoneal disease. In an attempt to relieve symptoms and improve quality of life, surgery is identified as the treatment with the most utility to treat this problem.

The use of surgery to remove bulky, symptomatic tumor dates back to the early twentieth century in the 1930s (Meigs 1934). It was initially labeled debulking surgery, and the first tumor type for which surgery was conducted was ovarian cancer. The rationale for considering surgery started with the rudimentary understanding of peritoneal metastasis. Conceptually, peritoneal metastasis is similar to the pro- cess of the shedding of skin cells, which is part of the life cycle of all cells in the human body. Microscopically cancer cells (and normal cells) are shed in the abdominal cavity; however, cancer cells develop molecular and biological changes that allow cancer cells to grow on other abdominal organs such as the omentum, bowel, liver, or spleen surfaces. 

Normal cells die after they are thrown into the abdominal cavity and the immune system eliminates these cells. Cancer cells, either through mutations or through cell path disturbances, develop mechanisms to survive in the abdominal cavity and avoid immune detection. Cancer cells that become peritoneal metastasis must have the ability to grow on the surface of another organ as microscopic cells and once established they grow and eventually become visible tumor implants. Tumors continue this cycle of cancer propagation and can be spread throughout the abdominal cavity, as well as growing/invading organs where microscopic cells implant.

The coating surface where these cells are bound is called the peritoneal layer (coating) and is composed of mesothelial cells. This peritoneal coating surface surrounds all abdominal muscles, diaphragm, and pelvic walls that house the organs called the parietal peritoneal layer, while the peritoneal coating in the organs such as the liver, the intestine, the spleen, etc. . Peritoneal metastasis (PM) has also been called peritoneal carcinomatosis (PC).

The first reported experiences with debulking surgery were in the 1930s with the goal of palliation to relieve symptoms of ascites, bowel obstructions, pain, and bowel fistulas. While patients did experience some symptom relief, this was transient as tumor (and symptoms) recurrence was frequent with only a minority of patients experiencing long-term survival benefits. Groups continued to explore how surgery might benefit more patients with peritoneal metastasis, and it was not until the late 1960s that published reports began to emerge demonstrating survival benefits for patients with advanced ovarian cancer who underwent a more aggressive and comprehensive resection of their peritoneal disease. 

This surgical approach, called Citorreductor Surgery (CRS), has the main objective of surgery to maximize the abdominal tumor load (ideally to eliminate all visible disease). This is different from the classical reduction of palliation since the objective of CRS is to eliminate the entire tumor, not only the tumor that causes symptoms.

In rapid succession, independent researchers began to confirm the survival benefit of aggressive CRs in patients with advanced organized ovarian cancer. As the experience expanded, these groups began to demonstrate that the size of the residual disease after CRS was the most important factor that predicted the survival benefit (Griffiths et al. 1979; Munnell 1968). Specifically, it was observed that patients without visible disease or minimal residual disease experience the longest survival benefit.

This renewed the medical communities’ interest in surgery for peritoneal metastasis with a change in the intent of surgery from a palliative procedure to a therapeutic procedure. Given the benefits observed with ovarian cancer, interest in using CRS for other cancer types with peritoneal metastasis as appendix, mesothelioma, and gastric - the most common being mucinous appendiceal neoplasms (MAN) that present as pseudomyxoma peritonei (PMP) - was also being explored (Ghosh et al. 1972).

Although aggressive CRS improved survival from 2 to 6 months without therapy to a 40% 5-year survival (Munnell 1968), long-term survival was observed in a minority of patients. The survival time was demonstrated 2-3 times longer; Most patients were still recurring in the peritoneal cavity (local recurrence), while distant metastatic events (hematogenous) were rare.

Around this time in the 1970s, laboratory research and clinical efforts began understanding what contributed to peritoneal recurrence. Both the lab and clinical evidence revealed residual disease, both microscopic and gross tumor, that remained after CRS was responsible for peritoneal cancer recurrence. Further investigation showed a clear inverse relationship between residual tumor size and long-term survival (Griffiths 1975).

Efforts to identify adjuvant treatments that could be given after CRS to prevent disease relapse, extend the time to relapse, or further improve patient survival were pursued. The early success of adjuvant radiation in other tumors caused a radiotherapy attempt after CRS, but this was full of many side effects and without clinical benefit. It is important to highlight that the development of chemotherapeutic drugs was gaining impulse in the late 1970s, and rehearsals for many cancers with these medications that were administered intravenously (IV) were investigated.

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Harvey I. Pass, Nicholas Vogelzang, Michele Carbone - Malignant Mesothelioma_ Pathogenesis, Diagnosis, and Translational Therapies-Springer (2005)
Mary Hesdorffer, Gleneara E. Bates-Pappas - Caring for Patients with Mesothelioma_ Principles and Guidelines-Springer International Publishing (2019)

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