Peritoneal Surgery	Chemotherapy Treatments	Radiation
	Chemotherapy Actions
	Chemotherapy Side-Effects
	Why Chemotherapy Doesn't Cure Mesothelioma

Peritoneal Surgery

The abdomen is a complex space, filled with a variety of easily damaged and extremely important organs. A cancer affecting the abdominal lining, or peritoneum (paira-tin-e-um) is therefore a very serious and hard to treat matter.

The peritoneum is made of two parts, the visceral and parietal peritoneum. The visceral peritoneum covers the internal organs and makes up most of the outer layer of the intestinal tract while the parietal peritoneum covers the abdominal cavity.

While both the pleural (chest) and the peritoneal (abdominal) space contain the same lining and suffer from the same cancer, the nature of the two spaces dictates that different treatment strategies must be used. The peritoneum is located in an area of soft tissues, easily accessed and pliable, where the pleura is found inside a rigid space (the rib cage) and is difficult to reach without cutting through bone. Thoracic (chest) surgery to remove the pleura almost always involves the permanent removal of at least one rib.

The peritoneal and pleural mesothelial cells are designed to provide lubricating secretions which allow the organs in each respective space to move freely. When the cells of the mesothelium malfunction due to the cancer's progress, an overproduction of this fluid often results. This is called ascites and causes many of the symptoms discussed earlier in the diagnostic section.

Unique structures inside the abdomen make treating peritoneal mesothelioma both more difficult and, in some ways, easier than pleural mesothelioma. There are two folds of the peritoneum called the greater and the lesser omentum.  These structures serve to connect the viscera and provide support for blood vessels.

In most mammals, the great omentum forms a great sac, which is attached to the transverse colon and the stomach. It is loaded with fat, and covers nearly all of the intestines. The lesser omentum connects the stomach and liver and contains the hepatic vessels. the surgical procedures employed in peritoneal dictate the removal of the omentum changing the structure of the abdominal space quite dramatically.

Cytoreductive surgery coupled with Intraperitoneal chemotherapy is now considered to be the standard of care in peritoneal mesothelioma. Though not curative extended survivals have been reported by a select group of surgeons who specialize in the treatment of peritoneal mesothelioma. There have been no comparative trials of systemic vs operative procedures in peritoneal mesothelioma but the survival statistics reported in surgical series far exceed survival statistics in chemotherapy trials. With this in mind one should proced cautiously as the numbers in these trials are small, the patients are selected thus creating a bias in favor of surgery. Unfortunately because the number of cases is reported at 250 new cases per year a trial to provide this information would not be able to accrue the number of patient necessary to answer the question. The treatment varies with the surgeon and research is still underway to develop the optimal treatment plan.

The initial surgery will including an exploration of both the peritoneum and pelvic structures. The disease is often described as salt like sand like structures that can be found on all surfaces of the abdomen.  This includes the length of bowel which needs to be painstakenly explored, the omentum is removed as it is usually studed with disease, and the tumor deposits are scraped off of the lining of all the visceral organs where it appears. Microscopic cells as well as small deposits of tumors are left behind and it is the expectation that a heated perfusion of chemotherapy will irridicate residual disease.  Like pleural mesothelioma imaging is not optimal and in many patients more disease than anticpated is found at the time of surgery.  

Unlike pleural mesothelioma the typical staging system is not applicable nor helful in predicting survival in peritoneal mesothelioma. Dr Paul Sugarbaker is credited with the creation of the peritoneal cancer index score. This staging system  takes place at the time of surgery. The abdomen and pelvis are divided into 13 sections and scores are assisgned based on the largest tumor found within each of these designated areas. A score is sometimes assigned prior to and following the surgical procedure.

The surgical procedure itself is  refered to as a cytoreduction. Long term survival is associated with a score of CC 0 or CC1 these are considered complete resections.  Scores of CC2-CC3 predict relapse and shortened survival. Grade of tumors amount of residual tumors post surgery are factored together to assisgn a score.

The relative ease of access to the abdomen has numerous interesting benefits, however. The stomach wall can easily be entered to allow access to the abdominal space and this means that the area can support multiple debulking surgeries and inspections to keep the tumor in check. Repeated surgeries often result in the formation of scar tissue which can result in mechanical small bowel obstructions, painful strictures and digestive problems. Repeated surgery is not a standard of care but is assessed thoroughly by surgical specialists on an individual basis.  innovative techniques such as heated chemoperfusion, , immunotherapy and radiation therapy.are being explored. These therapies are not recommended outside of a clinical trial setting at specialized centers.

Consequently, a very successful strategy for treating peritoneal mesothelioma has emerged that combines aggressive debulking of the tumor with one or more of the other techniques as adjuvants. This is considered to be a local technique for irradiating disease so in patients who have distant metastatic disease surgical resection in most cases is not an option. In the rare case where control of disease can be demonstrated over time surgery can be reconsidered in patients who have presented with dual compartment disease (chest and abdomen). To date this treatment option has not proved successful in sarcomatoid disease so these patients are usually referred on to systemic treatment. Those demonstrating a good response will be reconsidered for surgery.

Consequently, a very successful strategy for treating peritoneal mesothelioma has emerged that combines aggressive debulking of the tumor with one or more of the other techniques as adjuvants.

Several treatment centers now offer peritoneal mesothelioma treatment that involves several courses of surgery over a specific interval, with chemotherapy, radiation or other treatments either during or after the surgeries. Success with this approach has been excellent and there are now a number of long term 7+ year survivors of peritoneal mesothelioma as proof of the value of this multimodality approach. This surgery though similar is quite different from the debulking surgery approved for use in ovarian cancer. The doses and types of chemotherapy agents differ as do the resulting morbidity and mortality from surgery. This surgery should only be considerd if a patient is under the care of an experienced mesothelioma surgeon

Relapse patterns have been studied and interesting data has been reported that genetic mutations can also play a role in predicting poor survival and relapse in patients undergoing surgery and intraperitoneal mesothelioma. In time this will assit in determing who should be referred to surgical treatment or perhaps therapies will be developed to target these mutations prior to undergoing surgery. This is a major breakthough in understanding the natural history of this disease. 

The technique of using heated chemoperfusion to attack the residual mesothelioma tumor in the abdominal space was pioneered by the peritoneal surgeons and then was applied to the pleural mesothelioma environment where the strategy is under investigation by several institutions.  

Chemotherapy Treatments

Most cancer chemotherapy is applied systemically, meaning it is applied to your whole body via the circulatory system. The easiest way to deliver systemic chemotherapy is to ingest it in pill or liquid form via the digestive system. This approach works only for those chemicals that can survive the rigors of being digested in the stomach, and then only if the molecules are small enough to be absorbed into the circulatory system by the intestines.

Chemotherapy in mesothelioma is not curative.  That is not to say that chemotherapy is not without benefit to the patient affected by mesothelioma. Studies have demonstrated that the most active regimen can reduce tumors in 40% of patients and extend life in those that respond to chemotherapy.  Chemothery has also been shown to palliate symptoms including reducing shortness of breath, reduction of ascites or effusions, reduction of pain and improvement has been noted in quality of life studies.  Chemotherapy is also given as a neo adjuvant treatment (prior to a planned surgical intervention) post surgery (adjuvant therapy) or as a single modality.  In some cases patient who have been considered inoperable can become surgical candidates following administration of chemotherapy.

Some chemotherapy is cytotoxic which means that it is capable of killing malignant cells, others are cytostatic which means that it can inhibit cellular activity or cellular multiplication.  We now use a new term “targeted” therapy or “smart” drugs which refers to drugs that are specifically designed to act on genes that promote or suppress canceous cells.  Immunotherapy is a method of harnessing the bodies own immune system to activate and kill malignant cells.   A thorough discussion will take place in a section titled ‘Standard and Investigational Therapies in Mesothelioma”

Chemotherapy is most often administered via a vein accessed by a small needle.  Some chemotherapy comes in pill form.  Which ever way it is administered it is systemic which means that it is meant to attack the cancer in his primary location as well as metastatic deposits.  Some patients mistakenly believe that because a drug is given in a pill form that it is not as potent as an iv formulation.  Side effects of chemotherapy are also not indicative of strength and patients reports of tolerance differ considerably.  It can be the way a patient metabolizes a drug, a genetic alteration or past medical condition that can dictate how tolerable a drug will be to the individual..  Different drugs have different effects on the body and some are more severe than others.  Response to chemotherapeutic drugs do not correlate with the severity of symptoms.

The molecular structures of many chemotherapy agents are too fragile to allow the drug to be taken this way, or they are too large to be absorbed into the blood stream through the intestines. Therefore, most chemotherapies are given by an injection or an intravenous drip along with saline solution on a specific timetable. Your entire body is therefore exposed to the effects of a systemic poison and not just the cancer in a specific location. This can be an important benefit of a systemic treatment if the cancer has already metastasized and begun to move to secondary areas or other organs. Once in the blood stream, the chemical agents can go wherever your circulatory system can reach.

Since organs like the brain, kidneys, lungs, and liver are also exposed to the toxic effects of these drugs, dosages need to be carefully controlled so as not to kill healthy cells along with the cancer cells. Antidotes can also be given in advance for some chemotherapy agents that are known to carry high risks of morbidity to organs like the kidneys or liver. Since excreting these systemic poisons as quickly as possible is important, having healthy kidneys may dictate whether chemotherapy is an option.

The most effective alternative to systemic application is a regional or localized application where higher doses of the drugs can be administered directly to the affected area or organ. There are two variations to this technique of controlling the application of chemotherapy to specific surfaces. The first method is direct application and the second is intra-cavitary application via a special shunt or tube that is used to feed the chemicals directly into the peritoneal space. Both of these techniques allow much higher doses of chemicals to be used since most of the drug remains outside of the bloodstream, coating only the exposed tissue surfaces.

Some absorption of the chemo into the affected surfaces is necessary for it to work. For chemotherapy given in this manner during surgery, the surgeon will sometimes take tissue samples to analyze how deeply the drug has penetrated the tissue wall. Since penetration of the cell wall implies some entry of chemo into the bloodstream, the use of an antidote is an important precaution.

Which approach is used depends upon the goals of the treatment and the need to control side effects. In any case, the application methods are carefully selected to ensure that more damage happens to the cancer cells than to the healthy cells. Chemotherapy works because the rapid growth of cancer cells makes them more vulnerable to chemicals that block, destroy or interfere with fast growing cells.

Chemotherapy Actions:

Chemotherapy agents can act in two principal ways: disrupting cell reproduction (cell division) or physically destroying cancer cells. The process of cell reproduction is complicated and has several different and distinct stages. The first treatment approach uses chemotherapies that act at several different times during cell replication process. Such drugs are called Alkylating agents.

No matter how its done, when a cancer cell is blocked from replicating itself, the tumor stops growing. Unfortunately, many of these agents will have that effect on ANY fast replicating cell. Since we cant protect our healthy fast replicating cells, sperm, white and red blood cells, we often get nasty side effects such as low blood counts that may interfere with treatment if unresolved.

Recently, research scientists have discovered ways to begin producing chemical agents that only target specific types of cells. In some cases it has been possible to target specific subgroups of cancer cells, known to replicate themselves by using a specific receptor. One day soon, we hope to have unique chemical poisons for each type of tumor. Then we can spare the regular cells from the side effects of the treatment. Such targeted chemotherapies are not yet in standard clinical use but are being investigated in clinical trials.

Chemotherapy Side-Effects:

Chemotherapy can be strong medicine and the strain it places on the body can demand that a patient have a strong stomach, heart, liver, and kidneys. All are essential to help the patient absorb, circulate and then eliminate these chemicals from the body and still recover from the damaging side effects of the treatment. For many patients, reduced white cell counts, red blood cell counts and reduced platelets can all be evidence of systemic damage caused by chemotherapy.

Most patients suffer some measure of immune suppression because chemotherapy affects the bone marrow, where white blood cells are produced. There are a number of drugs available which can help restore red blood cell production, boost the production of white blood cells or help platelet production.

Weak immune systems can be helped by taking flu shots, pneumonia vaccine and other such measures to boost the bodys ability to fight infection before the chemotherapy regimen begins. Even the secondary effects of chemotherapy, nausea, vomiting and loss of appetite, fatigue and changed taste and smell, can be aided with modern counter-medicines, which can ease these symptoms. Consult with your doctor about what options are available for you, should you be facing a series of chemotherapy treatments.

Why Don't Chemotherapies Cure Mesothelioma?

For reasons that aren't entirely understood yet, chemotherapy works differently for nearly every patient. In some cases the difference can be dramatic. Certain drugs can make a major impact on one persons tumor but have absolutely no effect on the next. To date, the biggest obstacle to treating peritoneal mesothelioma with chemotherapy alone is either that the amount of tumor present is too large for the chemo to destroy it or that the tumor develops resistance to the chemo. Surgery can assist with the first problem by reducing the tumor remaining to a manageable amount that chemo can handle.

It is the second problem that is so intriguing and holds so much promise. It appears that not every tumor cell uses the same pathways to grow and to spread. Attacking some but not all of the pathways used by the tumor to replicate will reduce only a portion of the tumor burden, allowing the tumor that is left to grow unimpeded. This is the primary reason single chemotherapy protocols don't cure the tumor and seem to stop working after a number of months. Using multimodality chemotherapy treatments seems to be much more effective since it attacks multiple pathways at once, allowing the tumor no room to evade treatment. Once all the pathways have been identified and drugs found that will interfere with them, it may be possible to use chemo alone as a curative treatment. 

Our current knowledge of the development of cancer has established that each tumor is a reflection of the different genetic makeup of the host individuals cells.  Recently, attempts have been made to grow test tube cultures of a persons tumor and then expose them to a variety of chemical solutions in vitro (in a test tube solution). The problem appears to be that success in the test tube doesnt always translate into an effective tumor fighting treatment when it is tried in vivo or in a live subject. A vigorous debate is underway as to whether this approach has merit or not.

Chemotherapy protocols have changed and continue to change quickly. Multimodality treatment employing surgery, with Gemcitabine (Gemzar) Cisplatinum, Carboplatinum and other chemotherapies are now being adapted to use monoclonal antibodies like Iressa and Tarceva as well as anti-angiogenesis drugs like bevacizumab and endostatin as well as new targeted drugs like deacetylase inhibitor SAHA, to attack the tumor from multiple directions at once. Drugs like Interferon, Thalidomide and Cox2 inhibitors like Celebrex are being tried in various combinations to boost the effectiveness of chemotherapies.

The arrival of Alimta, the first drug that showed a significant response in mesothelioma as a single agent is now being tested in clinical trials looking at combination therapies.

Radiation Treatments:

Radiation has proved to be of limited use in abdominal mesothelioma as a primary treatment but has proved useful in preventing malignant seeding of the incision sites. Its use is highly recommended in both pleural and peritoneal mesothelioma to prevent the appearance of mesothelioma in the area of surgical incisions.

Because of the easy access to the peritoneal cavity, some consideration has been given to using photodynamic therapy as an adjuvant treatment for peritoneal mesothelioma. The surface to be treated is bathed in a chemical that is absorbed by both healthy cells and tumor cells. Healthy cells tend to clear this chemical more quickly. The chemical sensitizes cellular tissues to exposure to light, causing apoptosis or cell death. If timed correctly, only the cancer cells self destruct because only they retain the sensitizing chemical. Clinical trials for this have been attempted but the results aren't convincing enough to make this a standard therapy.