Until recently malignant mesothelioma was regarded as rarely treatable and always incurable. The diagnosis was uniformly predictive of a survival of about 12.5 months. Today there are a variety of treatment options that can be made available to patients with malignant mesothelioma Of the pleural cavity surrounding the lungs, comprising about 85% of patients, or the peritoneal cavity within the abdomen (15%). Some well-defined subsets of these patients may survive 5 years or much longer.
Mesothelioma of either the chest or the abdomen may begin with shortness of breath due to accumulation of fluid surrounding the lungs, referred to as a pleural effusion, or with swelling of the abdomen due to accumulation of fluid called ascites. A minority of patients will develop the disease in both the chest and the abdomen; sometimes established mesothelioma of one cavity can migrate to another. Removal of fluid brings temporary relief, and can provide samples for diagnostic evaluation. As a rule however, the diagnosis of mesothelioma should not be made from fluid samples alone, but can only be definitively arrived at by examination of the tumor tissue obtained by biopsy.
Mesothelioma very rarely can also arise in the pericardium and the testis; Patients in whom the diagnosis is suspected should undergo a complete x-ray evaluation by computed tomography (CT scan, chest abdomen and pelvis) to visualize abnormal fluid or tumor tissue accumulation, or more definitively by positron emission tomography (whole body PET scan), which can also evaluate the metabolic state and growth rate of tumors that are discovered.
Patients with pleural mesothelioma should be evaluated and biopsied by video asssisted thoracoscopy, in which the instrument, a telescopic tube along which a digital video camera lens and specially designed operating instruments can be passed, is inserted into the pleural cavity in the operating room through a small incision. Biopsies from abnormal appearing tissues are then obtained from the pleura lining the chest wall (parietal pleura) and from the pleural membrane encasing the lung (visceral pleura).
Once the diagnosis has been made, surgical treatment can be accomplished using the same instrument.The surgeon can drain fluid from the chest cavity, exercise large portions of the pleura (pleural stripping), or can perform resections of one or more portions of the lung (quadrantectomy, lobectomy, Wedge resection) or the lung in its entirety (pneumonectomy).
In some patients in whom pleural effusions accumulate and recur quickly, so us to interfere with breathing, the surgeon can inject a slurry of talc powder into the pleural cavity, which causes an inflammatory reaction which in turn, courses the parietal and visceral pleural surfaces to stick together, affectively eliminating the pleural space. This procedure, effective about 70% of the time significantly improves the patient's ability to breathe. On the negative side, even successful pleurodesis often leaves residual pockets of fluid, and the breathing improves only marginally. Equally important, tumor cells which remains in the pleural space continue to grow unless they are eradicated by systemic chemotherapy; however pleurodesis renders it difficult or impossible to directly place chemotherapy within the pleural cavity.
At Columbia University, we have endeavored to treat pleural mesothelioma with the additional modality of intrapleural chemotherapy. In selected patients, once the diagnosis is made, we used the thoracoscope to place 2 plastic catheter tubes into the pleural space, with their tips at the top (apex) and bottom (diaphragmatic sulcus) of the lung. These catheters are attached to Mediports which are placed under the skin and over ribs 9 and 10 laterally. Over the ensuing weeks, we can repeatedly remove fluid and inject chemotherapy through the mediport in the outpatient office setting, weekly for 9 to 12 weeks. This treatment is often combined with systemic chemotherapy. In patients with very small amounts of epithelioid disease, especially the elderly, this mode of treatment often suffices to prevent recurrence for several years. None of this treatment precludes the possibility of later, more extensive surgery (as described below) should it become necessary.
For younger patients able to tolerate more extensive surgery, the surgeon attempts to strip away the entire sheet of pleura enveloping the lungs from its attachments to the chest wall, the surfaces of the heart and lungs, and the upper surface of the diaphragm. This can be accomplished by a lengthy procedure carried out through three chest incisions. If successful, this procedure can greatly reduce or eliminate the mesothelioma, and yet largely spare the ipsilateral lung.
The procedure performed most often for mesothelioma until recently was extrapleural pneumonectomy, in which pleura attached to the chest wall heart and diaphragm is peeled away as a sac containing the ipsilateral lung which is then
removed. It has been usual in such cases to follow the operation with external beam radiotherapy to the entire ipsilateral chest. Overall, extrapeleural pneumonectomy is a simpler more direct operation, with the drawback however, of leaving the patient with the morbidity that accompanies the functional loss of a lung. Insufficient studies have been performed to assess which operation, or indeed if any major operation is of benefit to mesothelioma patients. In our institution, extrapleural penumonectomy may be indicated for mesothelioma patients in whom the affected lung has been already compromised and rendered non-functional; in most other cases we generally try to maintain as much lung function as possible.
Radiation Therapy
Currently, Radiation therapy is mainly used in conjunction with extrapleural pneumonectomy, to help eradicatge any small foci of disease that may have remained after surgery. There is no definite evidence that its use alters the outcome of treatment. Radiation has also been used in advanced, unresectable disease to treat painful disease sites, or sucutaneous nodules of grfowing tumor; it is generally regarded effective for those applications. At Columbia we have attempted experimentally to administer intrapleural solutions of radioactive phosphorus (p32), a beta emitter with an approximate effective range of 2-3 mm to target mesothelioma on the pleural surface. The procedure is well tolerated with no significant long-term effects, but its effectiveness at removing local disease has not yet been evaluated. This treatment remains in the experimental stage.
Chemotherapy
Chemotherapy given alone has not been shown to eradicate or cure mesothelioma. Its main use has been in advanced disease, to reduce the size of malignant effusions or unresectable tumors, thus relieving symptoms, possibly prolonging the time to progression of disease, or shrinking an otherwise unresectable tumor mass to a smaller size which can then be resected. The current most often used chemotherapy regimen for mesothelioma is pemetrexed given together with either cisplatin or carboplatin. An objective response (measurable shrinkage of the tumor on CT scan imaging by 25%) is seen in about 20% of cases. As reported in an international controlled clinical trial, The median overall survival of treated groups of patients is about 2.5 months longer than groups treated with cisplatin alone, thus confirming pemetrexed's effectiveness.
Although the combination of pemetrexed and cisplatin is the only FDA approved regimen for pleural mesothelioma, many other chemotherapy combinations have shown comparable activity in smaller non randomized clinical trials, or in anecdotal reports. Conventional combinations include gemcitabine plus cisplatin or carboplatin, doxorubicin plus cisplatin, and mitomycin plus cisplatin. Some patients may experience very substantial regression of disease with any of such regimens.
An important option for mesothelioma patients is enrollment in a clinical trial of a new agent, even before trying a conventional regimen. Delaying conventional chemotherapy in order to participate in a clinical trial can broaden the range of options to consider, especially for patients with a good performance status, or minimal symptoms not mandating immediate tumor shrinkage. Many trials of novel agents are limited to chemotherapy-naive subjects, so that this option is no longer available if the patient has already received a conventional regimen. Other trials may be opened only for a short time, enough to accrue an evaluable number of patients; thus the opportunity of receiving the drug can be lost by opting for conventional treatment first.
In general, a period of treatment lasting six to eight weeks should be sufficient to judge the effectiveness of a chemotherapy regimen, usually by repeat imaging. If during that time symptoms appear or there is clear evidence of progression, the treatment should be discontinued and the next regimen tried. At six weeks, if there is objective improvement, or improvement in symptoms with stable disease by imaging, the regimen is ordinarily continued and assessed at 6 week intervalas until a maximal response is achieved, after which the frequency of treatment may be cut back.
If there is Subjective or Objecive Progression of Symptomatic Disease while on treatment, palliative care services could effectively be introduced, while new treatments are sought or introduced.
Mesothelioma of either the chest or the abdomen may begin with shortness of breath due to accumulation of fluid surrounding the lungs, referred to as a pleural effusion, or with swelling of the abdomen due to accumulation of fluid called ascites. A minority of patients will develop the disease in both the chest and the abdomen; sometimes established mesothelioma of one cavity can migrate to another. Removal of fluid brings temporary relief, and can provide samples for diagnostic evaluation. As a rule however, the diagnosis of mesothelioma should not be made from fluid samples alone, but can only be definitively arrived at by examination of the tumor tissue obtained by biopsy.
Mesothelioma very rarely can also arise in the pericardium and the testis; Patients in whom the diagnosis is suspected should undergo a complete x-ray evaluation by computed tomography (CT scan, chest abdomen and pelvis) to visualize abnormal fluid or tumor tissue accumulation, or more definitively by positron emission tomography (whole body PET scan), which can also evaluate the metabolic state and growth rate of tumors that are discovered.
Patients with pleural mesothelioma should be evaluated and biopsied by video asssisted thoracoscopy, in which the instrument, a telescopic tube along which a digital video camera lens and specially designed operating instruments can be passed, is inserted into the pleural cavity in the operating room through a small incision. Biopsies from abnormal appearing tissues are then obtained from the pleura lining the chest wall (parietal pleura) and from the pleural membrane encasing the lung (visceral pleura).
Once the diagnosis has been made, surgical treatment can be accomplished using the same instrument.The surgeon can drain fluid from the chest cavity, exercise large portions of the pleura (pleural stripping), or can perform resections of one or more portions of the lung (quadrantectomy, lobectomy, Wedge resection) or the lung in its entirety (pneumonectomy).
In some patients in whom pleural effusions accumulate and recur quickly, so us to interfere with breathing, the surgeon can inject a slurry of talc powder into the pleural cavity, which causes an inflammatory reaction which in turn, courses the parietal and visceral pleural surfaces to stick together, affectively eliminating the pleural space. This procedure, effective about 70% of the time significantly improves the patient's ability to breathe. On the negative side, even successful pleurodesis often leaves residual pockets of fluid, and the breathing improves only marginally. Equally important, tumor cells which remains in the pleural space continue to grow unless they are eradicated by systemic chemotherapy; however pleurodesis renders it difficult or impossible to directly place chemotherapy within the pleural cavity.
At Columbia University, we have endeavored to treat pleural mesothelioma with the additional modality of intrapleural chemotherapy. In selected patients, once the diagnosis is made, we used the thoracoscope to place 2 plastic catheter tubes into the pleural space, with their tips at the top (apex) and bottom (diaphragmatic sulcus) of the lung. These catheters are attached to Mediports which are placed under the skin and over ribs 9 and 10 laterally. Over the ensuing weeks, we can repeatedly remove fluid and inject chemotherapy through the mediport in the outpatient office setting, weekly for 9 to 12 weeks. This treatment is often combined with systemic chemotherapy. In patients with very small amounts of epithelioid disease, especially the elderly, this mode of treatment often suffices to prevent recurrence for several years. None of this treatment precludes the possibility of later, more extensive surgery (as described below) should it become necessary.
For younger patients able to tolerate more extensive surgery, the surgeon attempts to strip away the entire sheet of pleura enveloping the lungs from its attachments to the chest wall, the surfaces of the heart and lungs, and the upper surface of the diaphragm. This can be accomplished by a lengthy procedure carried out through three chest incisions. If successful, this procedure can greatly reduce or eliminate the mesothelioma, and yet largely spare the ipsilateral lung.
The procedure performed most often for mesothelioma until recently was extrapleural pneumonectomy, in which pleura attached to the chest wall heart and diaphragm is peeled away as a sac containing the ipsilateral lung which is then
removed. It has been usual in such cases to follow the operation with external beam radiotherapy to the entire ipsilateral chest. Overall, extrapeleural pneumonectomy is a simpler more direct operation, with the drawback however, of leaving the patient with the morbidity that accompanies the functional loss of a lung. Insufficient studies have been performed to assess which operation, or indeed if any major operation is of benefit to mesothelioma patients. In our institution, extrapleural penumonectomy may be indicated for mesothelioma patients in whom the affected lung has been already compromised and rendered non-functional; in most other cases we generally try to maintain as much lung function as possible.
Radiation Therapy
Currently, Radiation therapy is mainly used in conjunction with extrapleural pneumonectomy, to help eradicatge any small foci of disease that may have remained after surgery. There is no definite evidence that its use alters the outcome of treatment. Radiation has also been used in advanced, unresectable disease to treat painful disease sites, or sucutaneous nodules of grfowing tumor; it is generally regarded effective for those applications. At Columbia we have attempted experimentally to administer intrapleural solutions of radioactive phosphorus (p32), a beta emitter with an approximate effective range of 2-3 mm to target mesothelioma on the pleural surface. The procedure is well tolerated with no significant long-term effects, but its effectiveness at removing local disease has not yet been evaluated. This treatment remains in the experimental stage.
Chemotherapy
Chemotherapy given alone has not been shown to eradicate or cure mesothelioma. Its main use has been in advanced disease, to reduce the size of malignant effusions or unresectable tumors, thus relieving symptoms, possibly prolonging the time to progression of disease, or shrinking an otherwise unresectable tumor mass to a smaller size which can then be resected. The current most often used chemotherapy regimen for mesothelioma is pemetrexed given together with either cisplatin or carboplatin. An objective response (measurable shrinkage of the tumor on CT scan imaging by 25%) is seen in about 20% of cases. As reported in an international controlled clinical trial, The median overall survival of treated groups of patients is about 2.5 months longer than groups treated with cisplatin alone, thus confirming pemetrexed's effectiveness.
Although the combination of pemetrexed and cisplatin is the only FDA approved regimen for pleural mesothelioma, many other chemotherapy combinations have shown comparable activity in smaller non randomized clinical trials, or in anecdotal reports. Conventional combinations include gemcitabine plus cisplatin or carboplatin, doxorubicin plus cisplatin, and mitomycin plus cisplatin. Some patients may experience very substantial regression of disease with any of such regimens.
An important option for mesothelioma patients is enrollment in a clinical trial of a new agent, even before trying a conventional regimen. Delaying conventional chemotherapy in order to participate in a clinical trial can broaden the range of options to consider, especially for patients with a good performance status, or minimal symptoms not mandating immediate tumor shrinkage. Many trials of novel agents are limited to chemotherapy-naive subjects, so that this option is no longer available if the patient has already received a conventional regimen. Other trials may be opened only for a short time, enough to accrue an evaluable number of patients; thus the opportunity of receiving the drug can be lost by opting for conventional treatment first.
In general, a period of treatment lasting six to eight weeks should be sufficient to judge the effectiveness of a chemotherapy regimen, usually by repeat imaging. If during that time symptoms appear or there is clear evidence of progression, the treatment should be discontinued and the next regimen tried. At six weeks, if there is objective improvement, or improvement in symptoms with stable disease by imaging, the regimen is ordinarily continued and assessed at 6 week intervalas until a maximal response is achieved, after which the frequency of treatment may be cut back.
If there is Subjective or Objecive Progression of Symptomatic Disease while on treatment, palliative care services could effectively be introduced, while new treatments are sought or introduced.