Malignant Mesothelioma: New Biological and Clinical Advances

Michele Carbone, MD, PhD; Hedy Lee Kindler, MD; Valerie Rusch, MD. (Transcribed from MARF Executive Director Chris Hahn's notes of a presentation made at ASCO, May 19, 2002.)

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Pathology and Genetics of Mesothelioma. Michele Carbone, MD, PhD

Pathology

Dr. Carbone first described the diagnosis of mesothelioma:

Diagnosis of mesothelioma should normally be accomplished with a thoracoscopy. In reaching the diagnosis, it is essential to consider the whole patient, including all of the following factors: the pathology slides, immunostains, x-ray, patient history, and tumor appearance at surgery. For example, despite all of the other factors indicating mesothelioma, if the patient is 6 years old Dr. Carbone would probably not diagnose mesothelioma where he would if the patient were 60 years old.

Mesothelioma cell types are usually categorized as epithelial, fibrous or sarcomatoid, biphasic, or poorly differentiated. However, in virtually 100% of the cases if you cut enough from the tumor, you will see some of both epithelial and sarcomatoid. Thus, if the analysis is deep enough, the tumor usually proves to be biphasic.

In 2002, with advances in immunostaining and histology, mesothelioma can be clearly distinguished from adenocarcinoma. This is true even of epithelial mesothelioma, which appears more similar to adenocarcinoma than does sarcomatoid. The spindle-cell, sarcomatoid mesothelioma is more often diagnosed incorrectly.

In mesothelioma, keratin, calretinin and WT-1 are usually positive. CEA, BerEp4, and PASD are usually negative. Epithelial mesothelioma has long branching microvilli. Where all of these factors are present, diagnosis is easy. Problems arise when the results are more mixed. In these situations, molecular pathology using an electroscope, rather than histology alone, can be used to make a definitive diagnosis.

It is important to follow up carefully on the conclusions stated in the pathologist's report. For example, the report may state that the immunostain is calretinin positive. But many types of tumors are calretinin positive. Are only 2% of the cells calretinin positive? If so, it is not mesothelioma, whereas if 100% are then the mesothelioma diagnosis may be appropriate. This is especially important with sarcomatoid mesothelioma. By its appearance, sarcomatoid mesothelioma could be virtually anything. Therefore, careful histology is essential. Again, if just 2% of the cells are positive for keratin, it is not mesothelioma; whereas if 100% are positive it may be.

An example of why careful pathology is so important arises with synovial sarcoma. This is often confused with sarcomatoid mesothelioma, because the histology of both tumors is very similar. However, synovial sarcoma is much more responsive to chemotherapy than is sarcomatoid mesothelioma. If synovial sarcoma is inaccurately diagnosed as sarcomatoid mesothelioma, treatment which would in fact likely be beneficial may not be administered. Similarly, "fantastic cures" of mesothelioma often are more benign or treatable tumors misdiagnosed.

The poorly differentiated mesothelioma cell type is the most difficult to diagnosis and frequently causes problems. This is to be expected, given that "poorly differentiated" basically means that it does not look like a mesothelioma. Poorly differentiated mesothelioma is usually an exclusion diagnosis, i.e. all other possible diseases are ruled out until mesothelioma is the only possibility left. This is a very difficult diagnosis to make.

Genetics

Dr. Carbone also described his work in mesothelioma genetics:

In the Cappodecia region of Turkey, there are three villages known as the mesothelioma villages, where it is said that 50% of the residents die of mesothelioma. This is supposedly from exposure to the mineral, erionite, which is common in the area. Indeed, the villages' houses are made from erionite. Investigators went looking in these villages for asbestos, did not find any, but found erionite in the lungs of those who had died from mesothelioma. They put the erionite in hamsters and the hamsters developed mesothelioma, so it was concluded that erionite was causing the mesothelioma in Cappodecia.

However, in some houses, 100% of the occupants develop mesothelioma (these are known as the houses of death), whereas in other houses, none of the occupants develop mesothelioma. Moreover, in the next village over, where erionite is just as prevalent, nobody develops mesothelioma.

With mesothelioma developing in only 5% of crocidolite asbestos workers, how does one explain the incidence of up to 50% in some families in Cappodecia? Dr. Carbone and his colleagues concluded that the connection is in the families themselves, not in their houses. In Cappodecia, the predisposition to mesothelioma is genetic, as an autosomal dominant trait, and erionite exposure may be a co-factor.

Dr. Carbone and his colleagues are very interested in cases of multiple family members developing mesothelioma here in the U.S.

Chemotherapy for in Mesothelioma
Hedy Lee Kindler, MD

Dr. Kindler briefly ran through the general results of the various chemotherapies, showing the basis for a new, cautious optimism:

Most of the various chemotherapies have been evaluated in mesothelioma, but few have shown response rates better than 20%. This has led to therapeutic nihilism. However, recent results provide the basis for a new, cautious optimism.

Among the "cytotoxic" chemotherapies, doxorubicin showed response rates of 14% and was the gold standard. Its analog, epirubicin was similar. The platinums were also in the low teens.

The antifolates appear active in mesothelioma. Edatrexate showed a 25% response rate, but had high toxicity. The toxicity was treatable, but treating it also lowered the drug effectiveness. Methotrexate has shown a good response rates, but is difficult to give where there is a pleural effusion. Pemetrexed has been evaluated with cisplatin in a phase III clinical trial, the results of which were announced by Dr. Vogelzang at ASCO. In a phase II, the results of pemetrexed alone were squarely in the mid-range of chemotherapies generally, but did include some dramatic responses.

Most studies of gemcitabine alone show no activity in mesothelioma. However, gemcitabine in combination with cisplatin is the current gold standard. This is based primarily on one study which showed a 48% response rate. However, later studies showed response rates of 26%, 16% and 9% for this combination.

Vinorelbine showed a response rate of 24% in one study.) were observed and 16 (55%) had stable disease. The median survival from start of treatment was 10.6 months.

The taxanes, which are natural products, have shown only minimal activity in mesothelioma. Paclitaxel and docetaxel have been evaluated.

Similarly, the camptothecins (e.g. topotecan and irinotecan) have not shown significant responses as single agents. However, in combination with other drugs good results have been reported.

Onconase is a novel antineoplastic ribonuclease derived from leopard frog eggs. A previous phase III clinical trial of onconase versus doxorubicin was flawed in that there were more poor-prognosis patients in the onconase arm than in the doxorubicin arm. When only those most likely to benefit from chemotherapy were considered, the median survival was 11.6 months for onconase and 9.6 months for doxorubicin. A second phase III trial is now open comparing onconase to onconase plus doxorubicin to doxorubicin alone.

A problem in evaluating the results from all of these studies is that chemotherapy often improves symptoms even when there is no measurable tumor response. For this reason, the UK is conducting a huge mesothelioma clinical trial, involving 840 patients, using quality of life as the measure.

The "noncytotoxic" drug therapies are starting to receive increased attention. Vascular endothelial growth factor (VEGF) is an autocrine growth factor for mesothelioma. VEGF is present in higher levels in patients with mesothelioma than patients with any other solid tumor. In mesothelioma VEGF expression correlates with microvessel density, and high microvessel density is associated with poor survival. in mesothelioma patients. Drugs which inhibit VEGF, angiogenesis inhibitors, include SU5416, bevacizumab, thalidomide, and PTK 787.

A phase II study of SU5416 at the University of Chicago [partially funded through a grant from MARF] showed "pretty good" results, with partial responses in 11% of the patients and minor responses in another 11%. Additionally, animal models show a striking symbiotic effect when angiogenesis inhibitors are combined with cytoxic drugs. Therefore, the University of Chicago is continuing its study using a more advanced angiogenesis inhibitor, bevacizumab, plus gemcitabine and cisplatin, versus gemcitabine and cisplatin alone. Thalidomide also is in phase II trials.

Epidermal growth factor receptor (EGFR) is also overexpressed in mesothelioma. EGFR has been shown to be overexpressed in 11 of 13 epithelioid tumors, two of four biphasic tumors, and one of seven sarcomatoid tumors. The Cancer and Leukemia Group B (CALGB) is studying ZD1839, or Iressa, an inhibitor of EGFR.

Another growth factor, PDGF (Platelet-derived growth factor) is, like VEGF, also thought to be an autocrine growth factor for mesothelioma. CALGB is studying the drug PTK 787, which inhibits both VEGF and PDGF. The drug Gleevec, STI-571, has had suprisingly successful results in leukemia, where it inhibits c-kit. However, Gleevec also inhibits PDGF, and therefore the University of Chicago will be studying Gleevec in a phase II mesothelioma trial.

In summary, these newer drugs are offering modest, but real responses. We need to further understand the biology of the mesothelioma tumor, in order to continue to develop these targeted therapies.

Diagnosis, Staging And Locoregional Therapy Of Mesothelioma
Valerie W. Rusch, MD

Dr. Rusch provided a very current overview on the status of diagnosis, staging and locoregional therapy of malignant mesothelioma:

Diagnosis

The typical mm patient is male (from occupational exposure to asbestos) with a latency of a minimum of 20 years between exposure and development of disease. Most patients present with pleural effusion and accompanying dyspnea (shortness of breath), and/or with chest pain. This reflects the stage at diagnosis, as pleural effusion reflects very early stage disease. This is a common misconception among primary care and pulmonary physicians who believe pleural effusion is late stage. In fact, it is in early stage that a large effusion is able to form while there is still free pleural space and minimal pleural tumor.

As the tumor progresses, the pleural space fuses and the tumor invades or encases the chest wall, causing chest pain which becomes intractable.

At presentation, distant metastasis is rare. The usual natural history of the disease is local progression, then developing metastatic disease late. This late metastasis can be widely disseminated to virtually all organs, but metastases to the other lung or to the peritoneum are most common. At autopsy, half of all patients have obvious metastatic disease.

For pathological diagnosis, the interaction between the pulmonary medicine physician, the thoracic surgeon and the pathologist is extremely important. With an experienced pathologist and good immunostains, it is sometimes possible now to make a definitive diagnosis merely from pleural fluid cytology or the cell block from a thoracentesis. More frequently Video Assisted Thoracoscopy (VATS) is required, or where the pleural space has fused, an open pleural biopsy with a small incision.

A thoracotomy is never necessary, and thoracic surgeons should be discouraged from performing exploratory thoracotomy for diagnosis. The VATS pleurectomy, which is also currently popular, should also be discouraged. It deprives the patient the opportunity of any form of definitive surgical therapy.

Staging

One of the major advances in the last decade is that the staging system proposed by the International Mesothelioma Interest Group (IMIG) has now been formally adopted by both the International Union Against Cancer (UICC) and the American Joint Committee on Cancer (AJCC). The development and international acceptance of this staging system will greatly facilitate the design and performance of clinical trials in mm.

The staging system is based on TNM (Tumor, Nodes, Metastasis), and recent evidence establishes that staging status under this system correlates with survival. T, extent of tumor, has four stages:

• T1a = very early disease, involving the parietal pleura only
• T1b = involvement of the parietal pleura and the visceral pleura, with free pleural space and pleural studding
• T2 = confluent pleural disease with invasion of the diaphragm muscle or lung.
• T3 = locally advanced, resectable
• T4 = locally advanced, unresectable.

The N component is currently identical to the lung cancer staging system. M0 or M1 is used to indicate whether metastasis exists.

In terms of the methods used for staging, the CT scan is still the standard for imaging. However, it does not define well the presence or absence of chest wall or diaphragm invasion. MRI is occasionally better for this purpose, but not so as to justify the cost of uniform MRI pre-surgery. PET is not good for T or N status, but sometimes, i.e. in 5 to 10% of patients, is useful for unsuspected metastases. PET is also starting to be used to measure response to induction therapy. To diagnose trans-diaphragm or peritoneal involvement, the laparoscopy is the gold standard.

Therapy

Surgical procedures can be categorized as having either palliative intent or curative intent. For palliative intent, the talc pleuradesis through a chest tube or VATS is an excellent option for patients who are elderly, have co-morbidities (other health conditions) or are otherwise not candidates for curative surgery. Also, the parietal pleurectomy is reasonable for patients with a partially trapped lung, to extend the lung and control the effusion, for palliation only.

The curative intent surgical procedures are either the EPP, extrapleural pneumonectomy, or the P/D, pleurectomy decortication. EPP is removal of the pleura and lung en blanc, usually with resection of the diaphragm, and sometimes the pericardium. P/D is the same operation, except leaving the lung in place.

Dr. Rusch's input on the long-running debate between EPP and P/D was as follows: The drawback of EPP is its higher mortality rate, between 5 and 8 percent, compared to 2 to 3 percent for P/D. However, those who have developed expertise with EPP have now reduced the mortality rate down to an acceptable 5 percent. With EPP, the tumor is completely resectable more often with P/D. With P/D, the tumor is completely resectable only in highly selected cases. Finally, EPP facilitates post operative adjuvant radiation therapy, since in effect there is "an empty box." Following P/D, radiation therapy is hampered by concern for the lung.

Pre-operative evaluation at Memorial Sloan Kettering includes CT scan of the chest and upper abdomen, PET scan, detailed cardiopulmonary function, and histology. Histology is evaluated because sarcomatoid or mixed cell type has a much worse prognosis than epithelial. Typically, surgeons are not keen to operate where cell type is sarcomatoid.

Adjuvant therapies include photodynamic therapy (PDT), chemotherapy and radiation therapy. PDT is applied following surgery to eradicate minimal gross residual tumor. In phase I and II trials, PDT has been shown to be usually safe; however, occasionally there are significant complications, so it has not become widely accepted. Its ability to accomplish long-term local control is undefined.

Chemotherapy following either type of surgery can be intrapleural or systemic. Intrapleural chemo is usually cisplatin-based. It is feasible, but offers poor long term local control. The value of hyperthermic perfusion is being studied but is still undefined. Systemic chemotherapy is also usually cisplatin-based. Its impact on outcome is also undefined.

Prophylactic radiation to the chest wall after thoracoscopy prevents incisional implants. Thus, for palliation, VATS and pleuradesis can be performed, followed by three days of radiation to prevent incisional implants.

The value of hemithoracic radiation following P/D is questionable, because of the difficulty of protecting the lung. 70-80% of patients experience local recurrence. A clinical trial at MSK has shown hemithoracic high dose radiation to be effective after EPP. It was safe, had very low complications, and dramatically reduced local recurrence to only 10%. Median survival of Stage I or II patients in this clinical trial with surgery and radiation only was 33.8 months. For Stage III and IV patients with more locally advanced disease the median survival was 10 months. These patients tended to have relapses in distant sites. So MSK's protocol for locally advanced disease patients (i.e. T3 or N2) is induction therapy first, then EPP followed by hemithoracic radiation therapy.