INTERVIEW

"Dr. Smythe, M. D. Anderson is one of the premier facilities for the treatment of mesothelioma. How many patients do you treat on average?"

"We are currently seeing 2-4 new patients a week in thoracic surgery with this disease, and a few additional patients are seen each week primarily by my medical oncology colleagues."

"Is mesothelioma becoming more prevalent, or are there just better diagnostic procedures in place now than before? Do you think that because people are living longer, that the latency period is having more of an opportunity to play out? Do you see a decrease in the average age of mesothelioma patients?"

"Those are all excellent questions. I think that we are seeing more cases of this tumor secondary to the growing population in general, and our ability to make the diagnosis. My intuition is that a large number of patients with this disease are still never being diagnosed in this country, and the number of patients in developing countries that are undiagnosed is potentially very significant. It is also possible that the avoidance of death at earlier ages due to now treatable benign diseases is relevant, as you ask. In regard to the age issue, I have personally been seeing a larger number of younger patients, but am unsure as to whether or not this is a trend, or something idiosyncratic about referral patterns. Many of the younger patients have either no asbestos exposure, or the latency period seems very short. That raises the possibility that other environmental or unrecognized genetic causation is responsible."

"You have a new protocol in which patients undergo an extrapleural pneumonectomy followed by intensity modulated radiation therapy. Why do you feel a dual modality approach is warranted?"

"We feel that this is important for two reasons. It has been demonstrated that the local recurrence rate for this malignancy is quite high following aggressive resection - as high as 30-80%. A majority of patients treated in the past with surgery have eventually succumbed to the locally recurrent tumor. In addition, we know that it is technically impossible to be assured that every mesothelioma tumor cell is removed from the pleural space following extrapleural pneumonectomy, even when all gross tumor is removed. The area is just too extensive. Some additional therapy to control and prevent local recurrence following surgery will be an important part of future treatment, regardless of what other agents are utilized."

"Obviously, EPP (extrapleural pneumonectomy) is a very radical surgery. What criteria do you follow in evaluating a patient for such surgery? Are all patients who are eligible for EPP also eligible for IMRT (intensity modulated radiation therapy)?"

"We very carefully evaluate candidates for this aggressive treatment approach, and feel that both the patient's baseline physiologic fitness and the extent of the tumor must be ascertained. In other words, if the patient will not tolerate the treatment, or if the treatment is unlikely to help the patient from an oncologic standpoint, we would suggest medical, rather than surgical treatment. We extensively evaluate both cardiac and pulmonary function first by a series of tests and consultation with Pulmonary and Cardiology specialists. If it appears the patient would tolerate the resection, we then evaluate the extent of the tumor. Obviously, everyone has undergone radiologic evaluation of the tumor, including a chest Xray and CT scan, and in some cases PET scan. Unfortunately, no radiographic test, including MRI, can accurately assess the full extent of the disease, therefore, we perform a mediastinoscopy and a laparoscopy on all patients to determine whether or not the tumor has spread to the lymph nodes on the uninvolved side of the chest, or if the tumor has spread to the abdominal cavity. These two procedures are performed on a out-patient basis. If we find disease in either of these two areas, we opt again for medical therapy. Basically, everyone that is a candidate for the surgical procedure is a candidate for IMRT. The ability to undergo IMRT following surgery is contingent, however, on the patient's successful recovery from surgery, and most do well. We do not exclude patients from any treatment on the basis of age, but this has an impact on whether or not they are treated on or off protocol."

"What is the average recuperation period following EPP? What are the major risk factors? How long is necessary between surgery and the initiation of IMRT?"

"Recovery is individual, as you know, but most patients are in the hospital for between 10 and 14 days. Many are able to be discharged much sooner when things go very smoothly. It is our policy and convention to have patients up and walking if possible by the second postoperative day. We like to begin the IMRT between 6 and 12 weeks following discharge - the time period it takes most to get back to a relatively normal activity level. In regard to risk factors, we try to screen people up front for these, but the things that seem to be most troublesome are lung complications such as pneumonia and malnutrition. We are working with some success to decrease the rate of pneumonia following surgery, and are now placing feeding tubes in some patients identified early on as being at risk for nutritional compromise. Many patients are malnourished before treatment due to a decreased appetite related to the effects of the tumor, pain medications and inactivity."

"Mesothelioma is considered a chemotherapy-resistant disease. Is this why you feel EPP/IMRT is more suitable than EPP/heated Cisplatin wash?"

"Both treatments are attempted in an effort to control local recurrence. Our approach is just different from local chemotherapy. The known resistance to conventional chemotherapy agents was a factor in our decision to utilize IMRT."

"Even if all gross disease is removed at the time of surgery, there is always microscopic disease to contend with. When IMRT is administered, how do you determine which areas to irradiate, i.e., are there areas to which the disease is most likely to "seed"? Where is the greatest risk of recurrence?"

"Our surgeons work very closely with the radiation therapists, and this multidisciplinary relationship, which is the common culture of the M. D. Anderson Cancer Center, is extremely important. We have worked out together a method for carefully marking the extent of the "true" pleural space prior to reconstruction of the diaphragm and pericardium. It is our contention that a number of "upper abdominal" recurrences in the past have actually been lower pleural recurrences in an area that has been classically ignored by the radiation therapists as it is so much lower in most cases than the reconstructed diaphragm. We personally sit down with the radiation therapist and help tailor the IMRT fields on the basis of what we know about the intraoperative findings and the pathology report. Any areas of concern regarding microscopic residual disease receive higher doses of radiation."

"What type of response rate has been achieved for EPP/IMRT? How much time can feasibly be added to a patient's life expectancy? Mesothelioma is considered incurable. Is there any hope this protocol might affect a cure?"

"To date, we have had no patients recur within the radiation field, a truly novel and exciting finding. It is too early to know whether or not this will have an impact on life expectancy, but knowing what we do about local recurrence and its importance, we are optimistic. We do hope to cure some patients, and significantly increase the survival of others. Although local recurrence is the paramount concern, patients do still run the risk of extrathoracic disease. We hope to add an effective systemic agent to the next group of patients we treat, perhaps one of the biologics that are currently in development."

"Are sarcomatous and/or biphasic patients eligible for EPP/IMRT, or is it limited to epithelial patients? Does the difference in type mean a difference in the success rate of the procedure?"

"We are not excluding any histology at this time from our treatment protocol. There have been no differences thus far in outcome, but we are following this carefully."

"What other protocols do you offer for those who may not be eligible surgical candidates?"

"We have a number of other Phase I and II protocols available, and several are in the planning and approval stages. In addition to mesothelioma specific protocols, we have access via our relationship with our medical colleagues here at M. D. Anderson to a number of the Phase I "solid tumor" protocols that utilize a number of biologic approaches such as anti-angiogenesis and molecular targeting."

"What do you see on the horizon for mesothelioma research?"

"I am very optimistic about the treatment for future patients with this disease. On the clinical research front, we and other centers are embarking on the evaluation of some of the novel biologic agents such as Alimta in addition to aggressive surgery and other local control modalities. It is likely that with ongoing refinements in surgical resection and radiation therapy combined with newer, apparently active chemotherapy agents, we will have a real and major impact on the survival of selected patients with this disease in the next few years. In addition, there is a great deal of more basic research ongoing in many good translational laboratories around the world. We have been working in my laboratory on a number of gene therapy and molecular therapy approaches based on what we have learned about the expression of certain genes that control programmed cell death in tumor cells - a process termed apoptosis. We have taken promising results from cell culture experiments into our animal models of the human disease, and we are encouraged with what we have seen so far. Other investigators are making progress in identifying other gene and protein targets for treatment capitalizing on techniques derived from the human genome initiative, as well as immunotherapy. I tell my patients without reservation that if they develop a recurrence despite our best efforts, there is a high likelihood that we will have many additional options in the next few years to treat them with. There is always room for improvement, however, and biomedical research is expensive. I would urge interested and concerned individuals to support and encourage research in this area by all means possible. In short, I see very good things on the horizon."

"Dr. Smythe, thank you for your time. I think all of us who work with mesothelioma patients on a regular basis are encouraged by your optimism."

Click Here for the IMRT interview with Dr. Stevens