"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."

"What is Intensity Modulated Radiation Therapy (IMRT), and why was it chosen as an adjuvant therapy with surgery for the treatment of mesothelioma?"

"Mesothelioma is a disease with a very high likelihood of recurrence within the chest even after extensive surgery. Traditionally, when any type of tumor recurs locally, the first thought is to add post-operative radiation therapy to "clean up" any tumor cells that might be left after surgery. Applying this strategy to mesothelioma has been quite challenging because the regions at risk are large (the entire chest cavity and chest wall, and the lymph node regions between the lungs), and there are many radiosensitive normal structures nearby (the remaining lung, heart, esophagus, liver, kidneys, etc.). Several groups have tried to get around the normal structure problem with novel radiation delivery techniques. Unfortunately, the published descriptions of the techniques suggest that some volumes would be under-dosed while others would get very high radiation doses. This led us to try IMRT.

"IMRT is a technique that allows for radiation doses to be delivered to very complex shapes or to tumors with nearby normal structures. The best results with IMRT have been obtained in prostate cancer and head & neck cancers. IMRT to the prostate has allowed 10-15 percent higher radiation doses to be delivered while lowering side effects caused by radiation to the nearby rectum and bladder. Similarly, IMRT to the head & neck has allowed for excellent tumor control while sparing the glands that make saliva. Technically, IMRT treatment planning breaks the target volumes up into tiny cubes, and the dose to each cube is optimized by very fast computers. IMRT has, until recently, only been used to treat relatively small tumors. We thought that IMRT had many advantages in the treatment of mesothelioma as well. Our initial experience confirmed that IMRT could deliver the complex radiation distributions needed to treat mesothelioma, so we began this trial."

"How long has IMRT been used in the treatment of cancer? How does IMRT differ from traditional radiotherapy? To date, radiation has proven of little value in the treatment of mesothelioma except perhaps for palliation. Why is IMRT different?"

"IMRT has been used for almost a decade now, and has had the most success with treatment of the prostate and head & neck. We think that IMRT has great potential to improve local control in mesothelioma, especially since there is now data from Memorial Sloan-Kettering Cancer Center to suggest that "conventional" radiation techniques can reduce local recurrence by about 50%. Since the dose distributions with IMRT will in most cases be superior to "conventional" treatment, we hope to do better. Clearly, mesothelioma is responsive to radiation. The problem has been delivering the radiation to the tumor-containing regions while sparing the normal nearby structures."

"When IMRT is being used over a large area such as the chest cavity, how is it possible to deliver different doses of radiation to different areas? How are highly sensitive areas such as the heart and spinal cord as well as areas of normal tissue protected? What percentage more radiation can be delivered with IMRT than with conventional radiation?"

"IMRT can deliver the doses by dividing both the target volumes and each radiation beam into much smaller regions, and then optimizing the doses. The most sensitive regions are the remaining lung and the liver. The heart and spinal cord doses are relatively easy to keep within tolerance. The advantage to IMRT is that the target volumes can be completely irradiated so that there are no "cold" spots with regions at high risk for recurrence."

"According to your protocol, 60 Gy is administered for gross disease with the intent of permanent local control; 45-50 Gy is used for areas suspect for microscopic disease. Since microscopic seems to present the biggest problem in mesothelioma, why is the dosage less than for gross disease?"

"Radiation treatment results in side effects. Higher doses result in more intense symptoms like nausea/vomiting, skin irritation, sore throat, etc., so we chose to treat with lower doses for our initial group of patients. There is data to suggest that doses greater than 40 Gy are sufficient to improve pain in patients treated palliatively with gross disease. We thought that doses above 40 Gy would be a good starting point for microscopic disease. 45 Gy is also a dose that would be used post-operatively for lung cancer, so it should be in the right ballpark. In fact, we aren't sure of the correct dose, that is why we designed the study as we did. The study begins at 45 Gy. If that is tolerable, the dose will be increased to 50 Gy. Patients will then be followed for side effects and local control/survival. It is too soon to know how well our treatment will work, but we have thus far had no local failures. We are cautiously optimistic."

"If, upon follow-up, there is a recurrence of disease either within or outside of the irradiated field, can the area be irradiated again? If there is remaining gross disease, does it make sense to use chemotherapy to try to shrink the remaining tumor before IMRT?"

"Because we irradiate large volumes to moderate doses, there is little room to deliver more dose if the tumor recurs. We need to get it right the first time. Local tumor recurrence has been the most common reason for death of patients with mesothelioma. This is why we chose to improve local control (by combining two local therapies like surgery and radiation) as a first step. We hope that this will actually cure some patients. Additional systemic therapy will probably also be necessary, although this is not yet clear. Recent positive results with Alimta are the first suggestion that chemotherapy has ANY effect on mesothelioma. Our next trial will likely use chemo/biotherapy prior to surgery/IMRT.

"In planning for IMRT, what information do you receive from the thoracic surgeon that helps you to formulate a treatment plan? What are the responsibilities of the radiation oncologist, radiation physicist, dosimetrist, and radiation therapist?"

"Involvement of the surgeon at the radiation treatment planning workstation is really critical to our approach. There is no substitute for the surgeon's knowledge of EXACTLY where the tumor was. The target volumes are initially generated by the radiation oncologist based on surgical clips, operative note, and pathology report. Direct review by the operating surgeon has changed the target volume in EVERY case. This type of quality control sets our program apart. The radiation physicist also needs to be present when the volumes are reviewed. This is because we sometimes need to accept lower-than-ideal doses to small regions of the target volume. Having the physicist present ensures that there is no compromise on the most important regions, as defined by the surgeon and radiation oncologist. The radiation oncologist must decide which radiation dose distribution best treats the target volumes which minimizing the doses to adjacent normal structures. The radiation oncologist must also manage the treatment-related side effects during and after IMRT, and to verify that the patient is positioned properly for treatment. The radiation therapist actually delivers the daily radiation treatment, much as a radiology technologist takes CAT scans for the radiologist to read."

"How long does each individual treatment last, and how long is the full course of treatment? What side effects are usually associated with the procedure, and how can they be controlled?"

"Each treatment takes about 45 minutes. The patient is first positioned in a grid of laser lights with the arms above the head (so that they are out of the radiation beams). Then the treatment is begun. We use 7-8 gantry positions, with 2-3 table positions. This means that 14-24 fields are treated per day. These take some time to deliver. 25 daily treatments are delivered.

"The most common side effects are nausea/vomiting and tiredness. In the vast majority of cases, the nausea/vomiting is completely controlled, but in about 10% of cases patients require hospitalization by the 4th week or so because of dehydration. There is not much to be done about the tiredness, but we encourage our patients to walk (or if possible, exercise) as much as possible because exercise reduces radiation-induced fatigue. The side effects essentially resolve within a few weeks of the end of treatment."

"What success have you seen with the EPP/IMRT protocol? What do you see in the future for mesothelioma treatment?"

"Since we have seen some distant metastases, it is likely that future trials will include systemic treatment either with chemotherapy or biologic therapy. As I mentioned before, the Alimta data is very encouraging and hopefully will be the first of many drugs discovered with efficacy against mesothelioma. We don't yet know how to best to integrate these agents into our treatment approach. Our next trial is under development, and will likely include chemo/biologic therapy followed by surgery and then IMRT."

"Thank you for taking the time to explain this approach. We will look forward to receiving more data as it becomes available."