INTERVIEW

"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."