SLIDES & TRANSCRIPTS
Tuesday, June 19

RADIOTHERAPY SECTION - CALGB EXPERIENCE WITH EXTERNAL BEAM RADIOTHERAPY

Jeffrey Bogart, MD

The rationale for using adjuvant radiotherapy with limited resection has been discussed in both good lobectomy candidates such as in the lung cancer study group and high-risk patients. There is an increased risk for local tumor recurrence following limited resection, especially wedge resection. It is not clear that postoperative radiotherapy reduces this, but there are some retrospective data that suggest perhaps this is the case, especially lesions greater than 2 centimeters and when the lesion crosses the intersegmental plane. There is obviously much less data for lesions less than 1 centimeter.

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CALGB-9335, Hani Shennib was the study chair. I believe it is the first cooperative group trial to really address high-risk patients with early stage lung cancer, and it was a Phase II trial looking at the feasibility of the video-assisted thoracoscopic wedge resection and postoperative radiotherapy for these patients.

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Schema is shown here. Only patients that had pathologic T1, N0 disease were continued on trial and were eligible for postoperative radiotherapy.

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In order to initially go on trial you did not need a diagnosis of malignancy. You needed a peripheral lesion 3 centimeters or less. You needed pulmonary dysfunction defined by any one of those criteria, no lymphadenopathy and for radiotherapy again had to be pathologic T1, N0 and radiotherapy began 2 to 6 weeks after surgery.

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There was a total of 58 patients that were eligible, this trial completed accrual in September 1999. It did take 4 years to accrue. So, there are not lots of these patients being entered on trial right now. Median age was 69 and as far as pulmonary function the median FEV1 was 0.88 with FEV1 as low as 0.49. Ten percent of patients were oxygen dependent prior to surgery.

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As far as the outcome of thoracoscopic wedge resection, the feasibility end point of this trial was not met because there were 19 technical failures meaning conversion to thoracotomy, surgery was aborted, or perioperative death or incompletely resected lesions.
The criteria for success was to be less than 15% technical failure.

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Pathologic classification similar to what we have seen before, 10 out of 58 were benign lesions. As far as upstaging there was about a 30% upstaging mainly due to pleural involvement with T2 lesions.

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Adjuvant radiotherapy 56 Gy was given for the majority of lesions. There were two with positive margins that were included. The target volume was the staple line on plain x-ray, CT was not mandatory, with margins. The main thing we saw is that the median tumor size was relatively small at about 1.5 centimeters but the median staple line was 7.5 centimeters.

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So, it gives you a relatively large radiation field size. The main problem with delivering postoperative radiotherapy was a large staple line which was very difficult to visualize on plain chest x-ray. There was often retraction, so preoperative films were basically useless as far as targeting the radiotherapy field.

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Here are a few examples. This is a patient with a 1-centimeter maximum dimension non-small cell lung cancer and the staple line is here. It is difficult to visualize even on the film up close, but it measures about 9 centimeters altogether.

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Here is another case where a postoperative CT was obtained, but even in the CT you can follow the staple down, it is still very difficult to target and still ends up being about a 6 or 7 centimeter staple line. Adding margin you end up with a relatively large radiotherapy field.

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As far as pulmonary toxicity following surgery and radiotherapy, of the 32 patients eligible for radiotherapy there were three with grade-3 dyspnea. All these resolved within 3 months. It is difficult in these patients that have poor lung function sometimes to decide whether a toxicity is really attributable to the treatment or whether it is just a routine COPD exacerbation. As far as long-term pulmonary function there was no long-term detriment following radiotherapy and wedge resection. Most of the surgeons think that is because the benefit of doing lung reduction surgery outweighs the toxicity of radiotherapy.

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As far as survival and relapse, median survival 32 months. We do have some preliminary relapse data showing that there are at least five local recurrences. There is one recurrence at the port site, one patient with pleural recurrence and one patient with multiple ipsilateral lung nodules.

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This is one patient who actually did not receive postoperative radiotherapy, showing a staple line recurrence.

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As far as the conclusion regarding radiotherapy from this study, it certainly did not define the role of radiotherapy adjuvant to limited resection. We don't know really whether radiotherapy should be administered routinely with wedge resection. Perhaps there might be a better role for radiotherapy when the tumor is still intact preoperatively. It would be much easier to target with a much smaller radiotherapy field especially with conformal technique. We really don't know if this data applies to lesions less than 1 centimeter. If radiotherapy is to be given after wedge resection we do need better methods for targeting the tumor bed, but overall there was limited toxicity despite the large radiotherapy field.

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I am going to talk a little bit about using primary conformal radiotherapy with no surgery for a similar set of patients. There have not been any prospective trials reported in the literature that are limited to T1, N0 patients. There are lots of problems with retrospective studies, selection criteria, staging, evaluation, different treatment fields, etc.

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There was a review in 1998 by Greg Sibley from Duke who looked at 10 retrospective trials, all giving greater than 55 Gy. What was clear is that survival was better for patients with T1 lesions compared with T2 lesions. There seemed to be some radiation dose response. There didn't seem to be a benefit from irradiating the lymph nodes, there was a low risk of isolated nodal recurrence and toxicity was very low.

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Overall in these patients there was, and this includes clinically staged T2sso we really don't know lymph node status, 15% overall survival, 60% recurrence rate, half local, half distant and the other patients died from intercurrent disease. In terms of large retrospective studies of radiotherapy, the largest series is almost 350 patients from Australia which shows a 32% 5-year overall survival for clinical T1 tumors, and then there is another trial from Europe showing a 35% 3-year survival for lesions less than 4 centimeters.

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If we look again at all the radiotherapy trials the main thing to notice is that size does matter. There really is a difference for the T1 lesions. It seems to be about a 30% survival rate overall in that group. The highlighted yellow areas are series that use more than 2 Gy per fraction or more than conventional fractionation which is something we are looking at in the CALGB.

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If we are going to talk about subcentimeter lesions then we are looking where the star is shown here. The hope is that with the smaller lesion that the higher dose of radiotherapy will move up the curve and give a better overall control rate than we have seen with these retrospective trials.

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The 3-dimensional conformal radiotherapy really has come into practice in the last decade. With improvement in imaging and computer technology we get more precise targeting of the tumor and the surrounding normal structures, improved evaluation tools, and we are better able to both make sure that we conform the dose to where the tumor is and we don't miss the tumor and we avoid the critical structures.

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One of the first steps for radiation therapy in general is making sure that we are treating the same thing each day and the best way to start is with custom immobilization either a foam cast, a vacuum cast or there are also thermoplastic sheets.

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When the patient is in that cast we would go ahead with the simulation as well as the CT scan with the patient in that same position. This is a patient with a small peripheral non-small cell. She previously had radiotherapy and surgery for stage IIIA non-small cell about 5 years prior to this. Her lesion really is not visible on her plain film. This is her simulation film.

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We then go ahead with targeting of both the tumor and the surrounding structures and there are different volume definitions for radiotherapy and conformal radiotherapy. GTV is the gross tumor volume, what we actually see. CTV is the clinical tumor volume where we include potential sites of disease so disease extension or nodal disease if that is at high risk and PTV is our planning volume where have to account for treatment setup, patient motion, and respiratory motion.

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We then go ahead and evaluate the actual 3D plan and this plan here actually has five different radiotherapy fields and we can see the isodose lines.

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We can then do fairly cool looking reconstructions where we can see reconstruction of the tumor relative to lungs, relative to any structure we like to evaluate where the beam is going.

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Then we can also look in a more precise fashion at exactly how much - this is hard to see but exactly how much of each structure is getting what dose of radiation, first off to make sure that all the tumor is getting a high dose radiation and that we are protecting the lungs, the spinal cord or any other tissue we want to protect. This lets us quantitate exactly how much lung gets what dose of radiation as well as making sure the tumor gets radiation.

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These are digitally reconstructed radiographs especially if the lesion is not visible on plain x-ray. This is reconstructed again from each CT slice. So, it tells us what our portal films are supposed to look like,

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and this is 3D representation of the isodose lines from radiotherapy. There is your tumor. The red is the high dose and as we go out there is a very sharp fall off.

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These are a few cases that we have treated in Syracuse. Altogether we treated about 15 patients in Syracuse and about half of them were oxygen dependent prior to therapy. Both these patients had complete responses. The one on top had a prior pneumonectomy for lung cancer about 5 years prior. The question is going to be though for those that don't have complete responses how is the best way to follow them and as was brought up before can we use PET scan? Can we use the rate of shrinkage of tumor?

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As far as potential pitfalls from conformal radiotherapy one of the major ones is making sure that we are shooting where we think we are shooting so that that means immobilization that is reproducible. This is a recent patient under fluoroscopy where you can see with respiration there is about a 2-centimeter movement in the diaphragm and in the lung tumor. So, there are some methods to control that. One method is to use respiratory gating which can be done with spirometry. You can have an automatic off/on in your machine. Another method is to teach patients breath hold techniques or shallow breathing techniques but for these patients frequent verification really is necessary.

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To continue on with more potential pitfalls, as far as physics and dosimetry the very small lesions there is a question about how big your margin has to be. If you use small radiation field size especially with high-energy photons there is some concern about not getting an adequate dose at your margins. It may be better to use low-energy photons. There is some question regarding using tissue heterogeneity corrections. There are different algorithms which may produce different results and the same thing as far as your 3D calculation algorithm.

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As far as current 3D trials which are ongoing, the two major trials are really targeting lung cancer patients for all stages.

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Let me talk about toxicity first. One thing that the dose volume histogram and three-dimensional planning will do is tell us exactly how much lung is getting which dose of radiotherapy, and we know from experience that the more lung that you treat the higher risk of your pulmonary toxicity is going to be. Those data are from Armstrong at Memorial Sloan-Kettering looking at the total lung volume and correlating the dose that gets greater than 25 Gy. If less than 30% of the total lung gets less than 25 Gy the risk of pneumonitis is quite low. Similar data looking at the ipsilateral lung volume from Mary Graham when she was at Washington University and it appears that using the total lung volume is the best way to go. As far as patients' report of lung function the relationship is less clear.

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The current prospective trials of 3D which again include all stages of non-small lung cancer are the RTOG-93-11. In both these trials patients are separated into bins depending upon how much of the lung volume is treated. If there is smaller lung volume then they go to a higher dose. For small lung volumes treated the RTOG is now up to 90.3 Gy in 2.15 Gy fractions over about 9 to 10 weeks and at the University of Michigan which is Behamen et al they are up to 102.9 Gy, 2.1 Gy fractions with heterogeneity. In both these trials there has been limited toxicity although even with going above 84 Gy there have been reports of local recurrences in 3 of the first 10 patients.

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CALGB-39904 takes a somewhat different tack for similar patients. In using conformal therapy the hope is that you can wrap the dose around your target better and perhaps deliver the treatment in a shorter period of time, move toward the stereotactic approach and in this trial which was just opened keep a total dose of 7000 cGy but progressively reduce the number of fractions and increase the fraction size.

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As far as accelerated radiotherapy there is both a biologic and practical rationale. As far as biologic rationale, it is more radiation per unit time or increased dose intensity similar to chemotherapy dose intensity, less time for tumor repopulation, heading towards the stereotactic approach. Practically speaking, in regard to ease of attending treatment for high-risk patients we may complete treatment in less than 4 weeks compared with 8 to 10 weeks in the other 3D trials. This would reduce cost and while stereotactic is becoming more popular it is still limited as far as the number of centers that offer it.

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Other trials have been done with accelerated radiotherapy, hyperfractionated with the CHART regime. It is somewhat different but it still gives a high dose in a short period of time. There was a prior RTOG trial, RTOG-83-12 for locally advanced disease where they were able to give somewhat large fractions, 2.68 Gy with low incidence of severe toxicity, and the real question we are looking at is can we take advantage of small tumor volumes by using conformal therapy? This really wraps the dose around the target and this is conventional 2D. We can see much more lung getting the radiotherapy dose.

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So, in conclusion we don't have any really mature prospective 3D data. We don't know what the local nodal failure really is. Will dose intensity through 3D IMRT or stereotactic radiotherapy improve tumor control? We would expect that subcentimeter lesions will be more radiosensitive but we don't know that, and ideally we would like to compare a 3D conformal therapy to limited resection. What about high-risk patients? As far as the ELCAP study, it includes high-risk patients outside of the US but not in the US. Treatment for multiple lesions needs to be studied, and the question remains can we extrapolate this data to patients with adequate pulmonary function?

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